NHA1 is a cation/proton antiporter essential for the water-conserving functions of the rectal complex in Tribolium castaneum.

More than half of all extant metazoan species on earth are insects. The evolutionary success of insects is linked with their ability to osmoregulate, suggesting that they have evolved unique physiological mechanisms to maintain water balance. In beetles (Coleoptera)-the largest group of insects-a specialized rectal ("cryptonephridial") complex has evolved that recovers water from the rectum destined for excretion and recycles it back to the body. However, the molecular mechanisms underpinning the remarkable water-conserving functions of this system are unknown. Here, we introduce a transcriptomic resource, BeetleAtlas.org, for the exceptionally desiccation-tolerant red flour beetle Tribolium castaneum, and demonstrate its utility by identifying a cation/H+ antiporter (NHA1) that is enriched and functionally significant in the Tribolium rectal complex. NHA1 localizes exclusively to a specialized cell type, the leptophragmata, in the distal region of the Malpighian tubules associated with the rectal complex. Computational modeling and electrophysiological characterization in Xenopus oocytes show that NHA1 acts as an electroneutral K+/H+ antiporter. Furthermore, genetic silencing of Nha1 dramatically increases excretory water loss and reduces organismal survival during desiccation stress, implying that NHA1 activity is essential for maintaining systemic water balance. Finally, we show that Tiptop, a conserved transcription factor, regulates NHA1 expression in leptophragmata and controls leptophragmata maturation, illuminating the developmental mechanism that establishes the functions of this cell. Together, our work provides insights into the molecular architecture underpinning the function of one of the most powerful water-conserving mechanisms in nature, the beetle rectal complex.

PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer.

BACKGROUND: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer. METHODS: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. CONCLUSIONS: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).

The landscape of somatic mutation in normal colorectal epithelial cells.

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.

Colorectal keratins: Integrating nutrition, metabolism and colorectal health.

The colon mucosa is lined with crypts of circa 300 cells, forming a continuous barrier whose roles include absorption of water, recovery of metabolic energy sources (notably short chain fatty acids), secretion of a protective mucus barrier, and physiological signalling. There is high turnover and replenishment of cells in the mucosa, disruption of this may lead to bowel pathologies including cancer and inflammatory bowel disease. Keratins have been implicated in the processes of cell death, epithelial integrity, response to inflammation and as a result are often described as guardians of the colonic epithelium. Keratin proteins carry extensive post-translational modifications, the cofactors for kinases, acetyl transferases and other modification-regulating enzymes are themselves products of metabolism. A cluster of studies has begun to reveal a bidirectional relationship between keratin form and function and metabolism. In this paper we hypothesise a mechanistic interaction between keratins and metabolism is governed through regulation of post-translational modifications and may contribute significantly to the normal functioning of the colon, placing keratins at the centre of a nutrition-metabolism-health triangle.

Comparison of etiological and physiological characteristics of fecal incontinence in men and women.

Fecal incontinence (FI) is often underreported and underestimated in men. Our aims were to clarify the causes and the physiological characteristics of FI in men and to underline the differences between etiological and physiological factors in men and women diagnosed with FI. The study cohort encompassed 200 men and 200 women who underwent anatomical and physiological evaluation for FI in a tertiary referral center specializing in pelvic floor disorders. All patients underwent endoanal ultrasound and anorectal manometry. Evacuation proctography was performed in some patients. Demographic, medical, anatomical, and physiological parameters were compared between the two study groups. Urge incontinence was the most frequent type of FI in both genders. In men, anal fistula, history of anal surgeries, rectal tumors, and pelvic radiotherapy were common etiologic factors, whereas history of pelvic surgeries was more common in women. Associated urinary incontinence was reported more frequently by women. External anal sphincter defects, usually anterior, were more common in women (M: 1.5%, F: 24%, P < 0.0001), whereas internal anal sphincter defect prevalence was similar in men and women (M: 6%, F: 12%, P = 0.19). Decreased resting and squeeze pressures were less common in men (M: 29%, F: 46%, P < 0.0001: M: 44%, F: 66%, P < 0.0001). The incidence of rectal hyposensitivity was higher in men (M: 11.1%, F: 2.8%, P < 0.0001), whereas rectal hypersensitivity was higher in women (M: 5.8%, F: 10.8%, P < 0.0001). Anorectal dyssynergia was more common in men (M: 66%, F: 37%, P < 0.0001). Significantly different etiological factors and physiological characteristics for FI were found in men. Acknowledging these differences is significant and may yield better treatment options.NEW & NOTEWORTHY Fecal incontinence (FI) in men has different etiological factors when compared with women. The prevalence of internal anal sphincter defect among men with FI was similar to women. Different manometric measurements were found among men with FI: decreased anal pressures were less common among men, whereas rectal hyposensitivity and anorectal dyssynergia were more common among men.

Sex differences in zymosan-induced behavioral visceral hypersensitivity and colorectal afferent sensitization.

Sex differences in visceral nociception have been reported in clinical and preclinical studies, but the potential differences in sensory neural encoding of the colorectum between males and females are not well understood. In this study, we systematically assessed sex differences in colorectal neural encoding by conducting high-throughput optical recordings in intact dorsal root ganglia (DRGs) from control and visceral hypersensitive mice. We found an apparent sex difference in zymosan-induced behavioral visceral hypersensitivity: enhanced visceromotor responses to colorectal distension were observed only in male mice, not in female mice. In addition, a higher number of mechanosensitive colorectal afferents were identified per mouse in the zymosan-treated male group than in the saline-treated male group, whereas the mechanosensitive afferents identified per mouse were comparable between the zymosan- and saline-treated female groups. The increased number of identified afferents in zymosan-treated male mice was predominantly from thoracolumbar (TL) innervation, which agrees with the significant increase in the TL afferent proportion in the zymosan group as compared with the control group in male mice. In contrast, female mice showed no difference in the proportion of colorectal neurons between saline- and zymosan-treated groups. Our results revealed a significant sex difference in colorectal afferent innervation and sensitization in the context of behavioral visceral hypersensitivity, which could drive differential clinical symptoms in male and female patients.NEW & NOTEWORTHY We used high-throughput GCaMP6f recordings to study 2,275 mechanosensitive colorectal afferents in mice. Our results revealed significant sex differences in the zymosan-induced behavioral visceral hypersensitivity, which were present in male but not female mice. Male mice also showed sensitization of colorectal afferents in the thoracolumbar pathway, whereas female mice did not. These findings highlight sex differences in sensory neural anatomy and function of the colorectum, with implications for sex-specific therapies for treating visceral pain.

Prognostic Relevance of Primary Tumor Sidedness in Early-stage Colorectal Cancer: An Integrated Analysis of 4 Randomized Controlled Trials (JCOG2003A).

OBJECTIVE: The aim of this study was to determine the genuine prognostic relevance of primary tumor sidedness (PTS) in patients with early-stage colorectal cancer (CRC). BACKGROUND: The prognostic relevance of PTS in early-stage CRC remains a topic of debate. Several large epidemiological studies investigated survival only and did not consider the risk of recurrence so far. METHODS: Patients with stage II/III adenocarcinoma of the colon and upper rectum from 4 randomized controlled trials were analyzed. Survival outcomes were compared according to the tumor location: right-sided (cecum to transverse colon) or left-sided (descending colon to upper rectum). RESULTS: A total of 4113 patients were divided into a right-sided group (N=1349) and a left-sided group (N=2764). Relapse-free survival after primary surgery was not associated with PTS in all patients and each stage [hazard ratio (HR) adjusted =1.024 (95% CI: 0.886-1.183) in all patients; 1.327 (0.852-2.067) in stage II; and 0.990 (0.850-1.154) in stage III]. Also, overall survival after primary surgery was not associated with PTS in all patients and each stage [HR adjusted =0.879 (95% CI: 0.726-1.064) in all patients; 1.517 (0.738-3.115) in stage II; and 0.840 (0.689-1.024) in stage III]. In total, 795 patients (right-sided, N=257; left-sided, N=538) developed recurrence after primary surgery. PTS was significantly associated with overall survival after recurrence (HR adjusted =0.773, 95% CI: 0.627-0.954). CONCLUSIONS: PTS had no impact on the risk of recurrence for stage II/III CRC. Treatment stratification based on PTS is unnecessary for early-stage CRC.

Azithromycin or Doxycycline for Asymptomatic Rectal Chlamydia trachomatis.

BACKGROUND: Rectal chlamydia is a common bacterial sexually transmissible infection among men who have sex with men. Data from randomized, controlled trials are needed to guide treatment. METHODS: In this double-blind trial conducted at five sexual health clinics in Australia, we randomly assigned men who have sex with men and who had asymptomatic rectal chlamydia to receive doxycycline (100 mg twice daily for 7 days) or azithromycin (1-g single dose). Asymptomatic chlamydia was selected as the trial focus because more than 85% of men with rectal chlamydia infection are asymptomatic, and clinical guidelines recommend a longer treatment course for symptomatic infection. The primary outcome was a negative nucleic acid amplification test for rectal chlamydia (microbiologic cure) at 4 weeks. RESULTS: From August 2016 through August 2019, we enrolled 625 men (314 in the doxycycline group and 311 in the azithromycin group). Primary outcome data were available for 290 men (92.4%) in the doxycycline group and 297 (95.5%) in the azithromycin group. In the modified intention-to-treat population, a microbiologic cure occurred in 281 of 290 men (96.9%; 95% confidence interval [CI], 94.9 to 98.9) in the doxycycline group and in 227 of 297 (76.4%; 95% CI, 73.8 to 79.1) in the azithromycin group, for an adjusted risk difference of 19.9 percentage points (95% CI, 14.6 to 25.3; P<0.001). Adverse events that included nausea, diarrhea, and vomiting were reported in 98 men (33.8%) in the doxycycline group and in 134 (45.1%) in the azithromycin group (risk difference, -11.3 percentage points; 95% CI, -19.5 to -3.2). CONCLUSIONS: A 7-day course of doxycycline was superior to single-dose azithromycin in the treatment of rectal chlamydia infection among men who have sex with men. (Funded by the National Health and Medical Research Council; RTS Australian New Zealand Clinical Trials Registry number, ACTRN12614001125617.).

Development and Validation of a Post-Radiotherapy Prediction Model for Bowel Dysfunction After Rectal Cancer Resection.

BACKGROUND & AIMS: The benefit of radiotherapy for rectal cancer is based largely on a balance between a decrease in local recurrence and an increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features. METHODS: Eligible patients more than 1 year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score at 3 national hospitals in China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by means of logistic regression on the basis of key factors with proportional weighs. The accuracy of the model for major LARS prediction was internally and externally validated. RESULTS: A total of 868 patients reported a mean LARS score of 28.4 after an average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathologic nodal stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835; 95% CI, 0.800-0.870, n = 521) and external dataset (0.884; 95% CI, 0.848-0.921, n = 347). The model achieved both sensitivity and specificity >0.83 in the external validation. In addition, PORTLARS outperformed the preoperative LARS score for prediction of major events. CONCLUSIONS: PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to identify patients who need additional support for long-term dysfunction in the early stage. CLINICALTRIALS: gov, number NCT05129215.

A Predictive Model to Identify the Effects of Transcutaneous Sacral Nerve Stimulation With Pelvic Floor Exercises in Fecal Incontinence After Surgery for Anorectal Malformation.

INTRODUCTION: Although the combination of transcutaneous sacral nerve stimulation (tSNS) and pelvic floor exercises (PFEs) has shown significant effectiveness in treating fecal incontinence (FI) after surgery for congenital anorectal malformation (CARM), not all patients achieve satisfactory continence. Therefore, identifying which individuals will benefit from this method is crucial. METHODS: A prospective cohort study enrolled 92 children with FI. All patients underwent tSNS with PFE treatment, and an improved outcome was defined as a Wexner score ≤4. A predictive model to identify the effects of tSNS with PFEs in FI was developed based on the analysis of magnetic resonance imaging and high-resolution anorectal manometry with area under the receiver-operating characteristic curve to evaluate the predictive value of external anal sphincter (EAS) thickness index and anal squeezing pressure (ASP). RESULTS: tSNS with PFEs improved outcomes in 72 patients and led to poor outcomes in 20 (4 had their rectums deviate from the puborectalis muscle center or puborectal muscle ruptures while 16 lacked EAS with a lower ASP). The areas under the receiver-operating characteristic curve for EAS thickness index and ASP in predicting the effects of tSNS with PFEs were 0.915 (95% confidence interval 0.846-0.983, P = 0.000) and 0.886 (95% confidence interval 0.819-0.952, P = 0.000), respectively. By applying cutoff values of 0.076 for EAS thickness index and 21.95 mm Hg for ASP, tSNS with PFEs was found to be ineffective. DISCUSSION: tSNS with PFEs is effective for most patients with FI after CARM surgery, except when the rectum deviates from the puborectal muscle center, puborectal muscle rupture occurs, or EAS is absent with a low ASP.

Changes in microbial composition and interaction patterns of female urogenital tract and rectum in response to HPV infection.

BACKGROUND: Previous studies have shown that changes in the microbial community of the female urogenital tract are associated with Human papillomavirus (HPV) infection. However, research on this association was mostly focused on a single site, and there are currently few joint studies on HPV infection and multiple sites in the female urogenital tract. METHODS: We selected 102 healthy women from Yunnan Province as the research object, collected cervical exfoliation fluid, vaginal, urethral, and rectal swabs for microbial community analysis, and measured bacterial load, and related cytokine content. The link between HPV, microbiota, and inflammation was comprehensively evaluated using bioinformatics methods. FINDINGS: The impact of HPV infection on the microbial composition of different parts varies. We have identified several signature bacterial genera that respond to HPV infection in several detection sites, such as Corynebacterium, Lactobacillus, Campylobacter, and Cutibacterium have been detected in multiple sites, reflecting their potential significance in cross body sites HPV infection responses. There was a solid microbial interaction network between the cervix, vagina, and urethra. The interrelationships between inflammatory factors and different bacterial genera might also affect the immune system's response to HPV infection. INTERPRETATION: It might be an effective strategy to prevent and treat HPV infection by simultaneously understanding the correlation between the microbial changes in multiple parts of the female urogenital tract and rectum and HPV infection, and controlling the microbial network related to HPV infection in different parts.

Complications Following Transrectal and Transperineal Prostate Biopsy: Results of the ProBE-PC Randomized Clinical Trial.

PURPOSE: Transrectal prostate biopsy has come under scrutiny due to potential for postbiopsy infections and transperineal prostate biopsy is being offered as the safer alternative. However, there is a lack of randomized comparative studies. Our goal was to directly evaluate infectious and noninfectious complications following the 2 biopsy procedures. MATERIALS AND METHODS: We conducted a prospective, pragmatic, randomized clinical study in men undergoing prostate biopsy. The participants underwent either transrectal or transperineal prostate biopsy in the office under local anesthesia. The primary outcome was a 30-day composite infectious complication rate, comprising of 1 or more components including fever, genitourinary infection, antibiotic prescriptions, office or emergency visits, hospitalization, or sepsis. Secondary outcomes included 30-day composite noninfectious complications (urinary or hemorrhagic). RESULTS: Of the 763 randomized participants, 718 underwent either transrectal (351) or transperineal (367) prostate biopsy. A composite infectious complication event occurred in 9 participants (2.6%) in the transrectal and 10 participants (2.7%) in the transperineal group (odds ratio, 1.06; 95% CI, 0.43 to 2.65; P = .99). None of the participants developed sepsis in either group. There were no between-group differences in any of the individual component infectious events. A composite noninfectious complication occurred in 6 (1.7%) and 8 (2.2%) participants in the transrectal and transperineal groups, respectively (odds ratio, 1.28; 95% CI, 0.44 to 3.73; P = .79). No participants required hospitalization or other interventions. CONCLUSIONS: Among men undergoing transperineal or transrectal prostate biopsy, we could not demonstrate any difference in the infectious or noninfectious complications. Both biopsy approaches remain clinically viable and safe.

Clinically Significant Prostate Cancer Detection Following Transrectal and Transperineal Biopsy: Results of the Prostate Biopsy Efficacy and Complications Randomized Clinical Trial.

PURPOSE: The comparative effectiveness of transrectal and transperineal prostate biopsy in detecting clinically significant prostate cancer is not well understood. We conducted a randomized clinical trial to determine whether transperineal biopsy improves the detection of clinically significant prostate cancer. MATERIALS AND METHODS: Of the 840 men randomized, 93% were White, 44% had a previous biopsy, with a median age of 66 years and median PSA density of 0.14. Of these, 384 underwent transrectal and 398 underwent transperineal prostate biopsy. Prebiopsy prostate MRI was performed in 96% of men. Grade Group ≥ 2 prostate cancer was classified as clinically significant. Odds ratios were calculated using logistic regression to evaluate the effect of biopsy procedures on cancer detection rates. RESULTS: The detection rates of clinically significant prostate cancer were 47.1% and 43.2% (odds ratio 1.17; 95% CI, 0.88-1.55) for transrectal and transperineal biopsy, respectively. Age, PSA density, clinical stage and Prostate Imaging Reporting and Data System score were associated with the diagnosis of clinically significant cancer, whereas history of previous biopsy, anterior tumors, and biopsy procedure (transrectal or transperineal) were not. Clinically significant cancer detection rates in biopsy-naïve men undergoing MRI-targeted transrectal or transperineal biopsy were 59% and 62%, respectively. The overall cancer detection rates following transrectal and transperineal biopsy were 72.1% and 70.4%, respectively. CONCLUSIONS: There was no significant difference noted in the detection of clinically significant prostate cancer following transrectal or transperineal prostate biopsy. Urologists may utilize either biopsy procedure that best suits their patients' needs and practice setting.

Esophageal Versus Rectal Temperature Monitoring During Whole-Body Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: Association with Short- and Long-Term Outcomes.

OBJECTIVE: To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. STUDY DESIGN: We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36 months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. RESULTS: Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. CONCLUSIONS: Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.

Twisted orientation of the muscle bundles in the levator ani functional parts in women: Implications for pelvic floor support mechanism.

This study presents a comprehensive investigation of the anatomical features of the levator ani muscle. The levator ani is a critical component of the pelvic floor; however, its intricate anatomy and functionality are poorly understood. Understanding the precise anatomy of the levator ani is crucial for the accurate diagnosis and effective treatment of pelvic floor disorders. Previous studies have been limited by the lack of comprehensive three-dimensional analyses; to overcome this limitation, we analysed the levator ani muscle using a novel 3D digitised muscle-mapping approach based on layer-by-layer dissection. From this examination, we determined that the levator ani consists of overlapping muscle bundles with varying orientations, particularly in the anteroinferior portion. Our findings revealed distinct muscle bundles directly attached to the rectum (LA-re) and twisted muscle slings surrounding the anterior (LA-a) and posterior (LA-p) aspects of the rectum, which are considered functional parts of the levator ani. These results suggest that these specific muscle bundles of the levator ani are primarily responsible for functional performance. The levator ani plays a crucial role in rectal elevation, lifting the centre of the perineum and narrowing the levator hiatus. The comprehensive anatomical information provided by our study will enhance diagnosis accuracy and facilitate the development of targeted treatment strategies for pelvic floor disorders in clinical practice.

Using Self-Reported Sexual Positioning as an Indicator for Rectal Chlamydia and Gonorrhea Screening Among Men Who Have Sex With Men in China: A Missed Opportunity.

BACKGROUND: Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among men who have sex with men (MSM) are escalating public health concerns. This study aimed to explore (1) the reliability of self-reported sexual positioning as an indicator for rectal CT and NG screening, and (2) factors associated with rectal CT and NG infections in Shenzhen, China. METHODS: A cross-sectional study was conducted in 2 settings in Shenzhen, China, from April 1, 2021, to March 31, 2022. Data on sociodemographic characteristics, sexual behaviors, and basic CT knowledge were collected. Urine and self-collected rectal swabs were collected for CT and NG testing. RESULTS: In total, 195 MSM participated in the study, and 5.1% tested positive for urogenital CT, 29.2% for rectal CT, 1.0% for urogenital NG, and 8.2% for rectal NG. Among those who reported exclusively insertive anal sex, 69.2% of CT infections and 85.7% of NG infections would have remained undetected with urine testing alone. Risk factors for rectal CT infection included engaging in both insertive and receptive anal sex, with a significant association found for coinfection with rectal NG. CONCLUSIONS: Self-reported sexual positioning was found to be an unreliable indicator for CT and NG screening, as a substantial proportion of infections would have remained undetected. The findings suggest that CT and NG screening in China should be offered to all MSM regardless of self-reported sexual positioning, and that the dual CT/NG testing is recommended.

The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. METHODS: This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local-regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. DISCUSSION: This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. TRIAL REGISTRATION: This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

Computed Diffusion-Weighted Images of Rectal Cancer: Image Quality, Restaging, and Treatment Response after Neoadjuvant Therapy.

BACKGROUND: Computed diffusion-weighted images (cDWI) of random b value could be derived from acquired DWI (aDWI) with at least two different b values. However, its comparison between aDWI and cDWI images in locally advanced rectal cancer (LARC) patients after neoadjuvant therapy (NT) is needed. PURPOSE: To compare the cDWI and aDWI in image quality, restaging, and treatment response of LARC after NT. STUDY TYPE: Retrospective. POPULATION: Eighty-seven consecutive patients. FIELD STRENGTH/SEQUENCE: 3.0 T/DWI. ASSESSMENT: All patients underwent two DWI sequences, including conventional acquisition with b = 0 and 1000 s/mm2 (aDWIb1000 ) and another with b = 0 and 700 s/mm2 on a 3.0-T MR scanner. The images of the latter were used to compute the diffusion images with b = 1000 s/mm2 (cDWIb1000 ). Four radiologists with 3, 4, 14, and 25 years of experience evaluated the images to compare the image quality, TN restaging performance, and treatment response between aDWIb1000 and cDWIb1000 . STATISTICAL TESTS: Interclass correlation coefficients, weighted κ coefficient, paired Wilcoxon, and McNemar or Fisher test were used. A significance level of 0.05 was used. RESULTS: The cDWIb1000 images were superior to the aDWIb1000 ones in both subjective and objective image quality. In T restaging, the overall diagnostic accuracy of cDWIb1000 images was higher than that of aDWIb1000 images (57.47% vs. 49.43%, P = 0.289 for the inexperienced radiologist; 77.01% vs. 63.22%, significant for the experienced radiologist), with better sensitivity in determining ypT0-Tis tumors. Additionally, it increased the sensitivity in detecting ypT2 tumors for the inexperienced radiologist and ypT3 tumors for the experienced radiologist. N restaging and treatment response were found to be similar between two sequences for both radiologists. DATA CONCLUSION: Compared to aDWIb1000 images, the computed ones might serve as a wise approach, providing comparable or better image quality, restaging performance, and treatment response assessment for LARC after NT. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Comparison of lumen-apposing metal stents versus endoscopic balloon dilation for the management of benign colorectal anastomotic strictures.

BACKGROUND AND AIMS: Limited data exist evaluating lumen-apposing metal stents (LAMSs) with endoscopic balloon dilation (EBD) for the treatment of benign colorectal anastomotic strictures (BCASs). This study compares outcomes of both interventions. METHODS: Patients with left-sided BCAS treated with LAMSs versus EBD were identified retrospectively. The primary outcome was a composite of crossover to another intervention to achieve clinical success or recurrence requiring reintervention. RESULTS: Twenty-nine patients (11 LAMS and 18 EBD) were identified with longer follow-up in the EBD group (734 vs 142 days; P = .003). No significant differences were found in the composite outcome, technical success, clinical success, or components of composite outcome. With LAMS, there was a nonsignificant trend toward fewer procedures (2.4 vs 3.3; P = .06) and adverse events (0% vs 16.7%; P = .26). CONCLUSIONS: LAMS appears to be as effective as EBD for the treatment of BCAS but may require fewer procedures and may be safer than EBD.

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.