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This systematic review aimed to assess the effects of upper gastrointestinal (UGI) dysmotility on outcomes of surgical treatment of colonic inertia (CI). This PRISMA-compliant systematic review and meta-analysis searched PubMed, Scopus, Google Scholar, and clinicaltrials.gov through October 2023 for studies that assessed outcomes of CI patients who underwent colectomy while putting data on UGI motility in context. The primary outcome was postoperative persistence or recurrence of constipation. Secondary outcomes were postoperative complications, continence, and quality of life (QoL) improvements. The revised tool to assess the risk of bias in nonrandomized studies of interventions was used to assess the risk of bias, and the certainty of evidence was graded using the GRADE approach. Eight studies (1991 to 2013) included data on UGI evaluation of CI patients; 12.8 to 24.3% were tested for concomitant GI dysmotility. High rates of motility abnormalities were in the small bowel (31.4%), stomach (34.1%), and esophagus (48.5%). Patients with UGI dysmotility and CI were more likely to experience constipation recurrence (OR: 10.71, 95% CI: 2.17; 52.87, P=0.004) and less likely to have postoperative QoL improvements (OR: 0.16, 95% CI: 0.04; 0.65, P=0.010) compared with patients with CI and no abnormal UGI testing. There were no differences in postoperative complications (OR: 1.59, 95% CI: 0.64; 4.267, P=0.542) or continence (OR: 0.29, 95% CI: 0.06; 1.47, P=0.0136) rates. Large subsets of CI patients with concomitant UGI dysmotility may be preoperatively underdiagnosed. UGI dysmotility may be associated with a higher risk of postoperative recurrence of constipation and suboptimal improvements in QoL. We recommend routine UGI evaluation before surgery for CI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective : This cross-sectional study evaluated whether preferences for attending mental health visits virtually or in-person vary by demographics and identified factors influencing these preferences among federally qualified health center (FQHC) patients. Methods : FQHC patients ( N = 350) completed a satisfaction survey of their mental health care experiences in 2022. Demographic data were obtained from the electronic health record. Fisher's Exact tests were used to determine whether modality preferences (phone, video, or in-person) varied across demographic factors. Open-ended comments were qualitatively evaluated using an inductive approach to identify themes related to modality preferences. Results : Modality preferences varied by age and language ( p 's <0.02) but not race and gender ( p 's >0.36). Reasons for modality preferences fell within six themes: (1) convenience, (2) connection, (3) transportation/accessibility, (4) health concerns, (5) caretaking responsibilities, and (6) technology. Conclusion : These findings clarify the reasons FQHC patients prefer telemental health care and identify gaps in its usage.

Background: Esophageal cancer remains a significant global health challenge. Several treatment modalities were explored in randomized controlled trials (RCTs) in recent decades. This study evaluates the robustness of RCTs focusing on esophageal cancer treatment using the fragility index (FI) and reverse fragility index (RFI)., Methods: A systematic review of RCTs studying different treatment modalities for esophageal cancer from 2000 to 2023 was conducted. The FI and RFI were utilized to gauge the robustness of statistically significant and non-significant outcomes, respectively. The FI represents the minimal number of patient outcomes that would need to alter to overturn a trial's statistical significance, while RFI indicates the minimal changes required to achieve significance in non-significant results., Results: Out of 4028 studies retrieved, 21 RCTs were included for final analysis. The studies spanned 2001 to 2023 with a mean followup of 66 months (range, 29-108 months) and median number of patients of 194 (range, 45-802). The most common treatment modalities examined in these studies were neoadjuvant chemoradiotherapy (n = 7, 33.3%), neoadjuvant chemotherapy (n = 4, 19.0%), and neoadjuvant immunotherapy (n = 2, 9.5%). Only 5 studies (23.8%) had a statistically significant primary outcome result with a median FI of 6 (IQR, 2.5-8.5). Non-significant primary outcomes were seen in 16 studies (76.2%) with a median RFI of 4 (IQR 1-11) and lost to followup of 0 (IQR 0-4). In the study with the highest FI (10), the FI was lower than the number of patients lost to followup (13)., Conclusion: Our findings demonstrate that most RCTs on esophageal cancer treatments did not report significant primary outcomes. The few studies that reported significant results had a low fragility index, suggesting a vulnerability in their findings., Competing Interests: Declarations. Disclosures: Drs. Noam Kahana, Elad Boaz, Nir Horesh, Sameh Hany Emile, Justin Dourado, Pauline Aeschbacher, Pete Rogers, Rachel Gefen, and Emanuele Lo Menzo have no conflicts of interest or financial ties to disclose. Dr. Raul Rosenthal receives speaker honoraria from Medtronics, serves on the Advisory Board and receives honoraria from Diagnostic Green; receives educational grants from Olympus, Stryker, Medtronic, Diagnostic Green, Arthrex, and Storz; is a shareholder in Medicad Simulation/Dendrite Imaging, and serves on the Advisory Board and as Interim CEO for Dendrite Imaging., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: To evaluate SPECT-CT in the diagnosis of single component aseptic loosening in patients with a problematic cemented stemmed TKR (Total Knee Replacement)., Methods: SPECT-CT was performed where aseptic loosening was suspected but was not clear on plain radiography. Demographics, suspected diagnosis and intention to revise were collected prospectively before and after SPECT-CT., Results: 30 patients were investigated. 43% (95% CI: 0.5-0.9) had clear evidence of loosening on SPECT-CT. In 23% (95% CI: 0.1-0.4) intention to perform revision surgery following SPECT-CT changed (7/30) (p = 0.0004, standard error = 42.1, z = 3.5). Intentions to perform revision surgery according to the radiologist's overall summary were: Normal SPECT-CT - 0% (95% CI: 0.0-0.8) intention to revise (0/2). Possibly abnormal SPECT-CT - 13% (95% CI: 0.0-0.4) intention to revise (2/15). Definitely abnormal SPECT-CT - 77% (95% CI: 0.5-0.9) intention to revise (10/13). We report that SPECT-CT had a test sensitivity of 90.9% (95% CI: 0.6-1.0), a specificity of 100% (95% CI: 0.9-1.0), a positive predictive value of 100% and a negative predictive value of 97.7%. In 70% (95% CI: 0.3-0.9) of cases where revision surgery was performed for aseptic loosening SPECT-CT provided information that guided pre-operative planning with regards single component or both component revision surgery (7/10)., Conclusion: When positive SPECT-CT was useful in determining single component revision. A normal SPECT-CT may have a negative predictive value; however, overall half of our series had a possibly abnormal or equivocal investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aim: Anastomotic stricture occurs in up to 30% of colorectal resections; however, evidence on risk factors and preventive measures remains scarce. This study aimed to identify technical factors responsible for increasing the risk for colorectal and coloanal anastomotic strictures., Method: This was a retrospective cohort study of patients with anastomotic stricture who underwent resection and/or redo anastomosis between January 1, 2011 and August 1, 2021 in a tertiary referral centre. Patients with anastomotic stricture were compared with an equal number of randomly selected patients without anastomotic complications, who were operated on during the same time period. The main outcome measures were technical risk factors of anastomotic stricture., Results: Each group included 50 patients who were similar for age, sex, American Society of Anesthesiologists score, distance of anastomosis to the dentate line and indication for surgery. Median follow-up was significantly longer in the non-stricture group (38.6 months vs. 12.6 months, p = 0.04). Splenic flexure mobilization [hazard ratio (HR) = 0.18 [2], 95% CI: 0.08-0.39, p < 0.001], high ligation of the inferior mesenteric artery (HR = 0.22, 95% CI: 0.09-0.5, p < 0.001) and high ligation of the inferior mesenteric vein (HR = 0.21, 95% CI: 0.09-0.50, p < 0.001) were associated with a lower likelihood of anastomotic stricture. Conversely, use of a 25-mm-diameter circular stapler (HR = 22.69, 95% CI: 2.69-191.10, p < 0.001), clinically significant anastomotic leak (HR = 3.94, 95% CI: 2.04-7.64, p < 0.001), firing the stapler more than once for rectal division (HR = 24.75, 95% CI: 6.85-89.38, p < 0.001) and diverting stoma (HR = 3.087, 95% CI: 1.736-5.491, p < 0.0001) were predictive of an anastomotic stricture., Conclusion: Failure to mobilize the splenic flexure and to perform high ligation of the inferior mesenteric vessels were associated with higher odds of anastomotic stricture. A small-diameter circular stapler and multiple distal stapler firings were also associated with anastomotic stricture. These data support routine splenic flexure ligation and high ligation of the inferior mesenteric vessels as well as avoidance of both multiple  stapler firings for rectal transection and a 25-mm circular stapler for anastomosis., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: A significant number of patients experience complications of the Kock pouch (KP) warranting revision or excision. This systematic review aimed to assess the pooled prevalence and risk factors for complications and failure of the KP., Methods: This Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review (CRD42023416961) searched PubMed, Scopus, and Web of Science for studies on adult patients with Kock continent ileostomy published after the year 2000. The main outcome measures were revision, complications, and failure of the KP. Risk factors for complications and failure were assessed using a meta-regression analysis. Risk of bias was assessed using the ROBINS-1 tool. A proportional meta-analysis of the main outcomes was performed., Results: A total of 19 studies (2042 patients) were included. The weighted mean prevalence of complications was 60.4% [95% confidence interval (CI): 46.1-74.7%], of pouch revision was 46.6% (95% CI: 38.5-54.7%), and of pouch failure was 12.9% (95% CI: 9.3-16.4%). Studies conducted in the USA had a mean failure prevalence of 12.6% (95% CI: 6.2-18.9%) comparable to studies conducted in Europe (11.1%; 95% CI: 7.5-14.7%). Factors associated with higher complications were increased body mass index (BMI) and previous ileoanal pouch anastomosis (IPAA); however, these factors were not associated with increased pouch failure., Conclusions: The KP is a highly complex operation as shown by a pooled complication prevalence of 60%, and thus, it should be only performed by experienced surgeons. Despite the high prevalence of complications and need for revisional surgery, patients are keen to preserve their KP. Increased BMI and a previous failed IPAA are risk factors for pouch complications, but not failure., (© 2024. The Author(s).)

Background: Surgical treatments of refractory gastroparesis include pyloromyotomy and gastric electrical stimulator (GES). It is unclear if patients may benefit from a combined approach with concomitant GES and pyloromyotomy., Methods: Retrospective cohort analysis of all patients with refractory gastroparesis treated with GES implantation with and without concomitant pyloromyotomy at Cleveland Clinic Florida from January 2003 to January 2023. Primary endpoint was efficacy (clinical response duration and success rate) and secondary endpoints included safety (postoperative morbidity) and length of stay. Success rate was defined as the absence of one of the following reinterventions during follow-up: Roux-en-Y gastric bypass (RYGB), pyloromyotomy, GES removal., Results: During a period of 20 years, 134 patients were treated with GES implantation. Three patients with history of previous surgical pyloromyotomy or RYGB were excluded from the analysis. Median follow-up was 31 months (IQR 10, 72). Forty patients (30.5%) had GES with pyloromyotomy, whereas 91 (69.5%) did not have pyloromyotomy. Most of the patients had idiopathic (n = 68, 51.9%) or diabetic (n = 58, 43.3%) gastroparesis. Except for preoperative use of opioids (47.5 vs 14.3%; p < 0.001), patient's characteristics were similar in both groups. There were no significant differences between the two groups in terms of overall postoperative complications (17.5% vs 14.3%; p = 0.610), major postoperative complications (0% vs 2.2%; p = 1), and length of stay (2(IQR 1, 2) vs 2(IQR 1, 3) days; p = 0.068). At 5 years, success rate was higher in patients with than without pyloromyotomy however not statistically significant (82% versus 62%, p = 0.066). Especially patients with diabetic gastroparesis seemed to benefit from pyloromyotomy during GES (100% versus 67%, p = 0.053). In an adjusted Cox regression, GES implantation without pyloromyotomy was associated with a 2.66 times higher risk of treatment failure compared to GES implantation with pyloromyotomy (HR 2.66, 95% CI 1.03-6.94, p = 0.044)., Conclusion: Pyloromyotomy during GES implantation for gastroparesis seems to be associated with a longer clinical response with similar postoperative morbidity and length of hospital stay than GES without pyloromyotomy. Patient with diabetic gastroparesis might benefit from a combination of GES implantation and pyloromyotomy., (© 2024. The Author(s).)

Background: This umbrella review aimed to summarize the findings and conclusions of published systematic reviews on the prophylactic role of mesh against parastomal hernias in colorectal surgery., Methods: PRISMA-compliant umbrella overview of systematic reviews on the role of mesh in prevention of parastomal hernias was conducted. PubMed and Scopus were searched through November 2023. Main outcomes were efficacy and safety of mesh. Efficacy was assessed by the rates of clinically and radiologically detected hernias and the need for surgical repair, while safety was assessed by the rates of overall complications., Results: 19 systematic reviews were assessed; 7 included only patients with end colostomy and 12 included patients with either ileostomy or colostomy. The use of mesh significantly reduced the risk of clinically detected parastomal hernias in all reviews except one. Seven reviews reported a significantly lower risk of radiologically detected parastomal hernias with the use of mesh. The pooled hazards ratio of clinically detected and radiologically detected parastomal hernias was 0.33 (95%CI: 0.26-0.41) and 0.55 (95%CI: 0.45-0.68), respectively. Six reviews reported a significant reduction in the need for surgical repair when a mesh was used whereas six reviews found a similar need for hernia repair. The pooled hazards ratio for surgical hernia repair was 0.46 (95%CI: 0.35-0.62). Eight reviews reported similar complications in the two groups. The pooled hazard ratio of complications was 0.81 (95%CI: 0.66-1)., Conclusions: The use of surgical mesh is likely effective and safe in the prevention of parastomal hernias without an increased risk of overall complications., (© 2024. The Author(s).)

Background: This study aimed to assess concordance between clinical and pathologic assessment of colon cancer., Patients and Methods: A retrospective cohort analysis of patients with stage I-III colon cancer in the National Cancer Database (2010-2019) was conducted. Concordance between clinical and pathologic assessment of colon cancer was calculated using Kappa coefficients and 95% confidence intervals (CIs)., Results: A total of 125,473 patients (51.2% female; mean age 68.2 years) were included. There was moderate concordance between clinical and pathologic T stage (Kappa = 0.606, 95%CI: 0.602-0.609) and between clinical and pathologic N stage (Kappa = 0.506, 95%CI: 0.501-0.511). For right-sided colon cancer, there was moderate agreement between clinical and pathologic T stage (Kappa = 0.594, 95%CI: 0.589-0.599) and N stage (Kappa = 0.530, 95%CI: 0.523-0.537). For left-sided colon cancer, there was substantial agreement between clinical and pathologic T stage (Kappa = 0.624, 95%CI: 0.619-0.630) and moderate agreement between N stage (Kappa 0.472, 95%CI: 0.463-0.480). Sensitivity of clinical assessment of T and N stage ranged from 64.3% to 77.2% and 41.6% to 54.5%, respectively. Specificity ranged from 96.7% to 97.7% for T stage and 95.7% to 97.3% for N stage., Conclusions: Clinical assessment of T and N stages of colon cancer had good diagnostic accuracy with moderate concordance with the final pathologic stage. While clinical assessment was highly specific with < 3% of patients being over-staged, it had modest sensitivity, especially for detection of nodal involvement. Diagnostic accuracy of clinical assessment of right and left colon cancers was similar, except for higher sensitivity and accuracy of assessment of nodal involvement in right than left colon cancers., (© 2024. The Author(s).)

Confirmatory factor analysis (CFA) is a fundamental method for evaluating the internal structural validity of measurement instruments. In most CFA applications, the measurement model serves as a means to an end rather than an end in itself. To select the appropriate model, prior validity evidence is crucial, and items are typically assessed on an ordinal scale, which has been used in the applied social sciences. However, textbooks on structural equation modeling (SEM) often overlook this specific case, focusing on applications estimable using maximum likelihood (ML) instead. Unfortunately, several popular commercial SEM software packages lack suitable solutions for handling this 'typical CFA', leading to confusion and suboptimal decision-making when conducting CFA in this context. This article conceptually contributes to this ongoing discussion by presenting a set of guidelines for conducting a typical CFA, drawing from recent empirical research. We provide a practical contribution by introducing and developing a tutorial example within the JASP and lavaan software platforms. Supplementary materials such as videos, files, and scripts are freely available., (© 2024. The Psychonomic Society, Inc.)

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that causes high fetal and neonatal mortality rates in ruminants and sometimes severe to fatal complications like encephalitis and hemorrhagic fever in humans. There is no licensed RVF vaccine for human use while approved livestock vaccines have suboptimal safety or efficacy. We designed self-amplifying RNA (saRNA) RVF vaccines and assessed their humoral immunogenicity in mice. Plasmid DNA encoding the Rift Valley fever virus (RVFV) medium (M) segment consensus sequence (WT consensus) and its derivatives mutated to enhance cell membrane expression of the viral surface glycoproteins n (Gn) and c (Gc) were assessed for in vitro expression. The WT consensus and best-expressing derivative (furin-T2A) were cloned into a Venezuelan equine encephalitis virus (VEEV) plasmid DNA replicon and in vitro transcribed into saRNA. The saRNA was formulated in lipid nanoparticles and its humoral immunogenicity in BALB/c mice was assessed. High quantities of dose-dependent RVFV Gn IgG antibodies were detected in the serum of all mice immunized with either WT consensus or furin-T2A saRNA RVF vaccines. Significant RVFV pseudovirus-neutralizing activity was induced in mice immunized with 1 µg or 10 µg of the WT consensus saRNA vaccine. The WT consensus saRNA RVF vaccine warrants further development.

Background: Robotic surgery is becoming increasingly popular in bariatric-metabolic surgery. However, its superiority regarding postoperative outcomes compared with conventional laparoscopy has not been clearly proven. With growing adoption of robotic surgery and improved technologies, benefits should become more evident., Objectives: Evaluate readmission and reoperation rates after bariatric-metabolic surgery performed by conventional laparoscopy versus robotic-assisted from 2015 to 2021., Setting: Academic institution., Methods: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) was reviewed for primary bariatric operations performed with conventional laparoscopy versus robotic-assisted. Postoperative outcomes were compared in a propensity score-matched sample., Results: Of 1,059,348 cases meeting inclusion criteria, 921,322 (87%) were conventional laparoscopic bariatric-metabolic surgeries, which were matched 1:1 with robotic-assisted cases (138,026). Reoperation (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.00-1.15, P = .0463), postoperative morbidity (OR 1.07; 95% CI 1.01-1.12, P = .0193), readmission (OR 1.14; 95% CI 1.09-1.18, P < .0001), and emergency department visits (OR 1.06; 95% CI 1.03-1.09, P = .0003) at 30 days postoperatively were significantly greater for robotic-assisted cases. Robotic-assisted cases had a similar mortality rate at 30 days postoperatively and length of stay >3 days when compared with conventional laparoscopic cases. Similar results were observed in cases from 2020 to 2021, except for reoperation and emergency department visits, which showed no difference between groups and length of stay >3 days, which was greater in robotic-assisted cases., Conclusions: Our results show a greater readmission and reoperation rate and greater morbidity at 30 days postoperatively in robotic-assisted bariatric-metabolic surgery compared with conventional laparoscopy. Analyzing only cases performed between 2020 and 2021, robotic surgery also does not show superiority over conventional laparoscopy., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Colon cancer pathological and clinical staging may be disoncordant. This study assessed patients with colon cancer in whom the nodal status was clinically understaged., Methods: Patients with stage I-III clinical node-negative colon cancer from the National Cancer Database were included. Regression analyses were conducted to elucidate risk factors for clinical nodal understaging and a scoring system was developed to identify high-risk patients., Results: The study included 94,945 patients with 78.4 ​% of patients correctly staged and 21.6 ​% clinically understaged. The predictors of nodal positivity in clinically understaged patients were age <65 (OR 1.43), left-sided tumors (OR 1.41), elevated CEA (OR 2.03), moderately (OR 1.81) or poorly/undifferentiated tumors (OR 3.76), T1 tumors (OR 1.29), signet-ring cell histology (OR 2.26), and microsatellite-stable tumors (OR 1.4)., Conclusion: Patients with colon cancer and the above factors are more likely to have their nodal status clinically understaged. A scoring system has been developed to identify high-risk patients., Competing Interests: Declaration of competing interest None of the authors has any relevant financial disclosures. Dr. Wexner is a consultant for Baxter, Becton, Dickinson and Co, Glaxo Smith Kline, Intuitive Surgical, Livsmed, Medtronic, OstomyCure, Stryker, Takeda, Virtual Ports, is a member of the Data Safety Monitoring Board of JSR/WCG/ACI (chair), Polypoid (chair), and Boomerang and receives royalties from Intuitive Surgical, Karl Storz Endoscopy America Inc., and Unique Surgical Solutions, LLC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We present an interesting case of a cystic, pituitary adenoma that showed up insidiously with non-traditional clinical symptoms. The standard of care for non-functioning pituitary adenomas is transsphenoidal surgery. However, with pharmacotherapy using cabergoline (a dopamine receptor agonist), the patient had a near disappearance of the tumor. This case report seeks to add to the medical literature the possibility of pharmacotherapy for treating non-functional pituitary adenomas., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rahman et al.)

This study presents a randomized controlled crossover experiment involving 73 patients with idiopathic bilateral Carpal Tunnel Syndrome (CTS). Patients received two combined physiotherapeutic treatments: myofascial mobilization (IASTM) and stretching. Participants were divided into two groups: one started with stretching followed by IASTM, and the other with IASTM followed by stretching. Of these, 43 underwent surgery and began physical therapy 30 days post-operation, while 30 received non-surgical treatment. The therapy sessions lasted four weeks, followed by a crossover of the treatment modalities and periodic reassessments up to six months. The dataset includes experimental design, patient demographics, diagnostic data, objective muscle strength tests, subjective sensitivity tests, clinical indicators, and self-reported measures. This data can be useful for researchers looking to replicate the study or compare outcomes between clinical and surgical CTS patients., (© 2024 The Authors.)

Objective: This national analysis aimed to calculate the diagnostic yield from gastroscopy for common symptoms, guiding improved resource utilisation., Design: A cross-sectional study was conducted of diagnostic gastroscopies between 1 March 2019 and 29 February 2020 using the UK National Endoscopy Database. Mixed-effect logistic regression models were used, incorporating random (endoscopist) and fixed (symptoms, age and sex) effects on two dependent variables (endoscopic cancer; Barrett's oesophagus (BO) diagnosis). Adjusted positive predictive values (aPPVs) were calculated., Results: 382 370 diagnostic gastroscopies were analysed; 30.4% were performed in patients aged <50 and 57.7% on female patients. The overall unadjusted PPV for cancer was 1.0% (males 1.7%; females 0.6%, p<0.01). Other major pathology was found in 9.1% of procedures, whereas 89.9% reported only normal findings or minor pathology (92.5% in females; 94.6% in patients <50).Highest cancer aPPVs were reached in the over 50s (1.3%), in those with dysphagia (3.0%) or weight loss plus another symptom (1.4%). Cancer aPPVs for all other symptoms were below 1%, and for those under 50, remained below 1% regardless of symptom. Overall, 73.7% of gastroscopies were carried out in patient groups where aPPV cancer was <1%.The overall unadjusted PPV for BO was 4.1% (males 6.1%; females 2.7%, p<0.01). The aPPV for BO for reflux was 5.8% and ranged from 3.2% to 4.0% for other symptoms., Conclusions: Cancer yield was highest in elderly male patients, and those over 50 with dysphagia. Three-quarters of all gastroscopies were performed on patients whose cancer risk was <1%, suggesting inefficient resource utilisation., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ http://www.icmje.org/disclosure-of-interest/. LS has unrestricted project grants from 3D-Matrix and Medtronic. TR is deputy editor at Gut journal. All other authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obesity and its associated lifestyle are known risk factors for early-onset colorectal cancer and are associated with poor postoperative and survival outcomes in older patients. We aimed to investigate the impact of obesity on the outcomes of early-onset colorectal cancers., Methods: Retrospective review of all patients undergoing primary resection of colon or rectal adenocarcinoma at our institution between 2015-2022. Patients who had palliative resections, resections performed at another institution, appendiceal tumors, and were underweight were excluded. The primary endpoint was survival according to the patient's body mass index: normal weight (18-24.9 kg/m 2 ), overweight (25-29.9 kg/m 2 ), and obesity (≥30 kg/m 2 ). Patient and tumor characteristics and survival were compared between the three groups., Results: A total of 279 patients aged <50 years with colorectal cancer were treated at our hospital; 120 were excluded from the analysis for the following reasons: main treatment or primary resection performed at another hospital (n = 97), no resection/palliative resection (n = 23), or body mass index <18 kg/m 2 (n = 2). Of these, 157 patients were included in the analysis; 61 (38.9%) were overweight and 45 (28.7%) had obesity. Except for a higher frequency of hypertension in the overweight (P = .062) and obese (P = .001) groups, no differences in patient or tumor characteristics were observed. Mean overall survival was 89 months with normal weight, 92 months with overweight, and 65 months with obesity (P = .032). Mean cancer-specific survival was 95 months with normal weight, 94 months with overweight, and 68 months with obesity (P = .018). No statistically significant difference in disease-free survival (75 vs 70 vs 59 months, P = .844) was seen., Conclusion: Individuals with early-onset colorectal cancer who are overweight or obese present with similar tumor characteristics and postoperative morbidity to patients with normal weight. However, obesity may have a detrimental impact on their survival. Addressing obesity as a modifiable risk factor might improve early-onset colorectal cancer prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Minimally invasive surgery is safe and effective in colorectal cancer. Conversion to open surgery may be associated with adverse effects on treatment outcomes. This study aimed to assess risk factors of conversion from minimally invasive to open colectomy for colon cancer and impact of conversion on short-term and survival outcomes. This case-control study included colon cancer patients undergoing minimally invasive colectomy from the National Cancer Database (2015-2019). Logistic regression analyses were conducted to determine independent predictors of conversion from laparoscopic and robotic colectomy to open surgery. 26,546 patients (mean age: 66.9 ± 13.1 years) were included. Laparoscopic and robotic colectomies were performed in 79.1% and 20.9% of patients, respectively, with a 10.6% conversion rate. Independent predictors of conversion were male sex (OR: 1.19, p = 0.014), left-sided cancer (OR: 1.35, p < 0.001), tumor size (OR: 1, p = 0.047), stage II (OR: 1.25, p = 0.007) and stage III (OR: 1.47, p < 0.001) disease, undifferentiated carcinomas (OR: 1.93, p = 0.002), subtotal (OR: 1.25, p = 0.011) and total (OR: 2.06, p < 0.001) colectomy, resection of contiguous organs (OR: 1.9, p < 0.001), and robotic colectomy (OR: 0.501, p < 0.001). Conversion was associated with higher 30- and 90-day mortality and unplanned readmission, longer hospital stay, and shorter overall survival (59.8 vs 65.3 months, p < 0.001). Male patients, patients with bulky, high-grade, advanced-stage, and left-sided colon cancers, and patients undergoing extended resections are at increased risk of conversion from minimally invasive to open colectomy. The robotic platform was associated with reduced odds of conversion. However, surgeons' technical skills and criteria for conversion could not be assessed., (© 2024. The Author(s).)

Study Objective: There is limited research examining the sexual and reproductive health (SRH) care needs and experiences of Black adolescents who are assigned female at birth (AFAB). This study aimed to understand the perspectives of Black AFAB adolescents in their receipt of SRH counseling in primary care and elicit preferences for SRH-related communication with clinicians., Methods: We interviewed English-speaking Black AFAB adolescents, ages 13-17, living in North Carolina between February and June 2022 about their SRH care experiences. The interviews were conducted via video conferencing, audio-recorded, professionally transcribed, and analyzed using a thematic approach., Results: We interviewed 23 adolescents (mean age 15.8 years) across 10 geographically diverse counties in North Carolina. Most conveyed positive perceptions of clinicians regarding trust and comfort. However, many expressed concerns about clinicians not doing enough to ensure patient confidentiality, provide them with enough information to make informed and autonomous decisions, and destigmatize discussing SRH issues during the clinical encounter. Suggested improvements include sociodemographic congruence between patients and clinicians (eg, younger Black women), ensuring time alone with clinicians across adolescence, and proactively sharing information to promote respect and autonomy., Conclusion: Although Black AFAB adolescents had positive perceptions of their health care providers regarding relational components of care, many participants shared significant gaps and areas for improvement in the quality of care received to better align services with their preferences for SRH care. These findings can inform the development of SRH counseling best practices and clinician education to support respect and autonomy, which are routinely denied to Black AFAB adolescents., Competing Interests: Conflicts of Interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Available platforms for local excision (LE) of early rectal cancer are rigid or flexible [trans‑anal minimally invasive surgery (TAMIS)]. We systematically searched the literature to compare outcomes between platforms., Methods: PRISMA-compliant search of PubMed and Scopus databases until September 2022 was undertaken in this random-effect meta-analysis. Statistical heterogeneity was assessed using I 2 statistic. Studies comparing TAMIS versus rigid platforms for LE for early rectal cancer were included. Main outcome measures were intraoperative and short-term postoperative outcomes and specimen quality., Results: 7 studies were published between 2015 and 2022, including 931 patients (423 females); 402 underwent TAMIS and 529 underwent LE with rigid platforms. Techniques were similar for operative time (WMD 11.1, 95%CI - 2.6 to 25, p = 0.11), percentage of defect closure (OR 0.7, 95%CI 0.06-8.22, p = 0.78), and peritoneal violation (OR 0.41, 95%CI 0.12-1.43, p = 0.16). Rigid platforms had higher rates of short-term complications (19.1% vs 14.2, OR 1.6, 95%CI 1.07-2.4, p = 0.02), although no significant differences were seen for major complications (OR 1.41, 95%CI 0.61-3.23, p = 0.41). Patients in the rigid platforms group were 3-times more likely to be re-admitted within 30 days compared to the TAMIS group (OR 3.1, 95%CI 1.07-9.4, p = 0.03). Rates of positive resection margins (rigid platforms: 7.6% vs TAMIS: 9.34%, OR 0.81, 95%CI 0.42-1.55, p = 0.53) and specimen fragmentation (rigid platforms: 3.3% vs TAMIS: 4.4%, OR 0.74, 95%CI 0.33-1.64, p = 0.46) were similar between the groups. Salvage surgery was required in 5.5% of rigid platform patients and 6.2% of TAMIS patients (OR 0.8, 95%CI 0.4-1.8, p = 0.7)., Conclusion: TAMIS or rigid platforms for LE seem to have similar operative outcomes and specimen quality. The TAMIS group demonstrated lower readmission and overall complication rates but did not significantly differ for major complications. The choice of platform should be based on availability, cost, and surgeon's preference., (© 2024. The Author(s).)

The adaptation of gene deletion methods based on the CRISPR-Cas9 system has facilitated the genetic manipulation of the pathogenic yeast Candida albicans , because homozygous mutants of this diploid fungus can now be generated in a single step, allowing the rapid screening of candidate genes for their involvement in a phenotype of interest. However, the Cas9-mediated double-strand breaks at the target site may result in an undesired loss of heterozygosity (LOH) on the affected chromosome and cause phenotypic alterations that are not related to the function of the investigated gene. In our present study, we harnessed Cas9-facilitated gene deletion to probe a set of genes that are constitutively overexpressed in strains containing hyperactive forms of the transcription factor Mrr1 for a possible contribution to the fluconazole resistance of such strains. To this aim, we used gene deletion cassettes containing two different dominant selection markers, caSAT1 and HygB , which confer resistance to nourseothricin and hygromycin, respectively, for simultaneous genomic integration in a single step, hypothesizing that this would minimize undesired LOH events at the target locus. We found that selection for resistance to both nourseothricin and hygromycin strongly increased the proportion of homozygous deletion mutants among the transformants compared with selection on media containing only one of the antibiotics, but it did not avoid undesired LOH events. Our results demonstrate that LOH on the target chromosome is a significant problem when using Cas9 for the generation of C. albicans gene deletion mutants, which demands a thorough examination of recombination events at the target site., Importance: Candida albicans is one of the medically most important fungi and a model organism to study fungal pathogenicity. Investigating gene function in this diploid yeast has been facilitated by the adaptation of gene deletion methods based on the bacterial CRISPR-Cas9 system, because they enable the generation of homozygous mutants in a single step. We found that, in addition to increasing the efficiency of gene replacement by selection markers, the Cas9-mediated double-strand breaks also result in frequent loss of heterozygosity on the same chromosome, even when two different selection markers were independently integrated into the two alleles of the target gene. Since loss of heterozygosity for other genes can result in phenotypic alterations that are not caused by the absence of the target gene, these findings show that it is important to thoroughly analyze recombination events at the target locus when using Cas9 to generate gene deletion mutants in C. albicans ., Competing Interests: The authors declare no conflict of interest.

Zinc cluster transcription factors (ZCFs) are a family of transcription regulators that are almost exclusively found in the fungal kingdom. Activating mutations in the ZCFs Mrr1, Tac1, and Upc2 frequently cause acquired resistance to the widely used antifungal drug fluconazole in the pathogenic yeast Candida albicans . Similar to a hyperactive Tac1, a constitutively active form of the ZCF Znc1 causes increased fluconazole resistance by upregulating the multidrug efflux pump-encoding gene CDR1 . Hyperactive forms of both Tac1 and Znc1 also cause overexpression of RTA3 , which encodes a seven-transmembrane receptor protein involved in the regulation of asymmetric lipid distribution in the plasma membrane. RTA3 expression is also upregulated by miltefosine, an antiparasitic drug that is active against fungal pathogens and considered for treatment of invasive candidiasis, and rta3 Δ mutants are hypersensitive to miltefosine. We found that activated forms of both Tac1 and Znc1 confer increased miltefosine resistance, which was dependent on RTA3 whereas CDR1 was dispensable. Intriguingly, the induction of RTA3 expression by miltefosine depended on Znc1, but not Tac1, in contrast to the known Tac1-dependent RTA3 upregulation by fluphenazine. In line with this observation, znc1 Δ mutants were hypersensitive to miltefosine, whereas tac1 Δ mutants showed wild-type tolerance. Forced expression of RTA3 reverted the hypersensitivity of znc1 Δ mutants, demonstrating that the hypersensitivity was caused by the inability of the mutants to upregulate RTA3 in response to the drug. These findings establish Znc1 as a key regulator of miltefosine-induced RTA3 expression that is important for wild-type miltefosine tolerance., Importance: Transcription factors are central regulators of gene expression, and knowledge about which transcription factor regulates specific genes in response to a certain signal is important to understand the behavior of organisms. In the pathogenic yeast Candida albicans , the RTA3 gene is required for wild-type tolerance of miltefosine, an antiparasitic drug that is considered for treatment of invasive candidiasis. Activated forms of the transcription factors Tac1 and Znc1 cause constitutive overexpression of RTA3 and thereby increased miltefosine resistance, but only Tac1 mediates upregulation of RTA3 in response to the known inducer fluphenazine. RTA3 expression is also induced by miltefosine, and we found that this response depends on Znc1, whereas Tac1 is dispensable. Consequently, znc1 Δ mutants were hypersensitive to miltefosine, whereas tac1 Δ mutants showed wild-type tolerance. These findings demonstrate that Znc1 is the key regulator of RTA3 expression in response to miltefosine that is important for wild-type miltefosine tolerance., Competing Interests: The authors declare no conflict of interest.

Background: We aimed to assess the efficacy and safety of low-pressure pneumoperitoneum (LPP) in minimally invasive colorectal surgery., Methods: A PRISMA-compliant systematic review/meta-analysis was conducted, searching PubMed, Scopus, Google Scholar, and clinicaltrials.gov for randomized-controlled trials assessing outcomes of LPP vs standard-pressure pneumoperitoneum (SPP) in colorectal surgery. Efficacy outcomes [pain score in post-anesthesia care unit (PACU), pain score postoperative day 1 (POD1), operative time, and hospital stay] and safety outcomes (blood loss and postoperative complications) were analyzed. Risk of bias2 tool assessed bias risk. The certainty of evidence was graded using GRADE., Results: Four studies included 537 patients (male 59.8%). LPP was undertaken in 280 (52.1%) patients and associated with lower pain scores in PACU [weighted mean difference: -1.06, 95% confidence interval (CI): -1.65 to -0.47, P  =   0.004, I 2   =   0%] and POD1 (weighted mean difference: -0.49, 95% CI: -0.91 to -0.07, P  =   0.024, I 2   =   0%). Meta-regression showed that age [standard error (SE): 0.036, P  <   0.001], male sex (SE: 0.006, P  <   0.001), and operative time (SE: 0.002, P  =   0.027) were significantly associated with increased complications with LPP. In addition, 5.9%-14.5% of surgeons using LLP requested pressure increases to equal the SPP group. The grade of evidence was high for pain score in PACU and on POD1 postoperative complications and major complications, and blood loss, moderate for operative time, low for intraoperative complications, and very low for length of stay., Conclusions: LPP was associated with lower pain scores in PACU and on POD1 with similar operative times, length of stay, and safety profile compared with SPP in colorectal surgery. Although LPP was not associated with increased complications, older patients, males, patients undergoing laparoscopic surgery, and those with longer operative times may be at risk of increased complications., Competing Interests: S.D.W. reports receiving consulting fees from Baxter, Becton, Dickinson and Co, Glaxo Smith Kline, Intuitive Surgical, Livsmed, Medtronic, OstomyCure, Stryker, Takeda, Virtual Ports, is a member of the Data Safety Monitoring Board of JSR/WCG/ACI (chair), Polypoid (chair), and Boomerang and receives royalties from Intuitive Surgical, Karl Storz Endoscopy America Inc., and Unique Surgical Solutions, LLC., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Background: Ureteric injury (UI) is an infrequent but serious complication of colorectal surgery. Prophylactic ureteric stenting is employed to avoid UI, yet its efficacy remains debated. Intraoperative indocyanine green fluorescence imaging (ICG-FI) has been used to facilitate ureter detection. This study aimed to investigate the role of ICG-FI in identification of ureters during colorectal surgery and its impact on the incidence of UI., Methods: A retrospective cohort study involving 556 consecutive patients who underwent colorectal surgery between 2018 and 2023 assessed the utility of routine prophylactic ureteric stenting with adjunctive ICG-FI. Patients with ICG-FI were compared to those without ICG-FI. Demographic data, operative details, and postoperative morbidity were analyzed. Statistical analysis included univariable regression., Results: Ureteric ICG-FI was used in 312 (56.1%) patients, whereas 43.9% were controls. Both groups were comparable in terms of demographics except for a higher prevalence of prior abdominal surgeries in the ICG-FI group. Although intraoperative visualization was significantly higher in the ICG-FI group (95.3% vs 89.1%; p = 0.011), the incidence of UI was similar between groups (0.3% vs 0.8%; p = 0.585). Postoperative complications were similar between the two groups. Median stent insertion time was longer in the ICG-FI group (32 vs 25 min; p = 0.001)., Conclusion: Ureteric ICG-FI improved intraoperative visualization of the ureters but was not associated with a reduced UI rate. Median stent insertion time increased with use of ureteric ICG-FI, but total operative time did not. Despite its limitations, this study is the largest of its kind suggesting that ureteric ICG-FI may be a valuable adjunct to facilitate  ureteric visualization during colorectal surgery., (© 2024. The Author(s).)

Aim: Splenic flexure mobilization (SFM) is commonly performed during left-sided colon and rectal resections. The aim of the present systematic review was to assess the outcomes of SFM in left-sided colon and rectal resections and the risk factors for complications and anastomotic leak (AL)., Method: This study was a PRISMA-compliant systematic review. PubMed, Scopus and Web of Science were searched for studies that assessed the outcomes of sigmoid and rectal resections with or without SFM. The primary outcomes were AL and total complications, and the secondary outcomes were individual complications, operating time, conversion to open surgery, length of hospital stay (LOS) and pathological and oncological outcomes., Results: Nineteen studies including data on 81 116 patients (49.1% male) were reviewed. SFM was undertaken in 40.7% of patients. SFM was associated with a longer operating time (weighted mean difference 24.50, 95% CI 14.47-34.52, p < 0.0001) and higher odds of AL (OR 1.19, 95% CI 1.06-1.33, p = 0.002). Both groups had similar odds of total complications, splenic injury, anastomotic stricture, conversion to open surgery, (LOS), local recurrence, and overall survival. A secondary analysis of rectal cancer cases only showed similar outcomes for SFM and the control group., Conclusions: SFM was associated with a longer operating time and higher odds of AL, yet a similar likelihood of total complications, splenic injury, anastomotic stricture, conversion to open surgery, LOS, local recurrence, and overall survival. These conclusions must be cautiously interpreted considering the numerous study limitations. SFM may have only been selectively undertaken in cases in which anastomotic tension was suspected. Therefore, the suboptimal anastomoses may have been the reason for SFM rather than the SFM being causative of the anastomotic insufficiencies., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Purpose: In 2005, the Food and Drug Administration (FDA) issued a decision memorandum regarding nonsteroidal anti-inflammatory drugs (NSAIDs). The memorandum recommended the withdrawal of certain NSAIDs due to potential cardiovascular adverse effects. It highlighted the issue of cardiovascular risk associated with NSAIDs as a class. The NSAID medication guide includes a wide range of adverse drug reactions (ADRs), such as increased blood pressure, liver failure, allergic reactions, heart attack, and intestinal bleeding. Although both sexes have an increased risk of ADRs with NSAID use, females have a greater risk than males due to differences in pharmacodynamics and higher medication concentrations (mg/kg). In particular, females with high blood pressure, coronary heart, kidney, and liver disease are at an additional risk of harm from NSAID ADRs. This study quantifies sex-specific differences and other factors associated with prescription NSAID use. Method: The data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES), a complex survey conducted by the Centers for Disease Control and Prevention (CDC) in two-year cycles. A survey-weighted logistic regression model was utilized to investigate potential sex differences with prescription NSAIDs in the context of other factors, including kidney disease, hypertension, liver disease, insurance status, coronary heart disease, and age, within the 2011-2018 NHANES survey data. Results: Females reported a slightly higher percentage of high blood pressure and kidney disease than males, while males reported a slightly higher percentage of coronary heart and liver disease than females. Last, the model indicated that females were 58% more likely to have used a prescription NSAID than males. Conclusion: The results confirm that women and people with medical conditions, who would potentially suffer greater harm from NSAID ADRs, are more likely to use a prescription NSAID than individuals without these conditions.

We used whole-genome sequencing to analyze a collection of 35 fluconazole-resistant and 7 susceptible Candida parapsilosis isolates together with coverage analysis and GWAS techniques to identify new mechanisms of fluconazole resistance. Phylogenetic analysis shows that although the collection is diverse, two persistent clinical lineages were identified. We identified copy number variation (CNV) of two genes, ERG11 and CDR1B , in resistant isolates. Two strains have a CNV at the ERG11 locus; the entire ORF is amplified in one, and only the promoter region is amplified in the other. We show that the annotated telomeric gene CDR1B is actually an artifactual in silico fusion of two highly similar neighboring CDR genes due to an assembly error in the C. parapsilosis CDC317 reference genome. We report highly variable copy numbers of the CDR1B region across the collection. Several strains have increased the expansion of the two genes into a tandem array of new chimeric genes. Other strains have experienced a deletion between the two genes creating a single gene with a reciprocal chimerism. We find translocations, duplications, and gene conversion across the CDR gene family in the C. parapsilosis species complex, showing that it is a highly dynamic family., Competing Interests: The authors declare no conflict of interest.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The purpose of this study was to examine the factors associated with vision impairment (VI), age-related eye disease (ARED), and frequency of eye examinations among older adults., Methods: A cross-sectional study (N = 166) was designed to identify barriers in vision and eye care services among adults 50 years and older in four counties in Appalachian Tennessee. Surveys were administered in March 2023. Simple and multiple logistic regression analyses were used to determine the risk factors of VI and ARED and the frequency of eye examinations., Results: In two out of the three regression models, predictors such as traveling >10 mi to an eye care provider, barriers to eye care, and a lack of exposure to eye health information emerged as significant factors. Individuals who traveled >10 mi to an eye care provider were more than twice as likely than individuals who traveled shorter distances to have VI and not maintain routine eye care (adjusted odds ratio [AOR] 2.69, 95% confidence interval [CI] 1.08-6.75; AOR 2.82, 95% CI 1.05-7.55, respectively). Reporting barriers to eye care doubled the odds of ARED (AOR 2.33, 95% CI 1.02-5.34) and substantially increased the odds of reporting a 3-year or longer interval since the last eye examination (AOR 7.45, 95% CI 1.85-29.96) compared with having no barriers to eye care. Moreover, limited exposure to eye health information tripled the odds of VI (AOR 3.26, 95% CI 1.15-9.24) and not maintaining routine eye care (AOR 3.07, 95% CI 0.97-9.70) compared with more exposure to eye health information. Other predictors also were uncovered in the analysis., Conclusions: This study contributes to the scarce literature on risk factors associated with vision health among older adults in Appalachia.

Background: The value of lower gastrointestinal endoscopy (LGIE; colonoscopy or sigmoidoscopy) relates to its ability to detect clinically relevant findings, predominantly cancers, preneoplastic polyps or inflammatory bowel disease. There are concerns that many LGIEs are performed on low-risk patients with limited benefit., Aims: To determine the diagnostic outcomes of LGIE for common symptoms., Methods: We performed a cross-sectional study of diagnostic LGIE between March 2019 and February 2020 using the UK National Endoscopy Database. We used mixed-effects logistic regression models, incorporating random (endoscopist) and fixed (symptoms, patient age, and sex) effects upon two dependent variables (large polyp [≥10 mm] and cancer diagnosis). Adjusted positive predictive values (aPPVs) were calculated., Results: We analysed 384,510 LGIEs; 33.2% were performed on patients aged under 50 and 53.6% on women. Regarding colonoscopies, the unadjusted PPV for cancer was 1.5% (95% CI: 1.4-1.5); higher for men than women (1.9% vs. 1.1%, p < 0.01). The PPV for large polyps was 3.2% (95% CI: 3.1-3.2). The highest colonoscopy cancer aPPVs were in the over 50s (1.9%) and in those with rectal bleeding (2.5%) or anaemia (2.1%). Cancer aPPVs for other symptoms were <1% despite representing 54.3% of activity. In patients under 50, aPPVs were 0.4% for cancer and 1.6% for large polyps. Results were similar for sigmoidoscopy., Conclusions: Most colonoscopies were performed on patients with low-risk symptoms, where cancer risk was similar to the general population. Cancer and large polyp yield was highest in elderly patients with rectal bleeding or anaemia, although still fell short of FIT-based screening yields., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target., (© 2024. The Author(s).)

We present an insightful case of a middle-aged male who presented to the emergency department (ED) with complaints of excessive weight loss, accompanied by shortness of breath and vomiting. Consequently, this case explores many facets of the pathophysiology of infective endocarditis (IE), including but not limited to the most heavily implicated microorganisms, symptoms, predispositions, and disease outcomes. IE is a pathology of variable presentation with uniquely extensive diagnostic criteria, making it a fascinating topic of medical discussion., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Rahman et al.)

Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance., (© 2024. The Author(s).)

Aim: Colostomy complication rates range widely from 10% to 70%. The psychological burden on patients, leading to lifestyle changes and decreased quality of life (QoL), is one of the largest factors. The aim of this work was to assess the history and efficacy of ostomy continence devices in improving continence and QoL., Method: In this PRISMA-compliant systematic review and meta-analysis, we searched PubMed, Scopus, Google Scholar and clinicaltrials.gov for studies on continence devices for all ostomies up to April 2023. Primary outcomes were continence and improvement in QoL. Secondary outcomes were leakage, patient's device preference and complications. Risk of Bias 2 and the revised tool to assess risk of bias in non-randomized studies of interventions (ROBINS-1) were used to assess risk of bias. Certainty of evidence was graded using GRADE., Results: Twenty-two studies assessed devices from 1978 to 2022. The two main types identified were ball-valve devices and plug systems. Conseal and Vitala were the two main devices with significant evidence allowing for pooled analyses. Conseal, the only currently marketed device, had a pooled rate of continence of 67.4%, QoL improvement was 74.9%, patient preference over a traditional appliance was 69.1%, leakage was 10.1% and complications was 13.7%. Since 2011, five studies have investigated experimental devices on both human and animal models., Conclusion: Ostomy continence has been a long-standing goal without a consistently reliable solution. We propose that selective and short-term usage of continence devices may lead to improved continence and QoL in ostomy patients. Further research is needed to develop a reliable daily device for ostomy continence. Future investigation should include the needs of ileostomates., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

The growing application of silver nanoparticles (AgNPs) in consumer, healthcare, and industrial products has raised concern over potential health implications due to increasing exposure. The evaluation of the immune response to nanomaterials is one of the key criteria to assess their biocompatibility. There are well-recognized sex-based differences in innate and adaptive immune responses. However, there is limited information available using human models. The aim was to investigate the potential sex-based differences in immune functions after exposure to AgNPs using human peripheral blood mononuclear cells (PBMCs) and plasma from healthy donors. These functions include inflammasome activation, cytokine expression, leukocyte proliferation, chemotaxis, plasma coagulation, and complement activation. AgNPs were characterized by dynamic light scattering and transmission electron microscopy. Inflammasome activation by AgNPs was measured after 6- and 24-hours incubations. AgNPs-induced inflammasome activation was significantly higher in the females, especially for the 6-hour exposure. No sex-based differences were observed for Ag ions controls. Younger donors exhibited significantly more inflammasome activation than older donors after 24-hours exposure. IL-10 was significantly suppressed in males and females after exposure. AgNPs suppressed leukocyte proliferation similarly in males and females. No chemoattractant effects, no alterations in plasma coagulation, or activation of the complement were observed after AgNPs exposure. In conclusion, the results highlight that there are distinct sex-based differences in inflammasome activation after exposure to AgNPs in human PBMCs. The results highlight the importance of considering sex-based differences in inflammasome activation induced by exposure to AgNPs in any future biocompatibility assessment for products containing AgNPs.

Objectives: At the time of the survey, just over 2000 pharmacists were employed in UK general practice. Little is known about their influence on prescribing, and more specifically, the extent of their use of Audit and Feedback (A&F), an evidence-based method for behaviour change. This study aimed to explore pharmacists' current influence on prescribing in UK general practice., Methods: A cross-sectional, online survey was open to general practice pharmacists in England, Northern Ireland, Scotland, and Wales between 9 September 2021 and 31 October 2021. The survey comprised 36 items, informed by the literature, including multiple choice and free-text questions about pharmacist responsibilities, involvement in prescribing audits (including use of A&F), use of prescribing guidelines, beliefs about influence on prescribing, and access to training and support. Descriptive statistics and frequencies were generated, and parametric analyses were conducted., Key Findings: In total, 155 responses were received from pharmacists in diverse practice locations, with a wide range of practice pharmacist experience. The majority (80%, n = 121) conducted prescribing audits, but only 21% (n = 32) reported undertaking A&F. Most respondents (90%, n = 140) used guidelines to inform their work, and 75% (n = 116) would welcome training on influencing prescribing. Pharmacists using A&F were more likely to believe in their ability to influence prescribing and to acknowledge this activity as part of their role., Conclusion: Despite substantial evidence of its effectiveness, A&F is under-used by practice pharmacists. An increased awareness and enablement of practice pharmacists in effective techniques might promote greater evidence-based prescribing in general practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Background: Transanal dissection is increasingly used in laparoscopic surgery for total mesorectal excision of lower rectal cancers. Several studies compared outcomes of laparoscopic total mesorectal excision with and without transanal dissection, yet there is a paucity of high-quality evidence. This meta-analysis aimed to provide a pooled comparative analysis of outcomes of laparoscopic total mesorectal excision with and without transanal dissection based on evidence from randomized controlled trials., Methods: This Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2022-compliant systematic review of randomized controlled trials compared laparoscopic total mesorectal excision with and without transanal dissection. PubMed, Scopus, and Web of Science were searched through March 2023. The Medical Subject Headings terms used in the search were Rectal neoplasms, Proctectomy, Laparoscopy, and Transanal. The main outcomes included operative and pathologic outcomes. The risk of bias was assessed using the Risk of Bias version 2 tool, and certainty of the evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. The primary study outcome was conversion to open surgery., Results: Four randomized controlled trials (1,339 patients; median age 61.2 years) were included; 671 patients underwent laparoscopic total mesorectal excision with transanal dissection, and 668 underwent laparoscopic total mesorectal excision without transanal dissection. Both groups were similar in age, body mass index, and disease stage, but the laparoscopic total mesorectal excision with transanal dissection group had a higher male-to-female ratio, received neoadjuvant therapy and had a hand-sewn anastomosis more often. Patients who underwent laparoscopic total mesorectal excision with transanal dissection had lower conversion rates (odds ratio = 0.179; P = .001), a higher likelihood of achieving complete total mesorectal excision (odds ratio = 1.435; P = .025), and fewer harvested lymph nodes (weighted mean difference = -1.926; P = .035). The groups had similar operative times (weighted mean difference = -3.476; P = .398), total complications (odds ratio = 0.94; P = .665), major complications (odds ratio = 1.112; P = .66), anastomotic leak (odds ratio = 0.67; P = .432), positive circumferential resection margin (odds ratio = 0.549; P = .155), and positive distal margins (odds ratio = 0.559; P = .171)., Conclusion: Laparoscopic total mesorectal excision with transanal dissection was associated with lower odds of conversion to open surgery, greater likelihood of achieving complete total mesorectal excision, and fewer harvested lymph nodes than laparoscopic total mesorectal excision without transanal dissection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Numerous studies have been conducted on the US Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database to assess post-marketing reporting rates for drug safety review and risk assessment. However, the drug names in the adverse event (AE) reports from FAERS were heterogeneous due to a lack of uniformity of information submitted mandatorily by pharmaceutical companies and voluntarily by patients, healthcare professionals, and the public. Studies using FAERS and other spontaneous reporting AEs database without drug name normalization may encounter incomplete collection of AE reports from non-standard drug names and the accuracies of the results might be impacted. In this study, we demonstrated applicability of RxNorm, developed by the National Library of Medicine, for drug name normalization in FAERS. Using prescription opioids as a case study, we used RxNorm application program interface (API) to map all FDA-approved prescription opioids described in FAERS AE reports to their equivalent RxNorm Concept Unique Identifiers (RxCUIs) and RxNorm names. The different names of the opioids were then extracted, and their usage frequencies were calculated in collection of more than 14.9 million AE reports for 13 FDA-approved prescription opioid classes, reported over 17 years. The results showed that a significant number of different names were consistently used for opioids in FAERS reports, with 2,086 different names (out of 7,892) used at least three times and 842 different names used at least ten times for each of the 92 RxNorm names of FDA-approved opioids. Our method of using RxNorm API mapping was confirmed to be efficient and accurate and capable of reducing the heterogeneity of prescription opioid names significantly in the AE reports in FAERS; meanwhile, it is expected to have a broad application to different sets of drug names from any database where drug names are diverse and unnormalized. It is expected to be able to automatically standardize and link different representations of the same drugs to build an intact and high-quality database for diverse research, particularly postmarketing data analysis in pharmacovigilance initiatives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Le, Chen, Harris, Fang, Lyn-Cook, Hong, Ge, Rogers, Tong and Zou.)

The increased risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) has been well documented in the literature. The present study aimed to assess the characteristics and outcomes of rectal cancer in patients with IBD. This study was a retrospective review of a prospectively maintained IRB-approved database at Cleveland Clinic Florida. Rectal cancer patients with or without IBD treated with curative surgery between 2016 and 2020 were compared for demographics, disease characteristics, and pathologic and oncologic outcomes. The primary outcomes were 3-year overall survival (OS) and disease-free survival (DFS). Secondary outcomes were clinicopathologic outcomes including disease stage, tumor histology and histologic features, and treatments received. 238 patients with rectal cancer were included, 15 (6.3%) of whom had IBD. IBD patients were significantly younger (52.9 vs 60.3 years, p = 0.033), presented more often with cT1-2 tumors (64.3% vs 30.4%, p = 0.008), and signet-ring cell pathology (14.3% vs 2%, p = 0.02). IBD patients received neoadjuvant chemoradiation less often (40% vs 72.6%, p = 0.029) and had shorter time between diagnosis and surgery (7.5 vs 25 weeks, p = 0.013) than did non-IBD patients. Both groups had similar OS (36 vs 34.7 months, p = 0.431) and DFS (36 vs 32.9 months, p = 0.121). IBD patients with rectal cancer tend to present at a younger age, with a less invasive disease, and signet-ring carcinomas, and receive neoadjuvant treatment less often than non-IBD patients. Based on low level of evidence, IBD and non-IBD rectal cancer patients might have similar survival., (© 2023. Italian Society of Surgery (SIC).)

Background: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19., Objective: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients., Methods: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed., Results: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality., Conclusion: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Pharmacists, as experts in medicines, are increasingly employed in general practices and undertake a range of responsibilities. Audit and feedback (A&F) interventions are effective in achieving behaviour change, including prescribing. The extent of pharmacist involvement in A&F interventions to influence prescribing is unknown. This review aimed to assess the effectiveness of A&F interventions involving pharmacists on prescribing in general practice compared with no A&F/usual care and to describe features of A&F interventions and pharmacist characteristics., Methods: Electronic databases (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, (Social) Science Citation Indexes, ISI Web of Science) were searched (2012, 2019, 2020). Cochrane systematic review methods were applied to trial identification, selection, and risk of bias. Results were summarized descriptively and heterogeneity was assessed. A random-effects meta-analysis was conducted where studies were sufficiently homogenous in design and outcome., Results: Eleven cluster-randomized studies from 9 countries were included. Risk of bias across most domains was low. Interventions focussed on older patients, specific clinical area(s), or specific medications. Meta-analysis of 6 studies showed improved prescribing outcomes (pooled risk ratio: 0.78, 95% confidence interval: 0.64-0.94). Interventions including both verbal and written feedback or computerized decision support for prescribers were more effective. Pharmacists who received study-specific training, provided ongoing support to prescribers or reviewed prescribing for individual patients, contributed to more effective interventions., Conclusions: A&F interventions involving pharmacists can lead to small improvements in evidence-based prescribing in general practice settings. Future implementation of A&F within general practice should compare different ways of involving pharmacists to determine how to optimize effectiveness.PRISMA-compliant abstract included in Supplementary Material 1., (© The Author(s) 2023. Published by Oxford University Press.)

Background: First described by Parks and Nicholls in 1978, the ileal pouch-anal anastomosis (IPAA) has revolutionized the treatment of mucosal ulcerative colitis (MUC) and familial adenomatous polyposis (FAP). IPAA is fraught with complications, one of which is pouch-vaginal fistulas (PVF), a rare but challenging complication noted in 3.9-15% of female patients. Surgical treatment success approximates 50%. Gracilis muscle interposition (GMI) is a promising technique that has shown good results with other types of perineal fistulas. We present the results from our institution and a comprehensive literature review., Methods: A retrospective observational study including all patients with a PVF treated with GMI at our institution from December 2018-January 2000. Primary outcome was complete healing after ileostomy closure., Results: Nine patients were included. Eight of nine IPAAs (88.9%) were performed for MUC, and one for FAP. A subsequent diagnosis of Crohn's disease was made in five patients. Initial success occurred in two patients (22.2%), one patient was lost to follow-up and seven patients, after further procedures, ultimately achieved healing (77.8%). Four of five patients with Crohn's achieved complete healing (80%)., Conclusion: Surgical healing rates quoted in the literature for PVFs are approximately 50%. The initial healing rate was 22.2% and increased to 77.8% after subsequent surgeries, while it was 80% in patients with Crohn's disease. Given this, gracilis muscle interposition may have a role in the treatment of pouch-vaginal fistulas., (© 2023. Springer Nature Switzerland AG.)

Introduction: Gastrointestinal symptoms correlate poorly with cancer diagnosis. A faecal immunochemical test (FIT) result of ≥10 µg has high sensitivity and negative predictive value for colorectal cancer (CRC) detection. An FIT-based diagnostic pathway may lead to more effective resource utilisation. We aimed to use National Endoscopy Database (NED) data to create a new colonoscopy performance measure, cancer detection rate (CDR) to assess the appropriate identification of target populations for colonoscopy; then to use CDR to assess the impact of implementing an FIT-based referral pathway locally., Methods: NED data were analysed to compare local diagnostic colonoscopic CDR in 2019 (prepathway revision) and 2021 (postpathway revision), benchmarked against overall national CDR for the same time frames., Results: 1, 123, 624 NED diagnostic colonoscopies were analysed. Locally, there was a significant increase in CDR between 2019 and 2021, from 3.01% (2.45%-3.47%) to 4.32% (3.69%-4.95%), p=0.003. The CDR increase was due to both a 10% increase in the number of CRCs detected and a 25% reduction in the number of diagnostic colonoscopies performed. Nationally, there was a smaller, but significant, increase in CDR from 2.02% (1.99%-2.07%) to 2.33% (2.29%-2.37%), p<0.001. The rate of increase in CDR% between 2019 and 2021 was significantly different locally compared with nationally., Conclusion: Our study indicates that the introduction of a robustly vetted FIT-based algorithm to determine whether diagnostic colonoscopy is required, is effective in increasing the colonoscopic CDR. Moreover, CDR appears to be a meaningful performance metric that can be automatically calculated through NED, enabling monitoring of the quality of referral and vetting pathways., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim of this study was to determine how mutations in CpERG11 and CpTAC1 contribute to fluconazole resistance in a collection of clinical isolates., Methods: Sequences of CpERG11 and CpTAC1 were determined for 35 resistant Candida parapsilosis clinical isolates. A plasmid-based CRISPR-Cas9 system was used to introduce mutations leading to amino acid substitution in CpTac1 and CpErg11. Triazole susceptibility was determined by broth microdilution and E-test. Differential expression of genes mediated by CpTAC1 mutation was determined by RNA sequencing, and relative expression of individual transporter genes was assessed with RT-qPCR., Results: Six isolates carried a mutation in CpTAC1 in combination with the CpERG11 mutation, leading to the CpErg11 Y132F substitution. When introduced into susceptible isolates, this CpERG11 mutation led to a 4- to 8-fold increase in fluconazole minimum inhibitory concentrations (MIC; 0.125 μg/mL vs. 0.5 μg/mL, 0.125 μg/mL vs. 0.5 μg/mL, and 0.5 μg/mL vs. 4 μg/mL). When introduced into a susceptible isolate, the CpTAC1 mutation leading to the G650E substitution resulted in an 8-fold increase in fluconazole MIC (0.25 μg/mL vs. 2 μg/mL), whereas correction of this mutation in resistant isolates led to a 16-fold reduction in MIC (32 μg/mL vs. 2 μg/mL). CpCDR1, CpCDR1B, and CpCDR1C were overexpressed in the presence CpTac1 G650E . Disruption of these genes in combination resulted in a 4-fold reduction in fluconazole MIC (32 μg/mL vs. 8 μg/mL)., Discussion: These results define the specific contribution made by the Y132F substitution in CpERG11 and demonstrate a role for activating mutations in CpTAC1 in triazole resistance in C. parapsilosis., (Copyright © 2023. Published by Elsevier Ltd.)