Editor’s Choice Articles

(1) Background: The association between polypharmacy and malnutrition has been investigated in several studies; however, few of these specifically deepened the relationship between potentially inappropriate medication and malnutrition. With a descriptive approach, the primary aim of our study was to evaluate the impact of the nutritional status, assessed with the Mini Nutritional Assessment (MNA), on potentially inappropriate medications (PIM), estimated 10-year survival, and the risk of adverse drug reactions in elderly patients; the secondary aim was to evaluate how the Screening Tool of Older People’s Prescriptions (STOPP), Screening Tool to Alert to Right Treatment (START), and BEERS 2019 criteria identify PIM compared to nutritional status. (2) Methods: In this study, 3091 subjects were enrolled, of whom 2748 (71.7%) were women; the median age was 80 years, with an interquartile range between 75 and 85 years of age. The subjects were assessed at the outpatient service for frail older people of the University Hospital of Cagliari. The study population was evaluated for their: MNA, Charlson Comorbidity Index, 10-year survival estimation, BEERS 2019, STOPP and START criteria, and ADR Risk scores. (3) Results: We divided the study population into three groups: MNA1 (MNA score ≥ 24), MNA2 (23.5–17), and MNA3 (<17): the severity of comorbidities, STOPP and START alerts, and BEERS 2019 criteria were significantly worse in both MNA2 and MNA3 compared to MNA1—with the exception of BEERS “non-anti-infective medications that should be avoided or have their dosage reduced with varying levels of kidney function in older adults”. Moreover, the estimated 10-year survival was significantly higher in MNA1 than in MNA2 and MNA3, and also in MNA2 compared to MNA3. Finally, the ADR risk scores were significantly lower in MNA1 than in MNA2 and MNA3. (4) Conclusions: Our study demonstrated the association between nutritional status and PIM checked with the BEERS 2019 criteria, and, for the first time, with the STOPP and START criteria. Full article

New, contextualized modern solutions must be found to solve the dilemma of catheter-associated urinary infection (CAUTI) in long-term care settings. In this paper, we describe the etiology, risk factors, and complications of CAUTI, explore different preventive strategies proposed in literature from the past to the present, and offer new insights on therapeutic opportunities. A care bundle to prevent CAUTI mainly consists of multiple interventions to improve clinical indications, identifying a timeline for catheter removal, or whether any alternatives may be offered in elderly and frail patients suffering from chronic urinary retention and/or untreatable urinary incontinence. Among the various approaches used to prevent CAUTI, specific urinary catheter coatings according to their antifouling and/or biocidal properties have been widely investigated. Nonetheless, an ideal catheter offering holistic antimicrobial effectiveness is still far from being available. After pioneering research in favor of bladder irrigations or endovesical instillations was initially published more than 50 years ago, only recently has it been made clear that evidence supporting their use to treat symptomatic CAUTI and prevent complications is needed. Full article

Background: Non-melanoma skin cancer (NMSC) stands as an umbrella term for common cutaneous malignancies, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), together with rarer cutaneous cancers, such as Merkel cell carcinoma (MCC) and other forms of adnexal cancers. The majority of NMSCs can be successfully treated with surgery or radiotherapy, but advanced and metastatic stages may require systemic approaches such as immunotherapy with immune checkpoint inhibitors (ICIs). Summary: Since immunotherapy is not effective in all patients and can potentially lead to severe adverse effects, an important clinical question is how to properly identify those who could be suitable candidates for this therapeutic choice. In this paper, we review the potential features and biomarkers used to predict the outcome of ICIs therapy for NMSCs. Moreover, we analyze the role of immunotherapy in special populations, such as the elderly, immunocompromised patients, organ transplant recipients, and subjects suffering from autoimmune conditions. Key messages: Many clinical, serum, histopathological, and genetic features have been investigated as potential predictors of response in NMSCs treated with ICIs. Although this field of research is very promising, definitive, cost-effective, and reproducible biomarkers are still lacking and further efforts are needed to validate the suggested predictors in larger cohorts. Full article

The neutrophil-to-lymphocyte ratio (NLR) predicts adverse outcomes in stable chronic obstructive pulmonary disease (COPD); however, its prognostic role in acute exacerbations (AECOPD) is less clear. We conducted a systematic review and meta-analysis of the association between the NLR on admission and adverse outcomes (mortality, need for mechanical ventilation, transfer to the intensive care unit, length of stay, pulmonary hypertension, or their combination) in AECOPD by searching PubMed, Web of Science, and Scopus from inception to April 2022. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development, and Evaluation, respectively. In 15 studies (n = 10,038 patients), the NLR was significantly associated with the risk of adverse outcomes (odds ratio = 1.054, 95% CI 1.016 to 1.093, p = 0.005; low certainty of evidence; standard mean difference = 0.82, 95% CI 0.57 to 1.06, p < 0.001; high certainty of evidence). Pooled sensitivity, specificity, and area under the curve were 0.71 (95% CI 0.64 to 0.77), 0.73 (95% CI 0.65 to 0.80), and 0.78 (95% CI 0.74 to 0.81), respectively. In our study, the NLR on admission was significantly associated with adverse outcomes in AECOPD patients, suggesting the potential utility of this biomarker for early risk stratification and management in this group. Full article

Epidemiological studies have shown that a substantial proportion of acute coronary events occur in individuals who lack the traditional high-risk cardiovascular (CV) profile. Mental stress is an emerging risk and prognostic factor for coronary artery disease and stroke, independently of conventional risk factors. It is associated with an increased rate of CV events. Acute mental stress may develop as a result of anger, fear, or job strain, as well as consequence of earthquakes or hurricanes. Chronic stress may develop as a result of long-term or repetitive stress exposure, such as job-related stress, low socioeconomic status, financial problems, depression, and type A and type D personality. While the response to acute mental stress may result in acute coronary events, the relationship of chronic stress with increased risk of coronary artery disease (CAD) is mainly due to acceleration of atherosclerosis. Emotionally stressful stimuli are processed by a network of cortical and subcortical brain regions, including the prefrontal cortex, insula, amygdala, hypothalamus, and hippocampus. This system is involved in the interpretation of relevance of environmental stimuli, according to individual’s memory, past experience, and current context. The brain transduces the cognitive process of emotional stimuli into hemodynamic, neuroendocrine, and immune changes, called fight or flight response, through the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. These changes may induce transient myocardial ischemia, defined as mental stress-induced myocardial ischemia (MSIMI) in patients with and without significant coronary obstruction. The clinical consequences may be angina, myocardial infarction, arrhythmias, and left ventricular dysfunction. Although MSIMI is associated with a substantial increase in CV mortality, it is usually underestimated because it arises without pain in most cases. MSIMI occurs at lower levels of cardiac work than exercise-induced ischemia, suggesting that the impairment of myocardial blood flow is mainly due to paradoxical coronary vasoconstriction and microvascular dysfunction. Full article

Objective: we performed a systematic review/meta-analysis to evaluate the impact of septate uterus and hysteroscopic metroplasty on pregnancy rate-(PR), live birth rate-(LBR), spontaneous abortion-(SA) and preterm labor (PL) in infertile/recurrent miscarriage-(RM) patients. Data sources: a literature search of relevant papers was conducted using electronic bibliographic databases (Medline, Scopus, Embase, Science direct). Study eligibility criteria: we included in this meta-analysis all types of observational studies that evaluated the clinical impact of the uterine septum and its resection (hysteroscopic metroplasty) on reproductive and obstetrics outcomes. The population included were patients with a diagnosis of infertility or recurrent pregnancy loss. Study appraisal and synthesis methods: outcomes were evaluated according to three subgroups: (i) Women with untreated uterine septum versus women without septum (controls); (ii) Women with treated uterine septum versus women with untreated septum (controls); (iii) Women before and after septum removal. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for the outcome measures. A p-value < 0.05 was considered statistically significant. Subgroup analysis was performed according to the depth of the septum. Sources of heterogeneity were explored by meta-regression analysis according to specific features: assisted reproductive technology/spontaneous conception, study design and quality of papers included Results: data from 38 studies were extracted. (i) septum versus no septum: a lower PR and LBR were associated with septate uterus vs. controls (OR 0.45, 95% CI 0.27–0.76; p < 0.0001; and OR 0.21, 95% CI 0.12–0.39; p < 0.0001); a higher proportion of SA and PL was associated with septate uterus vs. controls (OR 4.29, 95% CI 2.90–6.36; p < 0.0001; OR 2.56, 95% CI 1.52–4.31; p = 0.0004). (ii) treated versus untreated septum: PR and PL were not different in removed vs. unremoved septum(OR 1.10, 95% CI 0.49–2.49; p = 0.82 and OR 0.81, 95% CI 0.35–1.86; p = 0.62); a lower proportion of SA was associated with removed vs. unremoved septum (OR 0.47, 95% CI 0.21–1.04; p = 0.001); (iii) before-after septum removal: the proportion of LBR was higher after the removal of septum (OR 49.58, 95% CI 29.93–82.13; p < 0.0001) and the proportion of SA and PL was lower after the removal of the septum (OR 0.02, 95% CI 0.02–0.04; p < 0.000 and OR 0.05, 95% CI 0.03–0.08; p < 0.0001) Conclusions: the results show the detrimental effect of the uterine septum on PR, LBR, SA and PL. Its treatment reduces the rate of SA. Full article

(1) Introduction: Colistin combination therapy with other antibiotics is a way to enhance colistin activity. The purpose of this meta-analysis was to compare the efficacy and safety of treatment with colistin monotherapy versus colistin plus meropenem combination therapy in patients with drug-resistant Acinetobacter baumannii infection. (2) Methods: All studies were included if they reported one or more of the following outcomes: clinical improvement, complete microbiological response, 14-day mortality, hospital mortality, or nephrotoxicity. (3) Results: Three randomized controlled trials and seven retrospective studies were included in the meta-analysis. Colistin monotherapy has similar rates of clinical improvement, 14-day mortality, hospital mortality, and nephrotoxicity as colistin plus meropenem combination therapy. Regarding complete microbiological response, the colistin plus meropenem combination was better than colistin monotherapy. (4) Discussion: Previous meta-analyses demonstrated heterogeneity in study quality and a lack of evidence supporting the use of colistin-based combination therapy. Our meta-analysis clearly showed that colistin combined with meropenem was not superior to colistin monotherapy for the treatment of Acinetobacter baumannii infection. (5) Conclusions: The efficacy and safety of treatment with colistin monotherapy and that of colistin plus meropenem combination therapy in patients with drug-resistant Acinetobacter baumannii infection were comparable. The majority of the evidence was obtained from nonrandomized studies, and high-quality randomized controlled trials are needed to confirm the role of colistin plus meropenem combination therapy in the treatment of multidrug-resistant Acinetobacter baumannii infection. Full article

Infective endocarditis in children is a rare entity that poses multiple challenges. A history of congenital heart disease is the most common risk factor, although in recent years, other emerging predisposing conditions have gained relevance, such as central venous catheters carriers or children with chronic debilitating conditions; cases in previously healthy children with no medical history are also seen. Diagnosis is complex, although it has improved with the use of multimodal imaging techniques. Antibiotic treatment should be started early, according to causative microorganism and risk factors. Complications are frequent and continue to cause significant morbidity. Most studies have been conducted in adults and have been generalized to the pediatric population, with subsequent limitations. Our manuscript presents a comprehensive review of pediatric infective endocarditis, including recent advances in diagnosis and management. Full article

Healthcare-associated infections can occur in different care units and can affect both patients and healthcare professionals. Bacteria represent the most common cause of nosocomial infections and, due to the excessive and irrational use of antibiotics, resistant organisms have appeared. The most important healthcare-associated infections are central line-associated bloodstream infections, catheter-associated urinary tract infections, surgical site, soft tissue infections, ventilator-associated pneumonia, hospital acquired pneumonia, and Clostridioides difficile colitis. In Europe, some hospitalized patients develop nosocomial infections that lead to increased costs and prolonged hospitalizations. Healthcare-associated infection prevalence in developed countries is lower than in low-income and middle-income countries such as Romania, an Eastern European country, where several factors contribute to the occurrence of many nosocomial infections, but official data show a low reporting rate. For the rapid identification of bacteria that can cause these infections, fast, sensitive, and specific methods are needed, and they should be cost-effective. Therefore, this review focuses on the current situation regarding healthcare-associated infections in Europe and Romania, with discussions regarding the causes and possible solutions. As a possible weapon in the fight against the healthcare-associated infections, the diagnosis methods and tests used to determine the bacteria involved in healthcare-associated infections are evaluated. Full article

Purpose: The diagnosis of laryngopharyngeal reflux (LPR) is commonly based on non-specific symptoms and findings and a positive response to an empirical therapeutic trial. The therapeutic response is, however, unpredictable, and many patients need pH-impedance monitoring to confirm the diagnosis. Methods: A review of the recent literature was conducted in PubMED, Scopus, and Embase about the pH-study features of LPR patients. A summary of last evidence was proposed. Results: The awareness of otolaryngologists about indications and interpretation of pH-impedance monitoring is low. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring (HEMII-pH) is the most reliable examination determining the type and composition of hypopharyngeal reflux events (HRE) and the LPR features. The use of HEMII-pH is important to confirm the diagnosis in selected patients because non-specificity of symptoms and findings. There are no international consensus guidelines for the LPR diagnosis at the HEMII-pH. However, most studies supported the occurrence of >1 acid/weakly acid/nonacid HRE as diagnostic threshold. HREs are more frequently gaseous, weakly/nonacid compared with reflux events of gastroesophageal reflux. HREs occurred as daytime and upright, which does not support the value of double proton pump inhibitors or bedtime alginate. Oropharyngeal pH-monitoring is another approach reporting different sensitivity and specificity outcomes from HEMII-pH. The use of Ryan score for the LPR diagnosis at the oropharyngeal pH monitoring may be controversial regarding the low consideration of alkaline HREs. Conclusions: The awareness of otolaryngologists about HEMII-pH indication, features, and interpretation is an important issue regarding the high prevalence of LPR in outpatients consulting in otolaryngology. The HEMII-pH findings may indicate a more personalized treatment considering type and occurrence time of HREs. Full article

Background: Assessment of pulmonary hypertension (PH) is essential in neonates with congenital diaphragmatic hernia (CDH). Echocardiography is widely established to quantify PH severity, but currently used parameters have inherent limitations. The aim of our study was to investigate the prognostic utility of the index of the pulmonary artery acceleration time to the right ventricular ejection time (PAAT:ET) in CDH neonates assessed using echocardiography. Methods: PAAT:ET values were prospectively measured in CDH neonates on admission, on day of life (DOL) 2 and DOL 5–7. Optimal cut-off values to predict mortality and need for ECMO were calculated and PAAT:ET values were compared between non-ECMO survivors, ECMO-survivors, and ECMO-non-survivors. Results: 87 CDH neonates were enrolled and 39 patients required ECMO therapy. At baseline, PAAT:ET values were significantly lower in ECMO patients compared to non-ECMO patients (p < 0.001). ECMO survivors and ECMO non-survivors had similar values at baseline (p = 0.967) and DOL 2 (p = 0.124) but significantly higher values at DOL 5–7 (p = 0.003). Optimal PAAT:ET cut-off for predicting ECMO was 0.290 at baseline and 0.310 for predicting non-survival in patients on ECMO at DOL 5–7. Conclusion: PAAT:ET is a feasible parameter for early risk assessment in CDH neonates. Full article

Neuropathic pain affects more than one million people across the globe. The quality of life of people suffering from neuropathic pain has been considerably declining due to the unavailability of appropriate therapeutics. Currently, available treatment options can only treat patients symptomatically, but they are associated with severe adverse side effects and the development of tolerance over prolonged use. In the past decade, researchers were able to gain a better understanding of the mechanisms involved in neuropathic pain; thus, continuous efforts are evident, aiming to develop novel interventions with better efficacy instead of symptomatic treatment. The current review discusses the latest interventional strategies used in the treatment and management of neuropathic pain. This review also provides insights into the present scenario of pain research, particularly various interventional techniques such as spinal cord stimulation, steroid injection, neural blockade, transcranial/epidural stimulation, deep brain stimulation, percutaneous electrical nerve stimulation, neuroablative procedures, opto/chemogenetics, gene therapy, etc. In a nutshell, most of the above techniques are at preclinical stage and facing difficulty in translation to clinical studies due to the non-availability of appropriate methodologies. Therefore, continuing research on these interventional strategies may help in the development of promising novel therapies that can improve the quality of life of patients suffering from neuropathic pain. Full article

Objective: We systematically assessed the efficacy of liraglutide in non-diabetic obese adults. Methods: Six databases were searched up to July 2021 for randomized controlled trials (RCTs) assessing liraglutide versus placebo in obese adults. Primary outcomes were body weight and body mass index (BMI). Secondary outcomes were treatment-emergent adverse events (TEAEs), hypoglycemic episodes, HbA1c, and blood pressure. Effect measures were risk ratio (RR) or mean difference (MD) with their confidence interval (95%CI). Random-effects models and inverse variance meta-analyses were used. Quality of evidence was assessed using GRADE. Results: Twelve RCTs (n = 8249) were included. In comparison to placebo, liraglutide reduced body weight (MD −3.35 kg; 95%CI −4.65 to −2.05; p < 0.0001), and BMI (MD −1.45 kg/m²; 95%CI −1.98 to −0.91; p < 0.0001). Liraglutide did not reduce TEAEs (RR 1.08; 95%CI 0.92 to 1.27; p = 0.25), and Hb1Ac (MD −0.76%; 95%CI −2.24 to 0.72; p = 0.31). Furthermore, it did not increase hypoglycemic episodes (RR 2.01; 95%CI 0.37 to 11.02; p = 0.28). Finally, liraglutide reduced systolic blood pressure (MD −3.07 mmHg; 95%CI −3.66 to −2.48; p < 0.0001) and diastolic blood pressure (MD −1.01 mmHg; 95%CI −1.55 to −0.47; p = 0.0003). Seven RCTs had a high risk of bias. Subgroup analyses by length of treatment and doses had effects similar to the overall analyses. Quality of evidence was low or very low for most outcomes. Conclusions: In non-diabetic obese adults, liraglutide reduced body weight, BMI and blood pressure in comparison to placebo. Adverse events, Hb1Ac levels and hypoglycemic episodes were not different than placebo. Full article

The early endoscopic identification, resection, and treatment of precancerous adenoma and early-stage cancer has been shown to reduce not only the prevalence of colorectal cancer but also its mortality rate. Recent advances in endoscopic devices and imaging technology have dramatically improved our ability to detect colorectal lesions and predict their pathological diagnosis. In addition to this, rapid advances in artificial intelligence (AI) technology mean that AI-related research and development is now progressing in the diagnostic imaging field, particularly colonoscopy, and AIs (i.e., devices that mimic cognitive abilities, such as learning and problem-solving) already approved as medical devices are now being introduced into everyday clinical practice. Today, there is an increasing expectation that sophisticated AIs will be able to provide high-level diagnostic performance irrespective of the level of skill of the endoscopist. In this paper, we review colonoscopy-related AI research and the AIs that have already been approved and discuss the future prospects of this technology. Full article

Blood transfusions have been the cornerstone of life support since the introduction of the ABO classification in the 20th century. The physiologic goal is to restore adequate tissue oxygenation when the demand exceeds the offer. Although it can be a life-saving therapy, blood transfusions can lead to serious adverse effects, and it is essential that physicians remain up to date with the current literature and are aware of the pathophysiology, initial management and risks of each type of transfusion reaction. We aim to provide a structured overview of the pathophysiology, clinical presentation, diagnostic approach and management of acute transfusion reactions based on the literature available in 2022. The numbers of blood transfusions, transfusion reactions and the reporting rate of transfusion reactions differ between countries in Europe. The most frequent transfusion reactions in 2020 were alloimmunizations, febrile non-hemolytic transfusion reactions and allergic transfusion reactions. Transfusion-related acute lung injury, transfusion-associated circulatory overload and septic transfusion reactions were less frequent. Furthermore, the COVID-19 pandemic has challenged the healthcare system with decreasing blood donations and blood supplies, as well as rising concerns within the medical community but also in patients about blood safety and transfusion reactions in COVID-19 patients. The best way to prevent transfusion reactions is to avoid unnecessary blood transfusions and maintain a transfusion-restrictive strategy. Any symptom occurring within 24 h of a blood transfusion should be considered a transfusion reaction and referred to the hemovigilance reporting system. The initial management of blood transfusion reactions requires early identification, immediate interruption of the transfusion, early consultation of the hematologic and ICU departments and fluid resuscitation. Full article

Transcranial direct current stimulation (tDCS) has been proposed as a promising therapy for rehabilitation of neurodevelopmental disorders. In this review, we discuss studies on the impact of tDCS as a therapy for autism, schizophrenia, and attention deficit/hyperactivity disorder, as well as the tDCS’ mechanism of action, and propose future paths of research to optimize tDCS treatment protocols. The mechanism underlying tDCS effects is the modulation of excitatory and/or inhibitory activity, making it a valuable tool for restoring the excitation/inhibition (E/I) balance which is disrupted in many neurodevelopmental disorders. Clinical studies have shown that tDCS therapy is well-tolerated by patients and seems to ameliorate behavior and cognitive functions. Alterations in early development of neuronal circuits lead to disruptions in brain activity in neurodevelopmental disorders. An increasing amount of research into the effects of tDCS on neuronal activity has provided a foundation for its use as a therapy for behavior and cognitive characteristics of neurodevelopmental disorders. Clinical studies show that tDCS appears to ameliorate behavioral and cognitive outcomes of patients with autism, schizophrenia, and attention deficit/hyperactivity disorder. More research is needed to understand the mechanisms of action of tDCS and to optimize treatment protocols. Full article

Objectives: Ischemic stroke is a leading cause of mortality and acquired disability worldwide and thus plays an enormous health-economic role. Imaging of choice is computed-tomographic (CT) or magnetic resonance imaging (MRI), especially diffusion-weighted (DW) sequences. However, MR imaging is associated with high costs and therefore has a limited availability leading to low-field-MRI techniques increasingly coming into focus. Thus, the aim of our study was to assess the potential of stroke imaging with low-field MRI. Material and Methods: A scanner comparison was performed including 27 patients (17 stroke cohort, 10 control group). For each patient, a brain scan was performed first with a 1.5T scanner and afterwards with a 0.55T scanner. Scan protocols were as identical as possible and optimized. Data analysis was performed in three steps: All DWI/ADC (apparent diffusion coefficient) and FLAIR (fluid attenuated inversion recovery) sequences underwent Likert rating with respect to image impression, resolution, noise, contrast, and diagnostic quality and were evaluated by two radiologists regarding number and localization of DWI and FLAIR lesions in a blinded fashion. Then segmentation of lesion volumes was performed by two other radiologists on DWI/ADC and FLAIR. Results: DWI/ADC lesions could be diagnosed with the same reliability by the most experienced reader in the 0.55T and 1.5T sequences (specificity 100% and sensitivity 92.9%, respectively). False positive findings did not occur. Detection of number/location of FLAIR lesions was mostly equivalent between 0.55T and 1.5T sequences. No significant difference (p = 0.789–0.104) for FLAIR resolution and contrast was observed regarding Likert scaling. For DWI/ADC noise, the 0.55T sequences were significantly superior (p < 0.026). Otherwise, the 1.5T sequences were significantly superior (p < 0.029). There was no significant difference in infarct volume and volume of infarct demarcation between the 0.55T and 1.5T sequences, when detectable. Conclusions: Low-field MRI stroke imaging at 0.55T may not be inferior to scanners with higher field strengths and thus has great potential as a low-cost alternative in future stroke diagnostics. However, there are limitations in the detection of very small infarcts. Further technical developments with follow-up studies must show whether this problem can be solved. Full article

BACKGROUND: Corneal transplantation in keratoconus (KC) patients is generally considered to be successful with a high grade of patient satisfaction. Long-term studies suggest a 6% to 11% probability of KC recurrence manifested by keratometric instability and progressive corneal ectasia. METHODS: We propose to review the frequency, risk factors for the development, and the surgical options for the correction of high irregular astigmatism due to late graft ectasia following penetrating keratoplasty (PK). RESULTS: Post-keratoplasty ectasia is characterized by increasing corneal steepening with myopic shift and high irregular astigmatism, developing years or decades after PK, mostly occurring in KC patients. Contact lenses may adequately improve the visual acuity; however, because these patients are often elderly and intolerant to hard contact lenses, ultimately a surgical correction is proposed to the patient. Compressive suture and corneal wedge resection may improve corneal astigmatism, but the outcomes are unpredictable and often temporary. For this reason, a larger PK graft is often proposed for surgical rehabilitation with the consequence of removing more of the recipient’s healthy endothelium and exposing the patient to a renewed immunogenic stimulus and short-term graft failure for endothelial decompensation. More recently, lamellar keratoplasty using various techniques has been proposed as an alternative to PK in order to maximize the visual outcomes and minimize the complications. CONCLUSIONS: Management of advanced corneal ectasia is a significant challenge for corneal surgeons. Many surgical approaches have been developed, so there is a large arsenal of surgical operations to correct post-PK ectasia. Among them, large-diameter anterior lamellar keratoplasty may be a viable, safer, and effective alternative to PK for the correction of post-keratoplasty ectasia. Full article

The aim of this study was to evaluate the efficacy of dupilumab in the treatment of severe uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), with or without asthma as add-on therapy with intra-nasal corticosteroids in a real-life setting over the first year of treatment. Our data demonstrated that subcutaneous 300 mg dupilumab administered at home via a pre-filled auto-injector every two weeks, based on indications set by the Italian Medicines Agency, was rapidly effective in reducing the size of polyps, decreasing symptoms of disease, improving quality of life, and recovering olfaction. Significant improvement was observed after only 15 days of treatment, and it progressively increased at 6 and 12 months. Dupilumab was also effective in reducing the local nasal eosinophilic infiltrate, in decreasing the need for surgery and/or oral corticosteroids, and in improving control of associated comorbidities such as chronic eosinophilic otitis media and bronchial asthma. After 12 months of treatment, 96.5% of patients had a moderate/excellent response. From our data, it was evident that there was a group of patients that showed a very early response within one month of therapy, another group with early response within six months from baseline, and a last group that improved later within 12 months. The results of this study support the use of dupilumab as an effective option in the current standard of care for patients affected by severe uncontrolled CRSwNP. Full article

Background: In this study, we assessed the mid-term outcomes of patients who received a heart donation from a marginal donor (MD), and compared them with those who received an organ from a standard donor (SD). Methods: All patients who underwent HTx between January 2012 and December 2020 were enrolled at a single institution. The primary endpoints were early and long-term survival of MD recipients. Risk factors for primary graft failure (PGF) and mortality in MD recipients were also analyzed. The secondary endpoint was the comparison of survival of MD versus SD recipients. Results: In total, 238 patients underwent HTx, 64 (26.9%) of whom received an organ from an MD. Hospital mortality in the MD recipient cohort was 23%, with an estimated 1 and 5-year survival of 70% (59.2–82.7) and 68.1% (57.1–81), respectively. A multivariate analysis in MD recipients showed that decreased renal function and increased inotropic support of recipients were associated with higher mortality (p = 0.04 and p = 0.03). Cold ischemic time (p = 0.03) and increased donor inotropic support (p = 0.04) were independent risk factors for PGF. Overall survival was higher in SD than MD (85% vs. 68% at 5 years, log-rank = 0.008). However, risk-adjusted mortality (p = 0.2) and 5-year conditional survival (log-rank = 0.6) were comparable. Conclusions: Selected MDs are a valuable resource for expanding the cardiac donor pool, showing promising results. The use of MDs after prolonged ischemic times, increased inotropic support of the MD or the recipient and decreased renal function are associated with worse outcomes. Full article

Background: The aim of this prospective study was to evaluate the efficacy and safety of Platelet Rich Plasma (PRP) injections in patients affected by knee osteoarthritis (KOA). An autologous blood product containing a high percentage of various growth factors (GFs), cytokines and modulating factors as PRP has shown promising results in achieving this goal. Methods: One hundred and fifty-three patients (72 males, mean age 59.06 ± 8.78, range 40–81 years old) from January 2018 to January 2020 received three consecutive PRP injections and completed the follow ups. Western Ontario and McMaster University Osteoarthritis index (WOMAC), Knee society score (KSS) and Visual Analogic Scale (VAS) were evaluated before PRP injection (T0), one month (T1), three months (T2) and six months (T3) after the treatment. All patients underwent baseline and at 6 months MRI and X-ray evaluation. Results: A statistically significant VAS, KSS and WOMAC reduction emerged in the comparison between evaluations (p < 0.05), MRI demonstrated non-statistically significant improvement in cartilage thickness for both tibial plate and femoral plate (p = 0.46 and p = 0.33 respectively), and no radiographic changes could be seen in any patients. Conclusions: PRP injection represents a valid conservative treatment to reduce pain, improve quality of life and functional scores even at midterm of 6 months follow-up. Full article

Remimazolam has been suggested to improve the maintenance of hemodynamic stability when compared with other agents used for general anesthesia. This study aimed to compare the effects of remimazolam and sevoflurane anesthesia on hemodynamic stability in patients undergoing robotic gastrectomy. We retrospectively reviewed the electronic medical records of 199 patients who underwent robotic gastrectomy with sevoflurane (n = 135) or remimazolam (n = 64) anesthesia from January to November 2021. Propensity scores were used for 1:1 matching between the groups. The primary outcome was the difference in use of intraoperative vasopressors between groups. Secondary outcomes included differences in incidence and dose of vasopressors, as well as intraoperative hemodynamic variables, between groups. Remimazolam anesthesia was associated with a significantly less frequent use of ephedrine (odds ratio (OR): 0.13; 95% confidence interval (CI): 0.05–0.38, p < 0.001), phenylephrine (OR: 0.12; 95% CI: 0.04–0.40, p < 0.001), and any vasopressor (OR: 0.06; 95% CI: 0.02–0.25, p < 0.001) compared with sevoflurane anesthesia. Remimazolam anesthesia enables better maintenance of hemodynamic stability than sevoflurane anesthesia. Thus, remimazolam anesthesia may be beneficial for patients who are expected to experience hypotension due to the combined effects of CO₂ pneumoperitoneum and the head-up position utilized during robotic gastrectomy. Full article

Background: This systematic review and meta-analysis aimed to estimate the pooled prevalence of dysphagia in older adults, subgrouping by recruitment settings and varying dysphagia assessment methods. Methods: Five major databases were systematically searched through January 2022. A random-effects model for meta-analysis was conducted to obtain the pooled prevalence. Results: Prevalence of dysphagia in the community-dwelling elderly screened by water swallow test was 12.14% (95% CI: 6.48% to 19.25%, I² = 0%), which was significantly lower than the combined prevalence of 30.52% (95% CI: 21.75% to 40.07%, I² = 68%) assessed by Standardized Swallowing Assessment (SSA) and volume-viscosity swallow test (V−VST). The dysphagia prevalence among elderly nursing home residents evaluated by SSA was 58.69% (95% CI: 47.71% to 69.25%, I² = 0%) and by the Gugging Swallowing Screen test (GUSS) test was 53.60% (95% CI: 41.20% to 65.79%, I² = 0%). The prevalence of dysphagia in hospitalized older adults screened by the 10-item Eating Assessment Tool was 24.10% (95% CI: 16.64% to 32.44%, I² = 0%), which was significantly lower than those assessed by V-VST or GUSS tests of 47.18% (95% CI: 38.30% to 56.14%, I² = 0%). Conclusions: Dysphagia is prevalent in the elderly, affecting approximately one in three community-dwelling elderly, almost half of the geriatric patients, and even more than half of elderly nursing home residents. The use of non-validated screening tools to report dysphagia underestimates its actual prevalence. Full article

Risk stratification is one of the cornerstones of the management of acute pulmonary embolism (PE) and determines the choice of both diagnostic and therapeutic strategies. The first step is the identification of patent circulatory failure, as it is associated with a high risk of immediate mortality and requires a rapid diagnosis and prompt reperfusion. The second step is the estimation of 30-day mortality based on clinical parameters (e.g., original and simplified version of the pulmonary embolism severity index): low-risk patients without right ventricular dysfunction are safely managed with ambulatory anticoagulation. The remaining group of hemodynamically stable patients, labeled intermediate-risk PE, requires hospital admission, even if most of them will heal without complications. In recent decades, efforts have been made to identify a subgroup of patients at an increased risk of adverse outcomes (intermediate-high-risk PE), who might benefit from a more aggressive approach, including reperfusion therapies and admission to a monitored unit. The cur-rent approach, combining markers of right ventricular dysfunction and myocardial injury, has an insufficient positive predictive value to guide primary thrombolysis. Sensitive markers of circulatory failure, such as plasma lactate, have shown interesting prognostic accuracy and may play a central role in the future. Furthermore, the improved security of reduced-dose thrombolysis may enlarge the indication of this treatment to selected intermediate–high-risk PE. Full article

Background: Arterial stiffness (AS), measured by arterial stiffness index (ASI), can be considered as a major denominator in cardiovascular (CV) diseases. Thus, it remains essential to highlight the risk factors influencing its increase among healthy participants. Methods: According to European consensus, AS is defined as ASI > 10 m/s. The purpose of this study was to investigate the determinants of the arterial stiffness (ASI > 10 m/s) among UK Biobank normotensive and healthy participants without comorbidities and previous CV diseases. Thus, a cross-sectional study was conducted on 22,452 healthy participants. Results: Participants were divided into two groups, i.e., ASI > 10 m/s (n = 5782, 25.8%) and ASI < 10 m/s (n = 16,670, 74.2%). All the significant univariate covariables were included in the multivariate analysis. The remaining independent factors associated with AS were age (OR = 1.063, threshold = 53.0 years, p < 0.001), BMI (OR = 1.0450, threshold = 24.9 kg/m², p < 0.001), cystatin c (OR = 1.384, threshold = 0.85 mg/L, p = 0.011), phosphate (OR = 2.225, threshold = 1.21 mmol/L, p < 0.001), triglycerides (OR = 1.281, threshold = 1.09 mmol/L, p < 0.001), mean BP (OR = 1.028, threshold = 91.2 mmHg, p < 0.001), HR (OR = 1.007, threshold = 55 bpm, p < 0.001), Alkaline phosphate (OR = 1.002, threshold = 67.9 U/L, p = 0.004), albumin (OR = 0.973, threshold = 46.0 g/L, p < 0.001), gender (male, OR = 1.657, p < 0.001) and tobacco use (current, OR = 1.871, p < 0.001). Conclusion: AS is associated with multiple parameters which should be investigated in future prospective studies. Determining the markers of increased ASI among healthy participants participates in the management of future CV risk for preventive strategies. Full article

Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components’ immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients’ outcomes. Full article

The association between HLA and the risk of Graves’ disease (GD) has been analyzed for many years. However, the results were often inconsistent and mostly regarded Asian populations. The purpose of our study was to perform HLA genotyping using a next-generation sequencing (NGS) method in Caucasians, to find out which alleles are eventually correlated with GD morbidity as well as which of them can be considered protective. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 2376 persons, including 159 GD patients and 2217 healthy controls. We have demonstrated a significant association between the risk of GD and the following alleles: HLA-B*08:01, -B*39:06, -B*37:01, -C*07:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*03:01, -DRB1*11:01, -DRB1*13:03, -DRB1*01:03, -DRB1*14:01, -DQB1*03:01, DQB1*02:01. The alleles HLA-B*39:06, -B*37:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*14:01 are novel GD-associated, previously not-reported independent ones with no linkage disequilibrium with other high-risk alleles. On the other hand, the frequencies of HLA-B*07:02, -C*07:02, -C*03:04, DRB1*07:01, -DQB1*02:02, -DQB1*03:03 were significantly lower in GD compared to controls. This study demonstrated the actual relationships between HLA and GD based on the NGS method and provided a novel set of alleles as a reliable tool for an individual personalized risk assessment. Full article

Pandemic preparedness is an important issue in relation to future pandemics. The two studies described here aimed to identify factors predicting the presence and severity of coronavirus disease 2019 (COVID-19) symptoms. The CLOFIT study comprised an online survey among the Dutch population (n = 1415). Perceived immune fitness before the pandemic (2019) and during the first lockdown period (15 March–11 May 2020) and the number and severity of COVID-19 symptoms were assessed. The COTEST study, conducted between December 2020 and June 2021, replicated the CLOFIT study in n = 925 participants who were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Dutch commercial test locations. The CLOFIT study revealed that immune fitness before the pandemic was the greatest predictor of the number and severity of COVID-19 symptoms (20.1% and 19.8%, respectively). Other significant predictors included immune fitness during the lockdown (5.5% and 7.1%, respectively), and having underlying diseases (0.4% and 0.5%, respectively). In the COTEST study, for those who tested positive for SARS-CoV-2, immune fitness before the pandemic was the single predictor of the number (27.2%) and severity (33.1%) of COVID-19 symptoms during the pandemic. In conclusion, for those who tested positive for SARS-CoV-2, immune fitness before the pandemic was the strongest predictor of the number and severity of COVID-19 symptoms during the pandemic. Therefore, the development of strategies to maintain an adequate immune fitness must be regarded as an essential component of pandemic preparedness. Full article

Aim: To assess the prevalence of malnutrition, frailty, and sarcopenia and the relationships between them in patients hospitalized for COVID-19. Methods: This was a cross-sectional study of the prevalence, determinants, and associations between malnutrition (GLIM 2019 criteria), sarcopenia (SARC-F scale, dynamometry, and calf circumference), and frailty (FRAIL scale) upon discharge following hospitalization for COVID 19. Results: A total of 101 patients (67.3% men, mean age 66.3 years) were recruited. Malnutrition was diagnosed in 49.5%, sarcopenia in 32.7%, and frailty in 28.7% of patients. Of the patients with malnutrition, 48% were also sarcopenic, and 42% were frail. There was a significant association between malnutrition and the severity of pneumonia according to the CURB-65 scale (odds ratio [OR] 2.61, p = 0.036), between sarcopenia and a Barthel score lower than 60 points (OR 29.52, p < 0.001), and between frailty and both a Barthel score lower than 60 points (OR 32.27, p < 0.001) and a length of hospital stay of over 30 days (OR 9.11, p = 0.008). Conclusions: Malnutrition, sarcopenia, and frailty are prevalent and interrelated entities in patients hospitalized for acute SARS CoV-2 infection, especially in patients with greater baseline functional impairment prior to admission and a higher infection severity. Full article

Various ocular surface conditions such as dry eye disease can present with severe discomfort and pain. However, it is clinically challenging to establish etiology and prescribe correct treatment in patients who have a lot of discordance between symptoms and signs. To understand the basis of such discordance, we stratified subjects with ocular surface pain based on concordance between the severity of signs and symptoms and evaluated corneal structural features and tear molecular factors. All subjects underwent slit lamp examination, dry eye evaluation, and ocular surface disease index (OSDI) scoring. Subjects were stratified into group 1—without symptoms or clinical signs; group 2—without symptoms but with signs; group 3—with similar severity of symptoms and signs; and group 4—with symptom severity greater than that of the signs. Laser scanning in vivo confocal microscopy (IVCM) and tear fluid analysis for soluble factors by multiplex ELISA was performed for all subjects. Patients with a higher grade of symptoms and signs showed increased corneal dendritic cell (cDC) density (p < 0.05) which was more pronounced in subjects with discordance between the symptoms and signs (group 4). A significantly higher proportion of microneuroma-like structures and cDC were observed in group 4. IL-17A levels were significantly elevated in the tears of subjects with more discomfort. Our results demonstrate that corneal IVCM and the measurement of tear film factors can help clinicians improve diagnosis and treatment choice. Stratifying patients with ocular surface discomfort on the basis of discordance between symptoms and clinical signs may help identify patients who need additional adjunctive targeted therapy to resolve their condition. Full article

α-Klotho protein is a powerful predictor of the aging process and lifespan. Although lowered circulating soluble α-Klotho levels have been observed in aged non-healthy individuals, no specific reference values across a wide range of ages and sex using an enzyme-linked immunosorbent assay (ELISA) are available for larger cohorts of healthy individuals. The present analytical cross-sectional study was aimed to establish the reference values of soluble α-Klotho serum levels in healthy adults by age and sex groups. A total of 346 (59% women) healthy individuals aged from 18 to 85 years were recruited. Subjects were divided by sex and age as: (i) young (18–34.9 years), (ii) middle-aged (35–54.9 years), and (iii) senior (55–85 years) individuals. The soluble α-Klotho levels were measured in serum using ELISA. Senior adults were the age-group that presented the lowest soluble α-Klotho serum levels (p < 0.01), with age showing a negative association with soluble α-Klotho serum levels (p < 0.001). No differences between sexes were observed. Therefore, soluble α-Klotho levels were especially decreased—regardless of sex—in our cohort of healthy individuals because of the physiological decline derived from the aging process. We recommend routine assessments of soluble α-Klotho levels using ELISA as a simple and cheap detectable marker of aging that improves quality of life in the elderly. Full article

Background: There is a rapidly growing literature available on right hemicolectomy comparing the short- and long-term outcomes of robotic right colectomy (RRC) to that of laparoscopic right colectomy (LRC). The aim of this meta-analysis is to revise current comparative literature systematically. Methods: A systematic review of comparative studies published between 2000 to 2021 in PubMed, Scopus and Embase was performed. The primary endpoint was postoperative morbidity, mortality and long-term oncological results. Secondary endpoints consist of blood loss, conversion rates, complications, time to first flatus, hospital stay and incisional hernia rate. Results: 25 of 322 studies were considered for data extraction. A total of 16,099 individual patients who underwent RRC (n = 1842) or LRC (n = 14,257) between 2002 and 2020 were identified. Operative time was significantly shorter in the LRC group (LRC 165.31 min ± 43.08 vs. RRC 207.38 min ± 189.13, MD: −42.01 (95% CI: −51.06−32.96), p < 0.001). Blood loss was significantly lower in the RRC group (LRC 63.57 ± 35.21 vs. RRC 53.62 ± 34.02, MD: 10.03 (95% CI: 1.61–18.45), p = 0.02) as well as conversion rate (LRC 1155/11,629 vs. RRC 94/1534, OR: 1.65 (1.28–2.13), p < 0.001) and hospital stay (LRC 6.15 ± 31.77 vs. RRC 5.31 ± 1.65, MD: 0.84 (95% CI: 0.29–1.38), p = 0.003). Oncological long-term results did not differ between both groups. Conclusion: The advantages of robotic colorectal procedures were clearly demonstrated. RRC can be regarded as safe and feasible. Most of the included studies were retrospective with a limited level of evidence. Further randomized trials would be suitable. Full article

The vasoactive inotropic score (VIS) is calculated as a weighted sum of all administered vasopressor and inotropic medications and quantifies the amount of pharmacological cardiovascular support in patients with the most severe combined cardiopulmonary failure supported with extracorporeal membrane oxygenation (ECMO). This study evaluated (1) whether VIS prior to the initiation of ECMO is an independent predictor of survival in these patients and (2) whether VIS might guide the selection of the appropriate extracorporeal cannulation modality (Veno-Venous ‘V-V’ or Veno-VenoArterial ‘V-VA’). In this study, 39 V-VA and 182 V-V ECMO runs were retrospectively analyzed. VIS immediately prior to ECMO initiation (pre-ECMO) was 40 (10/113) in all patients, 30 (10/80) in patients with V-V ECMO and 207 (60/328) in patients with V-VA ECMO. Pre-ECMO VIS was an independent predictor of survival in univariate (AUC = 0.68, p = 0.001) and multi-variable analyses (p = 0.02). Pre-ECMO VIS was clearly associated with mortality (p = 0.001) in V-V ECMO group; however, V-VA ECMO disrupted this association (p = 0.18). Therefore, in conjunction with echocardiography, VIS might assist in selecting the appropriate ECMO cannulation strategy as patients with a pre-ECMO VIS ≥ 61.4 had significantly lower odds of survival compared to those with lower VIS. Full article

Curative therapy for sickle cell disease (SCD) currently requires gonadotoxic conditioning that can impair future fertility. Fertility outcomes after curative therapy are likely affected by pre-transplant ovarian reserve or semen analysis parameters that may already be abnormal from SCD-related damage or hydroxyurea treatment. Outcomes are also likely affected by the conditioning regimen. Conditioning with myeloablative busulfan and cyclophosphamide causes serious gonadotoxicity particularly among post-pubertal females. Reduced-intensity and non-myeloablative conditioning may be acutely less gonadotoxic, but more short and long-term fertility outcome data after these approaches is needed. Fertility preservation including oocyte/embryo, ovarian tissue, sperm, and experimental testicular tissue cryopreservation should be offered to patients with SCD pursing curative therapy. Regardless of HSCT outcome, longitudinal post-HSCT fertility care is required. Full article

(1) Background: Scleroderma (Sc) is a rare connective tissue disease classified as an autoimmune disorder. The pathogenesis of this disease is not fully understood. (2) Methods: This article reviews the literature on systemic scleroderma (SSc). A review of available scientific articles was conducted using the PubMed database with a time range of January 1985 to December 2021. (3) Results and Conclusions: The article is a review of information on epidemiology, criteria for diagnosis, pathogenesis, a variety of clinical pictures and the possibility of laboratory diagnostic in the diagnosis and monitoring of systemic scleroderma. Full article

Introduction: Hyaluronic acid, steroids and blood products are popularly injected into the temporomandibular joint (TMJs) to relieve pain and increase the extent of mandibular abduction. The purpose of this review is to identify other injectable substances and to evaluate them in the above-mentioned domains. Material and methods: The review included articles describing clinical trials of patients treated with intra-articular injections with or without arthrocentesis. Results: The following emerging substances were initially evaluated to be effective in treating TMJ pain and increasing the amplitude of mandibular abduction: analgesics, dextrose with lidocaine, adipose tissue, nucleated bone marrow cells and ozone gas. Discussion: Better effects of intra-articular administration are achieved by preceding the injection with arthrocentesis. Conclusions: The most promising substances appear to be bone marrow and adipose tissue. Full article

Artificial intelligence has the potential to revolutionize modern society in all its aspects. Encouraged by the variety and vast amount of data that can be gathered from patients (e.g., medical images, text, and electronic health records), researchers have recently increased their interest in developing AI solutions for clinical care. Moreover, a diverse repertoire of methods can be chosen towards creating performant models for use in medical applications, ranging from disease prediction, diagnosis, and prognosis to opting for the most appropriate treatment for an individual patient. In this respect, the present paper aims to review the advancements reported at the convergence of AI and clinical care. Thus, this work presents AI clinical applications in a comprehensive manner, discussing the recent literature studies classified according to medical specialties. In addition, the challenges and limitations hindering AI integration in the clinical setting are further pointed out. Full article

Chronic inflammation has long been linked to obesity and related conditions such as type 2 diabetes and metabolic syndrome. According to current research, the increased risk of cancer in people with certain metabolic diseases may be due to chronic inflammation. Adipocytokines, which are pro-inflammatory cytokines secreted in excess, are elevated in many chronic metabolic diseases. Cytokines and inflammatory mediators, which are not directly linked to DNA, are important in tumorigenesis. Cachexia, a type of metabolic syndrome linked to the disease, is associated with a dysregulation of metabolic pathways. Obesity and cachexia have distinct metabolic characteristics, such as insulin resistance, increased lipolysis, elevated free fatty acids (FFA), and ceramide levels, which are discussed in this section. The goal of this research project is to create a framework for bringing together our knowledge of inflammation-mediated insulin resistance. Full article

Background: While the thoracotomy approach was considered the gold standard until two decades ago, robotic surgery has increasingly strengthened its role in lung cancer treatment, improving patients’ peri-operative outcomes. In this study, we report our experience in robotic lobectomy for early-stage non-small cell lung cancer, with particular attention to oncological outcomes and nodal upstaging rate. Methods: We retrospectively reviewed patients who underwent lobectomy and radical lymphadenectomy at our Institute between 2016 and 2020. We selected 299 patients who met the inclusion criteria of the study. We analyzed the demographic features of the groups as well as their nodal upstaging rate after pathological examination. Then, we analyzed disease-free and overall survival of the entire enrolled patient population and we compared the same oncological outcomes in the upstaging and the non-upstaging group. Results: A total of 299 patients who underwent robotic lobectomy were enrolled. After surgery, 55 patients reported nodal hilar or mediastinal upstaging. The 3-year overall survival of the entire population was 82.8%. The upstaging group and the non-upstaging group were homogeneous for age, gender, smoking habits, clinical stage, tumor site, tumor histology. The non-upstaging group had better OS (p = 0.004) and DFS (p < 0.0001). Conclusion: Our results show that robotic surgery is a safe and feasible approach for the treatment of early-stage NSCLC, especially for its accuracy in mediastinal lymphadenectomy. The oncological outcomes were encouraging and consistent with previous findings. Full article

Since the birth of Louise Joy Brown, the first baby conceived via in vitro fertilization, more than 9 million children have been born worldwide using assisted reproductive technologies (ART). In vivo fertilization takes place in the maternal oviduct, where the unique physiological conditions guarantee the healthy development of the embryo. During early embryogenesis, a major wave of epigenetic reprogramming takes place that is crucial for the correct development of the embryo. Epigenetic reprogramming is susceptible to environmental changes and non-physiological conditions such as those applied during in vitro culture, including shift in pH and temperature, oxygen tension, controlled ovarian stimulation, intracytoplasmic sperm injection, as well as preimplantation embryo manipulations for genetic testing. In the last decade, concerns were raised of a possible link between ART and increased incidence of imprinting disorders, as well as epigenetic alterations in the germ cells of infertile parents that are transmitted to the offspring following ART. The aim of this review was to present evidence from the literature regarding epigenetic errors linked to assisted reproduction treatments and their consequences on the conceived children. Furthermore, we provide an overview of disease risk associated with epigenetic or imprinting alterations in children born via ART. Full article

CAR T cell therapy has revolutionized immunotherapy in the last decade with the successful establishment of chimeric antigen receptor (CAR)-expressing cellular therapies as an alternative treatment in relapsed and refractory CD19-positive leukemias and lymphomas. There are fundamental reasons why CAR T cell therapy has been approved by the Food and Drug administration and the European Medicines Agency for pediatric and young adult patients first. Commonly, novel therapies are developed for adult patients and then adapted for pediatric use, due to regulatory and commercial reasons. Both strategic and biological factors have supported the success of CAR T cell therapy in children. Since there is an urgent need for more potent and specific therapies in childhood malignancies, efforts should also include the development of CAR therapeutics and expand applicability by introducing new technologies. Basic aspects, the evolution and the drawbacks of childhood CAR T cell therapy are discussed as along with the latest clinically relevant information. Full article

Stroke is an acute neurovascular central nervous system (CNS) injury and one of the main causes of long-term disability and mortality. Post-stroke rehabilitation as part of recovery is focused on relearning lost skills and regaining independence as much as possible. Many novel strategies in neurorehabilitation have been introduced. This review focuses on current evidence of the effectiveness of repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation (NIBS), in post-stroke rehabilitation. Moreover, we present the effects of specific interventions, such as low-frequency or high-frequency rTMS therapy, on motor function, cognitive function, depression, and aphasia in post-stroke patients. Collected data suggest that high-frequency stimulation (5 Hz and beyond) produces an increase in cortical excitability, whereas low-frequency stimulation (≤1 Hz) decreases cortical excitability. Accumulated data suggest that rTMS is safe and can be used to modulate cortical excitability, which may improve overall performance. Side effects such as tingling sensation on the skin of the skull or headache are possible. Serious side effects such as epileptic seizures can be avoided by adhering to international safety guidelines. We reviewed clinical studies that present promising results in general recovery and stimulating neuroplasticity. This article is an overview of the current rTMS state of knowledge related to benefits in stroke, as well as its cellular and molecular mechanisms. In the stroke rehabilitation literature, there is a key methodological problem of creating double-blinding studies, which are very often impossible to conduct. Full article

Background: The healing of foot wounds in patients with diabetes mellitus is frequently complicated by critical limb threatening ischemia (neuro-ischemic diabetic foot syndrome, DFS). In this situation, imminent arterial revascularization is imperative in order to avoid amputation. However, in many patients this is no longer possible (“too late”, “too sick”, “no technical option”). Besides conservative treatment or major amputation, many alternative methods supposed to decrease pain, promote wound healing, and avoid amputations are employed. We performed a narrative review in order to stress their efficiency and evidence. Methods: The literature research for the 2014 revision of the German evidenced-based S3-PAD-guidelines was extended to 2020. Results: If revascularization is impossible, there is not enough evidence for gene- and stem-cell therapy, hyperbaric oxygen, sympathectomy, spinal cord stimulation, prostanoids etc. to be able to recommend them. Risk factor management is recommended for all CLTI patients. With appropriate wound care and strict offloading, conservative treatment may be an effective alternative. Timely amputation can accelerate mobilization and improve the quality of life. Conclusions: Alternative treatments said to decrease the amputation rate by improving arterial perfusion and wound healing in case revascularization is impossible and lack both efficiency and evidence. Conservative therapy can yield acceptable results, but early amputation may be a beneficial alternative. Patients unfit for revascularization or major amputation should receive palliative wound care and pain therapy. New treatment strategies for no-option CLTI are urgently needed. Full article

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment. Besides, several agents, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients. Novel therapies using RNA interference also offer clinical promise. Patisiran and inotersen are currently approved for ATTR-polyneuropathy of hereditary origin and are under investigation for ATTR-CM. Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance. Despite several drug candidates in the clinical development pipeline, the small ATTR-CM patient population raises several challenges. This review describes current and future therapies for ATTR-CM and sheds light on the clinical development hurdles facing them. Full article

Since the birth of Louise Brown in 1978 via IVF, reproductive specialists have acquired enormous knowledge and refined several procedures, which are nowadays applied in assisted reproductive technology (ART). One of the most critical steps in this practice is the fertilization process. In the early days of IVF, a remarkable concern was the unpleasant outcomes of failed fertilization, overtaken by introducing intracytoplasmic sperm injection (ICSI), delineating a real breakthrough in modern ART. ICSI became standard practice and was soon used as the most common method to fertilize oocytes. It has been used for severe male factor infertility and non-male factors, such as unexplained infertility or advanced maternal age, without robust scientific evidence. However, applying ICSI blindly is not free of potential detrimental consequences since novel studies report possible health consequences to offspring. DNA methylation and epigenetic alterations in sperm cells of infertile men might help explain some of the adverse effects reported in ICSI studies on reproductive health in future generations. Collected data concerning the health of ICSI children over the past thirty years seems to support the notion that there might be an increased risk of epigenetic disorders, congenital malformations, chromosomal alterations, and subfertility in babies born following ICSI compared to naturally conceived children. However, it is still to be elucidated to what level these data are associated with the cause of infertility or the ICSI technique. This review provides an overview of epigenetic mechanisms and possible imprinting alterations following the use of ART, in particular ICSI. It also highlights the sperm contribution to embryo epigenetic regulation and the risks of in vitro culture conditions on epigenetic dysregulation. Lastly, it summarizes the literature concerning the possible epigenetic disorders in children born after ART. Full article

Sleep disturbances and poor sleep are a common complaint in the population with multiple sclerosis (MS) disease. The most commonly reported scale is the Pittsburgh Sleep Quality Index (PSQI), measuring seven components of sleep quality. Yet, till today, the PSQI instrument has not been validated in people with multiple sclerosis (pwMS). The objective of our study was to add precision in sleep quality assessment by investigating the psychometric properties of PSQI (factor structure, reliability, validity based on relations with other variables, cut-off scores) in pwMS. The cross-sectional study included data on a total of 87 patients with MS and 216 control subjects. Demographic information, education level, and MS-related variables were ascertained. Psychometric properties were examined by estimating the validity, including factor structure, metric invariance, and relations with other MS- and non-MS-related variables, reliability, and discrimination ability of the PSQI. The Croatian version of the PSQI had a two-factor structure which demonstrated loading and partial intercept invariance between pwMS and the control group. The global score and both subscales had high internal consistencies (McDonald’s omega and Cronbach’s alpha coefficients) in pwMS and showed expected relations with demographic and MS-related variables. PwMS differed significantly in the PSQI global score from the control groups, although receiver operating characteristics (ROC) curve analysis did not indicate a clear cut-off point. The PSQI is a reliable and valid scale and can be applied in clinical settings for assessing sleep quality in pwMS. Full article

The crystalloid fluid of choice in sepsis remains debatable. We aimed to perform a comprehensive meta-analysis to compare the effect of balanced crystalloids (BC) vs. normal saline (NS) in adults with sepsis. A systematic search of PubMed, EMBASE, and Web of Sciences databases through 22 January 2022, was performed for studies that compared BC vs. NS in adults with sepsis. Our outcomes included mortality and acute kidney injury (AKI), need for renal replacement therapy (RRT), and ICU length of stay (LOS). Pooled risk ratio (RR) and mean difference (MD) with the corresponding 95% confidence intervals (CIs) were obtained using a random-effect model. Fifteen studies involving 20,329 patients were included. Overall, BC showed a significant reduction in the overall mortality (RR 0.88, 95% CI 0.81–0.96), 28/30-day mortality (RR 0.87, 95% CI 0.79–0.95), and AKI (RR 0.85, 95% CI 0.77–0.93) but similar 90-day mortality (RR 0.96, 95% CI 0.90–1.03), need for RRT (RR 0.91, 95% CI 0.76–1.08), and ICU LOS (MD −0.25 days, 95% CI −3.44, 2.95), were observed between the two groups. However, subgroup analysis of randomized controlled trials (RCTs) showed no statistically significant differences in overall mortality (RR 0.92, 95% CI 0.82–1.02), AKI (RR 0.71, 95% CI 0.47–1.06), and need for RRT (RR 0.71, 95% CI 0.36–1.41). Our meta-analysis demonstrates that overall BC was associated with reduced mortality and AKI in sepsis compared to NS among patients with sepsis. However, subgroup analysis of RCTs showed no significant differences in both overall mortality and AKI between the groups. There was no significant difference in the need for RRT or ICU LOS between BC and NS. Pending further data, our study supports using BC over NS for fluid resuscitation in adults with sepsis. Further large-scale RCTs are necessary to validate our findings. Full article

Several optical imaging techniques have been developed to ease the burden of skin cancer disease on our health care system. Hyperspectral images can be used to identify biological tissues by their diffuse reflected spectra. In this second part of a three-phase pilot study, we used a novel hand-held SICSURFIS Spectral Imager with an adaptable field of view and target-wise selectable wavelength channels to provide detailed spectral and spatial data for lesions on complex surfaces. The hyperspectral images (33 wavelengths, 477–891 nm) provided photometric data through individually controlled illumination modules, enabling convolutional networks to utilise spectral, spatial, and skin-surface models for the analyses. In total, 42 lesions were studied: 7 melanomas, 13 pigmented and 7 intradermal nevi, 10 basal cell carcinomas, and 5 squamous cell carcinomas. All lesions were excised for histological analyses. A pixel-wise analysis provided map-like images and classified pigmented lesions with a sensitivity of 87% and a specificity of 93%, and 79% and 91%, respectively, for non-pigmented lesions. A majority voting analysis, which provided the most probable lesion diagnosis, diagnosed 41 of 42 lesions correctly. This pilot study indicates that our non-invasive hyperspectral imaging system, which involves shape and depth data analysed by convolutional neural networks, is feasible for differentiating between malignant and benign pigmented and non-pigmented skin tumours, even on complex skin surfaces. Full article

Objectives: The purpose of this systematic review with meta-analysis is to identify clinical studies concerning the impact of intra-articular administration of hyaluronic acid (HA) on mandibular mobility and to make an attempt at determining the efficacy of HA in this indication. Methods: The review included primary studies involving groups of at least 10 patients who were diagnosed with pain in the temporomandibular joint and who were injected with hyaluronic acid as the only intervention. The outcomes pursued were changes in mandibular mobility and pain intensity. Four databases of medical articles were searched, including PubMed and BASE. The risk of bias was assessed using the Cochrane methodology tools. The therapy‘s efficacy was calculated in the domains of mandibular abduction, protrusive movement, lateral mobility, and pain relief. For these values, the regression and correlation with variables characterizing the interventions were analyzed. Results: In total, 16 reports on 20 study groups with a total of 1007 patients qualified for the review. The mean effectiveness in the domain of mandibular abduction over the 6-month follow-up period was 122% of the initial value, and the linear regression model can be expressed as 0.5x + 36. The level of pain in the same time frame decreased to an average of 29%. The severity of pain 6 months after the beginning of treatment positively correlates with the number of injections per joint (0.63), the total amount of drug administered in milliliters (0.62), and the volume of drug administered monthly per joint (0.50). Limitations: In some studies, the patient groups were heterogeneous in terms of diagnosis. The studies varied depending on the joint into which the HA was administered. The synthesized studies differed with regard to the method of measuring the mandible abduction amplitude. Conclusions: The increase in the amplitude of mandibular abduction was expressed as the quotient of the mean values during the observation periods, and the initial value was achieved in all study groups, and in the linear regression model, it was 0.5 mm on average per month. Multiple administrations of the drug may reduce the analgesic effectiveness of the treatment. Full article

(1) Objective: This review aims to identify the clinical and practical barriers to optimizing nutrition in newborn infants with congenital heart disease (CHD) and to describe updated evidence-based recommendations for clinical and nutritional management of these patients in a narrative review. (2) Research Methods and Procedures: We conducted a search of the relevant literature published from 2000 to December 2021. (3) Results: CHD patients undergo several nutritional challenges related to the underlying cardiac disease anomaly, the potential increased risk of NEC, and delayed enteral feeding, resulting in inadequate energy intake and sub-optimal growth, increased morbidity and mortality. (4) Conclusions: To optimize nutrition and growth in newborn infants with CHD, standardized protocols should be implemented. Regular nutritional and growth assessment with a multi-disciplinary team is essential. We propose a decisional algorithm that may represent a potentially useful tool to guide clinicians to optimize growth and nutrition. Full article