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Factitious disorder imposed on another, or medical child abuse, has been rarely reported to have primary ocular presentations. We report an unusual and difficult diagnosis of factitious disorder imposed by a mother on her infant resulting in bilateral blindness. An infant was referred with a history of recurrent periorbital cellulitis and sanguineous discharge associated with seizure-like episodes. Symptoms have been going on for more than 14 months, and child had been treated by different physicians from different specialties without a clear ophthalmic diagnosis. The right eye was previously enucleated at an outside hospital for secondary complications of similar symptoms. He was admitted for exhaustive diagnostic tests and multiple surgical treatments, and his hospital stay was complicated with multiple corneal perforations and apnoeic episodes despite optimal treatment. After suspicion of factitious disease, continuous electroencephalography and video monitoring revealed evidence of the mother inflicting physical harm to her child.

The 9-member Editorial Board of the American Society for Gastrointestinal Endoscopy performed a systematic literature search of original articles published during 2021 in Gastrointestinal Endoscopy and 10 other high-impact medical and gastroenterology journals on endoscopy-related topics. Votes from each editorial board member were tallied to identify a consensus list of the 10 most significant topic areas in GI endoscopy over the calendar year of study, with a focus on 3 criteria: significance, novelty, and global impact on clinical practice. The 10 areas identified collectively represent advances in the following endoscopic topics: colonoscopy optimization, bariatric endoscopy, endoscopic needle sampling and drainage, peroral endoscopic myotomy, endoscopic defect closure, meeting systemic challenges in endoscopic training and practice, endohepatology, FNA versus fine-needle biopsy sampling, endoscopic mucosal and submucosal procedures, and cold snare polypectomy. Each board member contributed a summary of important articles relevant to 1 to 2 of the consensus topic areas, leading to a collective summary that is presented in this document of the "top 10" endoscopic advances of 2021.

In this study, we aimed to assess the extent of dissemination of methicillin-resistant Mammaliicoccus sciuri in animal farms in Tunisia and evaluate the distribution of virulence and methicillin resistance genes in the M. sciuri population.Staphylococci and mammaliicocci isolated from unhealthy animals and healthy humans from adjacent farms in Tunisia were characterized for antimicrobial susceptibility, biofilm formation, agglutination, and hemolysis abilities. Mammaliicoccus sciuri relatedness and content in antibiotic resistance and virulence genes were analyzed by whole-genome sequencing (WGS).Mammaliicoccus sciuri was the most prevalent species (46.2%), showing the highest resistance rates to fusidic acid (94.6%), oxacillin (73%), penicillin (40.5%), clindamycin (37%), ciprofloxacin (27%), and cefoxitin (24.3%). Some isolates carried genes encoding resistance to nine different antibiotic classes. mecA was found in 35% of M. sciuri and mecC in 16.2%. All isolates carrying mecC were of S. sciuri subspecies carnaticus and carried the hybrid element SCCmec-mecC. Mammaliicoccus sciuri were able to produce strong biofilm (27%) and have clumping ability (16%). Additionally, they carried genes for capsule production (cap8, 100%), iron-regulated surface determinants (isdE, 24%; isdG, 3%), and virulence regulation (clpC and clpP, 100%). Single nucleotide polymorphisms (SNPs) analysis showed that 17 M. sciuri cross-transmission events probably occurred between different animal species and farms. Moreover, SCCmec was estimated to have been acquired five times by S. sciuri subsp. carnaticus.Multidrug resistant and pathogenic M. sciuri were frequently disseminated between different animal species within the farm environment. mecA and mecC can be disseminated by both frequent acquisition of the SCCmec element and clonal dissemination.

Cachexia is an acute syndrome that is very commonly observed in patients with cancer. Cachexia is the number one cause of death in patients with metastatic disease and is also the major factor for physical toxicity and financial burden. More importantly, the majority of patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) cancer undergo cachexia. Pancreatic cancer causes deaths of ∼50,000 Americans and about 400,000 people worldwide every year. The high mortality rates in metastatic PDAC are due to systemic pathologies and cachexia, which quickens death in these patients. About 90% of all patients with PDAC undergo wasting of muscle causing mobility loss and leading to a number of additional pathological conditions. PDAC-associated cancer cachexia emanates from complex signaling cues involving both mechanical and biological signals. Tumor invasion is associated with the loss of pancreatic function-induced digestive disorders and malabsorption, which causes subsequent weight loss and eventually promotes cachexia. Besides, systemic inflammation of patients with PDAC could release chemical cues (e.g., cytokine-mediated Atrogin-1/MAFbx expression) that participate in muscle wasting. Our understanding of genes, proteins, and cytokines involved in promoting cancer cachexia has evolved considerably. However, the role of epigenetic factors, particularly the role of noncoding RNAs (ncRNAs) in regulating PDAC-associated cachexia is less studied. In this review article, the most updated knowledge on the various ncRNAs including microRNAs (miRs), long noncoding RNA (lncRNAs), piwi interacting RNAs (PiwiRNAs), small nucleolar RNA (snoRNAs), and circular RNAs (circRNA) and their roles in cancer cachexia are described.

To assess if systematic (SBx) vs. transrectal or transperineal mpMRI-ultrasound targeted combined with systematic (TBx + SBx) biopsy confer different effects on treatment delay to radical prostatectomy measured as Gleason grade group (GGG) upgrade of prostate cancer (PCa).We relied on a multi-institutional cohort of localized PCa patients who underwent RP in Martini-Klinik, Hamburg, or Prostate Center Northwest, Gronau, between 2014 and 2022. Analyses were restricted to PCa GGG 1-3 diagnosed at SBx (n = 4475) or TBx + SBx (n = 1282). Multivariable logistic regression modeling (MVA) predicting RP GGG upgrade of ≥ 1 was performed separately for SBx and TBx + SBx.Treatment delay to RP of 90, 90-180 and 180-365 days was reported in 59%, 35% and 6.2% of SBx and in 60%, 34% and 5.9% of the TBx + SBx patients, respectively. Upgrade to GGG ≥ 4 at RP was detected in 15% of SBx patients and 0.86% of TBx patients. In MVA performed for SBx, treatment delay yielded independent predictor status (OR 1.17 95% CI 1.02-1.39, p = 0.028), whereas for TBx + SBx MVA, statistical significance was not achieved.Treatment delay remained independently associated with radical prostatectomy GGG upgrade after adjustment for clinical variables in the patients diagnosed with SBx alone, but not in those who received combined TBx + SBx. These findings can be explained through inherent misclassification rates of SBx, potentially obfuscating historical observations of natural PCa progression and potential dangers of treatment delay. Thus, mpMRI-guided combined TBx + SBx appears mandatory for prospective delay-based examinations of PCa.

What role do ADIPOQ variants play in controlling adiponectin concentrations and altered risk of polycystic ovary syndrome (PCOS)?Study subjects comprised 583 women with PCOS and 713 age-matched controls. Genotyping of rs182052, rs822393, rs822396, rs7649121, rs3774271, rs266729, rs3774261 and rs6773957 ADIPOQ polymorphisms was done by real-time polymerase chain reaction (PCR).Of the 16 ADIPOQ variants, the minor allele frequencies of rs182052, rs822393, rs822396, rs7649121, rs3774261 and rs6773957 were significantly different between PCOS cases and controls. Significant differences in rs266729 (P = 0.02), rs822396 (P = 0.02), rs3774261 (P0.001) and rs6773957 (P0.001) genotypes were also noted between PCOS cases and controls. Reduced PCOS risk was found with heterozygous rs266729, while increased risk was linked to heterozygous rs822396 and homozygous minor allele rs3774361, and in heterozygous and homozygous minor allele rs6773957 genotype carriers. Haplotype analysis identified two blocks based on linkage disequilibrium pattern; alleles coded as '1' (major) and '2' (minor). Within Block 1 (rs4632532, rs16861194, rs266729, rs182052, rs16861209, rs822393, rs822395, rs822396, rs7649121), haplotypes 111111111 and 212211221 were positively, while haplotypes 212212112 and 212211211 were negatively associated with PCOS. Within Block 2 (rs2241766, rs1501299, rs2241767, rs3774261, rs6773957, rs1063539) haplotypes 111221 and 112221 were positively, while haplotype 111111 was negatively associated with PCOS.This is the first study to confirm the association of rs182052, rs822393, rs7649121 and rs6773957 ADIPOQ variants with altered risk of PCOS. The varied association of ADIPOQ variants with PCOS in relation to earlier reports indicate there is an ethnic contribution to ADIPOQ association with PCOS.

Objective Standard surgical repair of acute type A aortic dissection is associated with high mortality rates, especially in high-risk patients. In an attempt to improve survival in frail patients, we evaluated the outcomes after ascending aorta wrapping in a high-risk patient cohort. Methods This single-center retrospective cohort study included all consecutive patients treated using ascending aorta wrapping for an acute type A aortic dissection from 2008 to 2019. The primary end points included 30-day mortality, survival during follow-up, and dissection-related mortality. Secondary end points included assessment of aortic remodeling after ascending aorta wrapping. Patients with an aortic anatomy suitable for adjunctive endografting of the ascending aorta were also identified. Results Thirty-five consecutive patients who underwent ascending aorta wrapping were included. Their median age was 77 years (range, 46-96 years). The 30-day all-cause mortality rate was 9%. Major complications occurred in 7 patients (21%), including early reinterventions in 11 (31%). Median follow-up was 36 months (range, 2.4-106.6; interquartile range, 72). The actuarial survival at 36 months was 82%. The dissection-related mortality was 11.4%. The median aortic growth of the nonwrapped descending thoracic aorta was 3.4 mm. Computed tomography scan analysis depicted that 88% of survivors were theoretical candidates for an additional endovascular procedure to exclude the primary entry tear. Conclusions Aortic wrapping is associated with favorable early outcomes and a low rate of aortic events during follow-up. This therapeutic option should be considered for patients considered too fragile for standard surgical repair.

This study explored medication errors in the perioperative care of patients with epilepsy and developed consensus-based recommendations to prevent/minimize these errors.A mixed method was used in this study. Medication error situations were explored in semi-structured in-depth interviews with nurses (n = 12), anesthesiologists (n = 5), anesthesia technicians (n = 5), surgeons (n = 4), neurologists (n = 4), and patients with epilepsy (n = 10). The qualitative data were analyzed using the qualitative interpretive description approach. A two-round Delphi technique was used among nurses (n = 22), anesthesiologists (n = 9), anesthesia technicians (n = 7), surgeons (n = 7), and neurologists (n = 5).A total of 1400 minutes of interview time was analyzed in this study. Of the panelists, 39 (78.0%) agreed that patients with epilepsy present unique challenges to providers of perioperative care that make them prone to medication errors. The interviewees in this study described 32 different medication error situations that occurred while providing perioperative care services to patients with epilepsy. In this study, 35 consensus-based recommendations to prevent/minimize medication errors in the perioperative care of patients with epilepsy were developed.The findings of this study are informative to decision-makers in health care facilities and other stakeholders in health regulatory authorities who need to design measures to prevent/minimize medication errors and improve perioperative outcomes of patients with epilepsy. Studies are needed to investigate if these recommendations can be effective in preventing/reducing medication errors in the perioperative care of patients with epilepsy.

Matcha tea has been used as an adjunct in weight loss programs. The weight loss effects of matcha tea were evaluated in a prospective non-randomized open-label comparative study of overweight and obese individuals who followed a specified low-calorie diet (LCD) plan. A total of 40 participants were enrolled and assigned to either matcha tea or control groups. The matcha tea group followed a LCD plan and received matcha tea once daily, whereas the control group followed only the LCD diet plan. The study lasted 12 weeks. The main outcome measures included anthropometric measurements, fasting blood glucose, hemoglobin A1c (HbA1c), lipid profile, obesity-related hormone peptides, pro-inflammatory and anti-inflammatory cytokines, and oxidative stress biomarkers. Thirty-four participants had completed the study. The matcha tea and control groups showed significant reductions in body weight, body mass index, waist circumference, water content, minerals, and fat mass at week 12. The post-treatment body composition and anthropometric measurements were not significantly different between the two groups. The matcha tea group showed a potential increase in HDL-C, a potential decrease in blood glucose, and a potential increase in HbA1c. Furthermore, the study indicated a potential decrease in insulin and leptin levels, a potential increase in the activity of superoxide dismutase, and a potential decreased activity of glutathione peroxidase. IL-10 was increased by matcha tea consumption. The data suggest that matcha tea may have some potential effect on weight loss, along with anti-inflammatory properties. The findings of this study will be used to design a multicenter randomized clinical trial to examine the potential weight loss benefits of matcha tea.

Purpose: To investigate differences in athletes’ knowledge, beliefs, and training practices during COVID-19 lockdowns with reference to sport classification and sex. This work extends an initial descriptive evaluation focusing on athlete classification. Methods: Athletes (12,526; 66% male; 142 countries) completed an online survey (May–July 2020) assessing knowledge, beliefs, and practices toward training. Sports were classified as team sports (45%), endurance (20%), power/technical (10%), combat (9%), aquatic (6%), recreational (4%), racquet (3%), precision (2%), parasports (1%), and others (1%). Further analysis by sex was performed. Results: During lockdown, athletes practiced body-weight-based exercises routinely (67% females and 64% males), ranging from 50% (precision) to 78% (parasports). More sport-specific technical skills were performed in combat, parasports, and precision (∼50%) than other sports (∼35%). Most athletes (range: 50% [parasports] to 75% [endurance]) performed cardiorespiratory training (trivial sex differences). Compared to prelockdown, perceived training intensity was reduced by 29% to 41%, depending on sport (largest decline: ∼38% in team sports, unaffected by sex). Some athletes (range: 7%–49%) maintained their training intensity for strength, endurance, speed, plyometric, change-of-direction, and technical training. Athletes who previously trained ≥5 sessions per week reduced their volume (range: 18%–28%) during lockdown. The proportion of athletes (81%) training ≥60 min/session reduced by 31% to 43% during lockdown. Males and females had comparable moderate levels of training knowledge (56% vs 58%) and beliefs/attitudes (54% vs 56%). Conclusions: Changes in athletes’ training practices were sport-specific, with few or no sex differences. Team-based sports were generally more susceptible to changes than individual sports. Policy makers should provide athletes with specific training arrangements and educational resources to facilitate remote and/or home-based training during lockdown-type events.

The purpose of this study was to investigate the effect of a surgically constructed bilateral peritoneal flap (PIF) as an adjunct to robot-assisted radical prostatectomy (RARP) and pelvic lymph node dissection (PLND) on the incidence of lymphoceles.A total of 530 men with localized prostate cancer underwent a RARP with bilateral extended standardized PLND in a prospective randomized controlled trial. In group A, a PIF was created by suturing the margins of the bladder peritoneum to the ipsilateral endopelvic fascia at 2 points on each side. In group B, no PIF was created. The patients were followed 30 and 90 days after the surgery to assess the incidence, extent and treatment of lymphoceles.Lymphoceles occurred in 22% of group A patients and 33% of group B patients (p=0.008). Symptomatic lymphoceles were observed in 3.3% of group A patients and 8.1% of group B patients (p=0.027). Lymphoceles requiring intervention occurred significantly less frequently in group A patients (1.3%) than in group B patients (6.8%, p=0.002). The median lymphocele size was 4.3 cm in group A and 5.0 cm in group B (p=0.055). No statistically significant differences were observed in minor or major complications unrelated to lymphocele, blood loss, or surgical time between groups A and B.Bilateral PIFs in conjunction with RARP and PLND significantly reduce the total incidence of lymphoceles, the frequency of symptomatic lymphoceles and the rate of associated secondary interventions.

Cytokine release syndrome (CRS) is a potentially fatal systemic inflammatory response that can occur in patients undergoing peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT). Severe CRS has previously been associated with increased infection risk. IL-6 inhibitors, such as tocilizumab, are useful in moderate to severe CRS, but their effect on infection risk has not been established in this setting. We examined the effect of tocilizumab on blood stream infections (BSIs) in the early post-transplant period in 235 patients who underwent haplo-HCT from 2013 to 2020. Mild CRS was associated with a lower incidence of BSI than severe CRS (OR 0.31, 95% CI 0.13-0.74). In the tocilizumab group, 31% of patients had positive blood cultures versus 14% in the non-tocilizumab group (OR 1.61, 95% CI 0.30-8.60

This 79-year-old woman was involved in a road traffic collision in which another driver rear-ended her stationary car at a speed of around 70 m/h. She was transferred to the nearest Major Trauma Centre, where her observations remained stable and initial primary survey was unremarkable. She had a

To assess suitability of Comprehensive Complication Index (CCIA total of 128 patients with bladder cancer (BCa) undergoing intracorporeal RARC with pelvic lymph node dissection between 2015 and 2021 were included in a retrospective bi-institutional study, which adhered to standardized reporting criteria. Thirty-day complications were captured according to a procedure-specific catalog. Each complication was graded by the CDC and the CCI381 complications were identified in 118 patients (92%). 55 (43%), 43 (34%), and 20 (16%) suffered from CDC grade I-II, IIIa, and ≥ IIIb complications, respectively. 16 (13%), 27 (21%), and 2 patients (1.6%) were reoperated, readmitted, and died within 30 days, respectively. 31 patients (24%) were upgraded to most severe complication (CCIThe CCI

The management of hyperglycemia in patients admitted to hospital is mainly based on insulin therapy. However, the positive and rapid effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes raises the possibility that they might confer benefits to hospitalized patients. In recent, well designed, randomized trials (SOLOIST-WHF and EMPULSE) recruiting inpatients with heart failure (HF), SGLT2i demonstrated the potential to improve survival and quality of life and reduce the number of HF events, time to first HF event, hospitalizations, and urgent visits for HF compared with placebo. They were also well tolerated, whereas incidence of diabetic ketoacidosis was low. In EMBODY, empagliflozin was shown to be protective against the deleterious effects of cardiac injury in patients with acute myocardial infarction. In DARE-19, the administration of dapagliflozin to inpatients with cardiometabolic risk factors and COVID-19 was based on the hypothesis that the anti-inflammatory properties of SGLT2i could alleviate organ damage. Although the findings did not reach statistical significance, the efficacy and safety profiles of the drug were encouraging. These promising findings in the field of cardiometabolic medicine set the stage for future research to explore whether the benefits of gliflozins can expand to inpatients with non-cardiometabolic disorders, including sepsis, cirrhotic ascites, and malignancies. The concept of inpatient use of SGLT2i has evolved greatly over the past few years. The latest evidence suggests that SGLT2i may be effective and safe in the hospital setting, provided patients are carefully selected and closely monitored. Real-world data will prove whether present hope about inpatient use of gliflozins will transform into future confidence.

Objective When considering increased morbidity of apical biopsies, the added diagnostic value of separate targeting of mid-gland and apical segment of the pan-segmental mid-apical mpMRI prostate cancer (PCa) suspicious lesions was assessed. Materials and methods A total of 420 patients with a single mpMRI PCa-suspicious PI-RADS ≥ 3 intraprostatic lesion extending from the mid-gland to the apical segment of the gland underwent transrectal MRI-targeted (TBx) and systematic prostate biopsy. Clinically significant PCa (CsPCa) was defined as Gleason Score (GS) ≥ 3 + 4. PCa detection rates of TBx cores were assessed according to targeted anatomical segments. Finally, the diagnostic values of two theoretical TBx protocols utilizing 1-core (A) vs. 2-cores (B) per anatomical segment were compared. Results TBx within the pan-segmental mid-apical lesions yielded 44% of csPCa. After stratification into mid- vs. apical segment of the lesion, csPCa was detected in 36% (mid-gland) and 32% (apex), respectively. Within the patients who had no csPCa detection by mid-gland sampling (64%, n = 270), extreme apical TBx yielded additional 8.1% of csPCa. Comparison of extreme apical TBx strategy B vs. overall PCa detection in our cohort revealed corresponding similar rates of 49 vs.50% and 31 vs.32%, respectively. Conclusion Separate analyses of both segments, mid-gland and apex, clearly revealed the diagnostic contribution of apical TBx. Our findings strongly suggest to perform extreme apical TBx even within pan-segmental lesions. Moreover, our results indicate that a higher number of cores sampled from the mid-gland segment might be avoided if complemented with a two-core extreme apical TBx.

Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs).The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk.This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study.A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital.Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs.

Intestinal ischemia (II) is the most critical factor to determine in patients with incarcerated groin hernia (IGH) because II could be reversible, and it is considered as a "time sensitive condition." Although predictive factors of II were identified in several previous studies, preoperative diagnosis of II cannot be reliably made or excluded by any known parameter. The aims of this study were: to devise and to validate a clinic-biologic score, with a strong discriminatory power, for predicting the risk of II in patients with IGH.We conducted a retrospective bicentric study including 335 patients with IGH. Logistic regression analysis was used to identify independent predictive factors of II. We assigned points for the score according to the regression coefficient. The area under the curve (AUC) was determined using receiver operating characteristic (ROC) curves. The scoring system was then prospectively validated on a second independent population of 45 patients admitted for IGH in the same departments (internal validation).Four independent predictive factors of II were identified: heart rate, duration of symptoms before admission, prothrombin, and neutrophil-to-lymphocyte ratio (NLR). A predictive score of II was established based on these independent predictive factors. Sensitivity was 94.50%; specificity was 92.70%. The AUC of this score was 0.97. The AUC was 0.96 when the score was applied on the second population of patients.We performed a score to predict the risk of intestinal II with a good accuracy (the AUC of our score was 0.97). This score is reliable and reproducible, so it can help a surgeon to prioritize patients with II for surgery (especially at this time of COVID-19 pandemic), because ischemia could be reversible, avoiding thus intestinal necrosis.

The primary outcome was to assess the correlation between anxiety and pain, fatigue, nausea, and vomiting. The secondary outcome was to determine the predictive roles of pain, fatigue, nausea, and vomiting in anxiety among patients undergoing Hematopoietic Stem Cell Transplantation (HSCT). The present prospective cohort study was conducted on 200 patients treated by HSCT referred to the centers affiliated to Shiraz University of Medical Sciences. The data were collected using Spielberger Anxiety Questionnaire, Numerical Pain Scale, Brief Fatigue Inventory, and Rhodes Nausea and Vomiting Index. The data were analyzed using Spearman's test and multiple regression analysis. The means of state anxiety, trait anxiety, pain, fatigue, and nausea, vomiting, and retching were 41.67 (SD = 9.71), 43.78 (SD = 9.00), 3.79 (SD = 2.79), 4.23 (SD = 2.48), and 6.31 (SD = 7.53), respectively. The results showed that the participants with higher pain and fatigue scores had higher anxiety levels. Those with more nausea and vomiting had higher anxiety levels, as well. This indicated that fatigue, pain, severity and frequency of nausea, and type of HSCT were the predictors of trait anxiety. The results also showed the predictor role of pain, fatigue, and type of HSCT in state anxiety. The findings revealed a correlation between anxiety and pain, fatigue, nausea, and vomiting among the HSCT patients. The results also showed fatigue and pain as the predictors of anxiety among these patients. Yet, future studies are recommended to determine the other factors contributing to anxiety amongst HSCT patients.

To compare surgical, oncological and functional outcomes between obese vs. normal-weight prostate cancer (PCa) patients treated with robotic-assisted radical prostatectomy (RARP).We assessed 4555 consecutive RARP patients from a high-volume center 2008-2018. Analyses were restricted to normal-weight vs. obese patients (≥ 30 kg/mBefore matching, higher rates of pathological Gleason Grade group ≥ 4 (14 vs. 18%; p = 0.004) and pT3 stage (33 vs. 35%; p = 0.016) were observed in obese patients, with similar observations for surgery time, blood loss and 30-day wound- and surgical complication rates. For normal-weight vs. obese patients, BCR- and MP-free rates were 86 vs. 85% (p = 0.97) and 97.5 vs.97.8% (p = 0.8) at 48 months. Similarly, rates of erectile function at 36 months and urinary continence at 12 months were 56 vs. 49% (p = 0.012) and 88 vs. 85% (p = 0.003), respectively. Before and after propensity score matching, obesity had no effect on BCR or MP, but a negative effect on erectile function (matched HR 0.87, 95%CI 0.76-0.99; p = 0.029) and urinary continence recovery (matched HR 0.91, 95%CI 0.84-0.98; p = 0.014).Obesity did not represent a risk factor of BCR or MP after RARP despite higher rates of adverse pathological features. However, obesity was associated with higher risk of perioperative morbidity and impaired functional outcomes. Such information is integral for patient counselling. Thus, weight loss before RARP should be encouraged.

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion–positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion–positive cholangiocarcinoma. Significance: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion–positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171

In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology.

Ethanol has been demonstrated to exert profound effects upon cells and tissues via multiple mechanisms. One recently appreciated means by which cells can communicate with other cells is via the production and release of extracellular vesicles. Though smaller exosomes have been demonstrated to be released in response to ethanol exposure, the ability of ethanol to modulate the generation and release of larger microvesicle particles (MVP) is lesser studied. The present studies examined the ability of exogenous ethanol to generate MVP with a focus on skin cells. Acute ethanol exposure resulted in augmented MVP release in keratinocytes and in the skin and blood of mice. Unlike other stimuli such as ultraviolet B radiation or thermal burn injury, ethanol-mediated MVP release was independent of the Platelet-activating Factor receptor (PAFR). However, ethanol pretreatment was found to augment thermal burn injury-induced MVP in a PAFR-dependent manner. These studies provide a novel mechanism for ethanol-mediated effects, that could be relevant in the significant toxicity associated with thermal burn injury in the setting of alcohol intoxication.

Aims The aim of this study was to investigate the efficacy and safety of ticagrelor monotherapy in patients undergoing percutaneous coronary intervention (PCI) stratified according to the baseline white blood cell (WBC) count. Methods and results This is a post hoc analysis of the GLOBAL LEADERS trial, a multi-centre, open-label, randomized all-comer trial in patients undergoing PCI, comparing the experimental strategy (23-month ticagrelor monotherapy following 1-month dual anti-platelet therapy [DAPT]) with the reference strategy (12-month aspirin monotherapy following 12-month DAPT). Patients were stratified into two WBC groups, either < or ≥median WBC count of 7.8 × 109 cells/L (lower or higher WBC group, respectively). The primary endpoint was a composite of all-cause mortality or new Q-wave myocardial infarction at 2 years. Of 14 576 patients included in the present study, 7212 patients (49.5%) were classified as the lower WBC group, who had a significantly lower risk of both ischaemic and bleeding outcomes at 2 years. At 2 years, the experimental strategy was associated with a significant lower incidence of the primary endpoint compared with the reference strategy in the lower WBC group [2.8% vs. 4.2%; hazard ratio (HR): 0.67; 95% confidence interval (CI): 0.52–0.86] but not in the higher WBC group (4.8% vs. 4.7%; HR: 1.01; 95% CI: 0.82–1.25; Pinteraction=0.013). There were no significant differences in the risks of Bleeding Academic Research Consortium type 3 or 5 bleeding between two anti-platelet strategies regardless of the WBC groups. Conclusion Increased WBC counts, which may reflect degree of inflammation, at the time of index procedure may attenuate the anti-ischaemic benefits of ticagrelor monotherapy observed in patients with lower WBC counts.

OBJECTIVES Obesity may increase the risk of vascular complications in transfemoral (TF) transcatheter aortic valve replacement (TAVR) procedures. The transcarotid (TC) approach has recently emerged as an alternative access in TAVR. We sought to compare vascular complications and early clinical outcomes in obese patients undergoing TAVR either by TF or TC vascular access. METHODS Multicentre registry including obese patients undergoing TF- or TC-TAVR in 15 tertiary centres. All patients received newer-generation transcatheter heart valves. For patients exhibiting unfavourable ileo-femoral anatomic characteristics, the TC approach was favoured in 3 centres with experience with it. A propensity score analysis was performed for overcoming unbalanced baseline covariates. The primary end point was the occurrence of in-hospital vascular complications (Valve Academic Research Consortium-2 criteria). RESULTS A total of 539 patients were included, 454 (84.2%) and 85 (15.8%) had a TF and TC access, respectively. In the propensity-adjusted cohort (TF: 442 patients; TC: 85 patients), both baseline and procedural valve-related characteristics were well-balanced between groups. A significant decrease in vascular complications was observed in the TC group (3.5% vs 12% in the TF group, odds ratio: 0.26, 95% CI: 0.07–0.95, P = 0.037). There were no statistically significant differences between groups regarding in-hospital mortality (TC: 2.8%, TF: 1.5%), stroke (TC: 1.2%, TF: 0.4%) and life-threatening/major bleeding events (TC: 2.8%, TF: 3.8%). CONCLUSIONS In patients with obesity undergoing TAVR with newer-generation devices, the TC access was associated with a lower rate of vascular complications. Larger randomized studies are warranted to further assess the better approach for TAVR in obese patients.

Surgeons commonly repeat preoperative endoscopy before planned colorectal resections. The reasons for this are not entirely clear, and repeat endoscopy may lead to delays in curative resection, increased costs, and patient discomfort.This study aimed to determine practice patterns, localization techniques, and processes of communication undertaken by endoscopy specialists in a high-volume regional health authority.This was a qualitative study involving standardized, semi-structured, in-depth interviews that were conducted in person. Data were analyzed using a thematic analysis approach.The study was conducted at Canadian tertiary and community facilities.Ten general surgeons and 10 gastroenterologists were included using a convenience sampling technique.Interview questions were developed to understand the perspectives and practice patterns of endoscopists when approaching patients diagnosed with colorectal lesions requiring surgical resection. The decision-making process to perform a repeat preoperative endoscopy was assessed.Three key themes emerged: 1) patterns of communication, 2) feedback, and 3) trust. Thematic analysis revealed that poor communication and ambiguous documentation increased the likelihood of performing repeat preoperative endoscopy. Inconsistencies in tattooing practices and lesion location were important factors. Negative experiences and factors related to interprofessional trust emerged as key contributors to repeat preoperative endoscopy.The transferability of findings to health care systems outside Canada may be limited and requires further study.Suboptimal endoscopic reporting contributes to gaps in communication among endoscopists. In addition, lack of consistent feedback and mutual trust may increase the likelihood of performing repeat preoperative lower endoscopy. Inconsistent tattooing practices pose significant concerns for accurate intraoperative lesion localization. Establishing collaborative work environments through joint educational initiatives may enhance communication and mitigate unnecessary repeat procedures. These results support the need for standardized guidelines and endoscopic reporting in the management of colorectal lesions. See Video Abstract at http://links.lww.com/DCR/B879 .ANTECEDENTES:Los cirujanos suelen repetir la endoscopia preoperatoria antes de las resecciones colorrectales planificadas. Las razones de esto no están del todo claras y la repetición de la endoscopia puede provocar retrasos en la resección curativa, aumento de los costos y malestar del paciente.OBJETIVO:Nuestro objetivo fue determinar patrones de práctica, técnicas de localización y procesos de comunicación realizados por especialistas en endoscopia, en una autoridad sanitaria regional, de alto volumen.DISEÑO:Este fue un estudio cualitativo, que involucró entrevistas estandarizadas, semiestructuradas y en profundidad que se llevaron a cabo en persona. Los datos se analizaron mediante un enfoque de análisis temático.ENTORNO CLINICO:El estudio se llevó a cabo en instalaciones comunitarias y terciarias canadienses.PARTICIPANTES:Se incluyeron 10 cirujanos generales y 10 gastroenterólogos, utilizando una técnica de muestreo por conveniencia.PRINCIPALES MEDIDAS DE VALORACION:Las preguntas de la entrevista se desarrollaron para comprender las perspectivas y los patrones de práctica de los endoscopistas, cuando se acercan a pacientes diagnosticados con lesiones colorrectales que requieren resección quirúrgica. Se evaluó el proceso de toma de decisiones para realizar una nueva endoscopia preoperatoria.RESULTADOS:Surgieron tres temas clave: 1) patrones de comunicación, 2) retroalimentación y 3) confianza. El análisis temático reveló que la pobre comunicación y la ambigua documentación aumentaron la probabilidad de realizar una nueva endoscopia preoperatoria. Las inconsistencias en las prácticas de tatuaje y la ubicación de las lesiones fueron factores importantes. Las experiencias pasadas negativas y los factores relacionados con la confianza interprofesional surgieron como contribuyentes clave para repetir la endoscopia preoperatoria.LIMITACIONES:La transferibilidad de los hallazgos a los sistemas de atención médica fuera de Canadá, puede ser limitada y requiere más estudios.CONCLUSIONES:Los informes endoscópicos subóptimos contribuyen a las brechas en la comunicación entre los endoscopistas. Además, la falta de retroalimentación consistente y la confianza mutua pueden aumentar la probabilidad de realizar una nueva endoscopia baja preoperatoria. Las prácticas inconsistentes de tatuaje, plantean preocupaciones importantes para la localización precisa de las lesiones intraoperatorias. El establecimiento de entornos de trabajo colaborativo a través de iniciativas educativas conjuntas pueden mejorar la comunicación y mitigar la repetición de procedimientos innecesarios. Estos resultados apoyan la necesidad de pautas estandarizadas e informes endoscópicos en el tratamiento de las lesiones colorrectales. Consulte Video Resumen en http://links.lww.com/DCR/B879 . (Traducción-Dr. Fidel Ruiz Healy ).

Objective In a convenience sample of athletes, we conducted a survey of COVID-19-mediated lockdown (termed ‘lockdown’ from this point forward) effects on: (i) circadian rhythms; (ii) sleep; (iii) eating; and (iv) training behaviors. Methods In total, 3911 athletes [mean age: 25.1 (range 18–61) years, 1764 female (45%), 2427 team-sport (63%) and 1442 elite (37%) athletes] from 49 countries completed a multilingual cross-sectional survey including the Pittsburgh Sleep Quality Index and Insomnia Severity Index questionnaires, alongside bespoke questions about napping, training, and nutrition behaviors. Results Pittsburgh Sleep Quality Index (4.3 ± 2.4 to 5.8 ± 3.1) and Insomnia Severity Index (4.8 ± 4.7 to 7.2 ± 6.4) scores increased from pre- to during lockdown (p