3' Uridylation Confers miRNAs with Non-canonical Target Repertoires.

Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3' uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Embedded multilevel regression and poststratification: Model-based inference with incomplete auxiliary information.

Health disparity research often evaluates health outcomes across demographic subgroups. Multilevel regression and poststratification (MRP) is a popular approach for small subgroup estimation as it can stabilize estimates by fitting multilevel models and adjust for selection bias by poststratifying on auxiliary variables, which are population characteristics predictive of the analytic outcome. However, the granularity and quality of the estimates produced by MRP are limited by the availability of the auxiliary variables' joint distribution; data analysts often only have access to the marginal distributions. To overcome this limitation, we embed the estimation of population cell counts needed for poststratification into the MRP workflow: embedded MRP (EMRP). Under EMRP, we generate synthetic populations of the auxiliary variables before implementing MRP. All sources of estimation uncertainty are propagated with a fully Bayesian framework. Through simulation studies, we compare different methods of generating the synthetic populations and demonstrate EMRP's improvements over alternatives on the bias-variance tradeoff to yield valid subpopulation inferences of interest. We apply EMRP to the Longitudinal Survey of Wellbeing and estimate food insecurity prevalence among vulnerable groups in New York City. We find that all EMRP estimators can correct for the bias in classical MRP while maintaining lower standard errors and narrower confidence intervals than directly imputing with the weighted finite population Bayesian bootstrap (WFPBB) and design-based estimates. Performances from the EMRP estimators do not differ substantially from each other, though we would generally recommend using the WFPBB-MRP for its consistently high coverage rates.

Use of kidney failure risk equation as a tool to evaluate referrals from primary care to specialist nephrology care.

BACKGROUND: With rising costs and burden of chronic kidney disease (CKD), timely referral of patients to a kidney specialist is crucial. Currently, Kidney Health Australia (KHA) uses a 'heat map' based on severity and not future risk of kidney failure, whereas the kidney failure risk equation (KFRE) score predicts future risk of progression. AIMS: Evaluate whether a KFRE score assists with timing of CKD referrals. METHODS: Retrospective cohort of 2137 adult patients, referred to tertiary hospital outpatient nephrologist between 2012 and 2020, were analysed. Referrals were analysed for concordance with the KHA referral guidelines and, with the KFRE score, a recommended practice. RESULTS: Of 2137 patients, 626 (29%) did not have urine albumin-to-creatinine ratio (UACR) measurement at referral. For those who had a UACR, the number who met KFRE preferred referral criteria was 36% less than KHA criteria. If the recommended KFRE score was used, then fewer older patients (≥40 years) needed referral. Positively, many diabetes patients were referred, even if their risk of kidney failure was low, and 29% had a KFRE over 3%. For patients evaluated meeting KFRE criteria, a larger proportion (76%) remained in follow-up, with only 8% being discharged. CONCLUSIONS: KFRE could reduce referrals and be a useful tool to assist timely referrals. Using KFRE for triage may allow those patients with very low risk of future kidney failure not be referred, remaining longer in primary care, saving health resources and reducing patients' stress and wait times. Using KFRE encourages albuminuria measurement.

Opioid Prescribing Rate for Nonoperative Distal Radius Fractures and Clinician Response to a Clinical Decision Support Alert.

BACKGROUND: Opioids are commonly prescribed for the management of acute orthopedic trauma pain, including nonoperative distal radius fractures. OBJECTIVES: This prospective study aimed to determine if a clinical decision support intervention influenced prescribing decisions for patients with known risk factors. We sought to quantify frequency of opioid prescriptions for acute nonoperative distal radius fractures treated. METHODS: We performed a prospective study at one large health care system. Utilizing umbrella code S52.5, we identified all distal radius fractures treated nonoperatively, and the encounters were merged with the Prescription Reporting with Immediate Medication Mapping (PRIMUM) database to identify encounters with opioid prescriptions and patients with risk factors for opioid use disorder. We used multivariable logistic regression to determine patient characteristics associated with the prescription of an opioid. Among encounters that triggered the PRIMUM alert, we calculated the percentage of encounters where the PRIMUM alert influenced the prescribing decision. RESULTS: Of 2984 encounters, 1244 (41.7%) included an opioid prescription. Age increment is a significant factor to more likely receive opioid prescriptions (p < 0.0001) after adjusting for other factors. Among encounters where the physician received an alert, those that triggered the alert for early refill were more likely to influence physicians' opioid prescribing when compared with other risk factors (p = 0.0088). CONCLUSION: Over 90% of patients (106/118) continued to receive an opioid medication despite having a known risk factor for abuse. Additionally, we found older patients were more likely to be prescribed opioids for nonoperatively managed distal radius fractures.

Complications After Renal Mass Biopsy: Frequency, Nature, Timing, and Associated Characteristics.

BACKGROUND. Observation periods after renal mass biopsy (RMB) range from 1 hour to overnight hospitalization. Short observation may improve efficiency by allowing use of the same recovery bed and other resources for RMBs in additional patients. OBJECTIVE. The purpose of this study was to evaluate the frequency, timing, and nature of complications after RMB, as well as to identify characteristics associated with such complications. METHODS. This retrospective study included 576 patients (mean age, 64.9 years; 345 men, 231 women) who underwent percutaneous ultrasound- or CT-guided RMB at one of three hospitals, performed by 22 radiologists, between January 1, 2008, and June 1, 2020. The EHR was reviewed to identify postbiopsy complications, which were classified as bleeding-related or non-bleeding-related and as acute (< 24 hours), subacute (24 hours to 30 days), or delayed (> 30 days). Deviations from normal clinical management (analgesia, unplanned laboratory testing, or additional imaging) were identified. RESULTS. Acute and subacute complications occurred after 3.6% (21/576) and 0.7% (4/576) of RMBs, respectively. No delayed complication or patient death occurred. A total of 76.2% (16/21) of acute complications were bleeding-related. A deviation from normal clinical management occurred after 1.6% (9/551) of RMBs that had no associated postbiopsy complication. Among the 16 patients with bleeding-related acute complications, all experienced a deviation, with mean time to deviation of 56 ± 47 (SD) minutes (range, 10-162 minutes; ≤ 120 minutes in 13/16 patients). The five non-bleeding-related acute complications all presented at the time of RMB completion. The four subacute complications occurred from 28 hours to 18 days after RMB. Patients with, versus those without, a bleeding-related complication had a lower platelet count (mean, 197.7 vs 250.4 × 109/L, p = .01) and greater frequency of entirely endophytic renal masses (47.4% vs 19.6%, p = .01). CONCLUSION. Complications after RMB were uncommon and presented either within 3 hours after biopsy or more than 24 hours after biopsy. CLINICAL IMPACT. A 3-hour monitoring window after RMB before patient discharge (in the absence of deviation from normal clinical management and complemented by informing patients of the low risk of a subacute complication) may provide both safe patient management and appropriate resource utilization.

Associations between dairy fat intake, milk-derived free fatty acids, and cardiometabolic risk in Dutch adults.

PURPOSE: Milk-derived free fatty acids (FFAs) may act as both biomarkers of intake and metabolic effect. In this study we explored associations between different types of dairy consumption, a selection of milk-derived free fatty acids, and cardiometabolic disease (CMD) risk factors. METHODS: Sixty-seven FFAs were quantified in the plasma of 131 free-living Dutch adults (median 60 years) using gas chromatography-flame ionization detector. Intakes of different dairy foods and groups were assessed using a food frequency questionnaire. Twelve different CMD risk factors were analyzed. Multiple linear regressions were used to evaluate the associations under study. RESULTS: Based on the fully adjusted models, 5 long-chain unsaturated FFAs (C18:1 t13 + c6 + c7 + u, C18:2 c9t11 + u, C20:1 c11, C20:3 c8c11c14, and C20:4 c5c8c11c14), 2 medium-chain saturated FFAs (C15, C15 iso), and a trans FFA (C16:1 t9) were positively associated with at least one variable of dairy intake, as well as plasma total and LDL cholesterol, blood pressure, and SCORE (p ≤ 0.05). A long-chain PUFA associated with high-fat fermented dairy intake (C18:2 t9t12), was negatively associated with serum triglyceride levels, and a long-chain saturated FFA associated with cheese intake (C18:1 u1) was negatively associated with plasma LDL cholesterol and serum triglyceride levels. No clear associations were observed between dairy intake and CMD risk factors. CONCLUSION: Milk-derived FFAs could act as sensitive biomarkers for dairy intake and metabolism, allowing the association between dairy and CMD risk to be more precisely evaluated.

Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls. METHODS: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.

Promoting Bone Formation and Healing in Segmental Defects Through Ectopic Induced Membrane.

We aimed to determine whether addition of an in vivo ectopic induced membrane (EM) to the Masquelet Technique enhanced angiogenesis and bone formation in a segmental defect. After generating and stabilizing a diaphyseal femur defect, 10 rats received a polymethylmethacrylate (PMMA) spacer within the defect (control); 10 received another PMMA spacer implanted subcutaneously (EM). We removed the spacers and added autograft; the excised EM was added to their autograft (EM group). Post-mortem x-rays assessed bone formation and bridging. Osteogenesis in the proximal defect was significantly more uniform (p < 0.01), and there was greater amount of bone remodeling distally in the EM group (p < 0.05). There was no difference in bone formation (p = 0.19) but greater degrees of bridging in the EM group (2.20 vs. 1.20, p = 0.09). The EM resulted in more homogeneous proximal osteogenesis and increased bone remodeling distally. These findings could lead to more consistent and predictable bone healing. (Journal of Surgical Orthopaedic Advances 31(3):161-165, 2022).

Relationship Between Combined Histologic and Endoscopic Endpoints and Efficacy of Ustekinumab Treatment in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Ustekinumab induces and maintains histologic improvement in patients with ulcerative colitis (UC). The clinical relevance of this endpoint alone, and in combination with endoscopic improvement, is unknown. METHODS: Histologic disease activity was evaluated in 2630 colonic biopsy samples from patients with UC treated in the UNIFI phase 3 UC clinical studies of ustekinumab. We evaluated associations between histologic improvement (defined as the composite of neutrophil infiltration in less than 5% of crypts and no crypt destruction, erosions, ulcerations, or granulation tissue) and clinical endpoints at the end of induction (week 8 and 16) and maintenance (week 44) periods. We assessed the validity of a combined histologic and endoscopic (Mayo endoscopy subscore, 0 or 1) improvement endpoint, which we called histo-endoscopic mucosal healing (or histo-endoscopic mucosal improvement). RESULTS: Histologic improvement was significantly (P < .0001) associated with clinical remission, lower mean disease activity scores, and greater improvement in disease activity at the end of induction and maintenance studies. Ustekinumab induced and maintained significantly higher rates of histologic improvement at induction week 8 and maintenance week 44 than placebo when more stringent definitions of histologic improvement were used. Histologic improvement and endoscopic improvement following induction were associated with 10% to 20% higher rates of histo-endoscopic mucosal healing, clinical remission, and corticosteroid-free remission at week 44 (all P < .05) in patients who received ustekinumab maintenance therapy. At week 44, 61% of patients (56/92) with histo-endoscopic mucosal healing after induction therapy achieved clinical remission, versus 39% of patients (9/23, P = .0983) and 34% of patients (24/71, P = .0009) with endoscopic or histologic improvement alone after induction, respectively. CONCLUSION: Data from the UNIFI program of ustekinumab in patients with UC treated with ustekinumab indicated the achievement of histo-endoscopic mucosal healing after induction therapy is associated with lower disease activity at the end of maintenance therapy than either histologic or endoscopic improvement alone. ClinicalTrials.gov number: NCT02407236.

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells.

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630.

Effects of Ustekinumab on Histologic Disease Activity in Patients With Crohn's Disease.

BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.

Pregnancy and fertility-related adverse outcomes associated with Chlamydia trachomatis infection: a global systematic review and meta-analysis.

BACKGROUND: Genital chlamydia infection in women is often asymptomatic, but may result in adverse outcomes before and during pregnancy. The purpose of this study was to examine the strength of the relationships between chlamydia infection and different reproductive health outcomes and to assess the certainty of the evidence. METHODS: This review was registered and followed the Cochrane guidelines. We searched three databases to quantitatively examine adverse outcomes associated with chlamydia infection. We included pregnancy and fertility-related outcomes. We performed meta-analyses on different study designs for various adverse outcomes using unadjusted and adjusted analyses. RESULTS: We identified 4730 unique citations and included 107 studies reporting 12 pregnancy and fertility-related outcomes. Sixty-eight studies were conducted in high-income countries, 37 studies were conducted in low-income or middle-income countries, and 2 studies were conducted in both high-income and low-income countries. Chlamydia infection was positively associated with almost all of the 12 included pregnancy and fertility-related adverse outcomes in unadjusted analyses, including stillbirth (OR=5.05, 95% CI 2.95 to 8.65 for case-control studies and risk ratio=1.28, 95% CI 1.09 to 1.51 for cohort studies) and spontaneous abortion (OR=1.30, 95% CI 1.14 to 1.49 for case-control studies and risk ratio=1.47, 95% CI 1.16 to 1.85 for cohort studies). However, there were biases in the design and conduct of individual studies, affecting the certainty of the overall body of evidence. The risk of adverse outcomes associated with chlamydia is higher in low-income and middle-income countries compared with high-income countries. CONCLUSION: Chlamydia is associated with an increased risk of several pregnancy and fertility-related adverse outcomes in unadjusted analyses, especially in low-income and middle-income countries. Further research on how to prevent the sequelae of chlamydia in pregnant women is needed. TRIAL REGISTRATION NUMBER: CRD42017056818.

A Secondary Mixed Methods Analysis of a Pay-it-Forward Gonorrhea/Chlamydia Testing Program Among Men Who Have Sex With Men in China.

BACKGROUND: Gonorrhea and chlamydia are common among Chinese men who have sex with men (MSM), but testing rates are low. We developed a pay-it-forward program where men receive a free gonorrhea/chlamydia test and can then donate toward future participants' tests. This study aims to investigate drivers of testing uptake and donation using a mixed methods approach. METHODS: We used a sequential explanatory design to explore drivers of testing uptake and donation unique to pay-it-forward through a quantitative cross-sectional survey and a qualitative thematic analysis of semistructured interviews. We collected data on sociodemographics and perceived benefits of pay-it-forward among men offered the pay-it-forward interventionand analyzed testing uptake and donations using descriptive statistics and logistic regression. We then conducted 30 semistructured interviews with men and coded interview data to identify themes. RESULTS: Three hundred and one MSM were offered pay-it-forward and 55% (165/301) received gonorrhea/chlamydia testing. Ninety-one percent (150 of 165) donated any amount with a mean of 58.31 ± 53.39 RMB (US $8.61 ± 7.88), or 39% of the standard price of gonorrhea/chlamydia testing. Getting tested was not associated with income, but donations were higher in the highest income bracket (adjusted odds ratio, 7.12; 95% confidence interval, 1.61-31.52). Fifty-eight percent (94 of 162) selected "more MSM can get tested," and 54% (88 of 162) selected "I can help someone else" as benefits of pay-it-forward. Qualitative themes for drivers of testing and donation included flexible pricing, generosity and reciprocity, and MSM community identity. CONCLUSIONS: Quantitative and qualitative results suggest that this pay-it-forward program may increase gonorrhea/chlamydia testing by reducing cost barriers, leveraging generosity and reciprocity, and mobilizing community altruism.

Lack of sexual behavior disclosure may distort STI testing outcomes.

BACKGROUND: Men who have sex with men (MSM) globally have a high burden of curable sexually transmitted infections (STIs). MSM do not frequently receive rectal STI testing because of several barriers, such as not being out (disclosure of sexual behavior). We evaluate whether Chinese MSM select an STI test (rectal vs urethral) appropriate for their sexual behavior (insertive and/or receptive), and the interactions with being out. METHODS: This was a secondary analysis of data from a cross sectional MSM survey conducted at a multisite randomized controlled trial (RCT) (December 2018 to January 2019) around uptake of gonorrhea and chlamydia testing among Chinese MSM (N = 431). We collected socio demographics, relevant medical and sexual history, and disclosure of sexual behavior (outness). We estimated the decision to test and test choice, and the extent to which disclosure plays a role in decision making. RESULTS: Among 431 MSM, mean age was 28 years (SD = 7.10) and 65% were out to someone. MSM who indicated versatile sexual behavior and were out to someone had a 26.8% (95%CI = 6.1, 47.5) increased likelihood for selecting the rectal test vs the ure thral test, compared to those versatile and not out. Versatile MSM out to their health provider outside of the study context had a 29.4% (95%CI = 6.3, 52.6) greater likelihood for selecting the rectal STI test vs the urethral test, compared to versatile MSM not out to their health provider. CONCLUSIONS: Sexual behavior and outness may affect gonorrhea and chlamydia testing provision. Apart from clinicians, community based efforts may reduce stigma based barriers to testing.

High-Throughput Characterization of Blood Serum Proteomics of IBD Patients with Respect to Aging and Genetic Factors.

To date, no large scale, systematic description of the blood serum proteome has been performed in inflammatory bowel disease (IBD) patients. By using microarray technology, a more complete description of the blood proteome of IBD patients is feasible. It may help to achieve a better understanding of the disease. We analyzed blood serum profiles of 1128 proteins in IBD patients of European descent (84 Crohn's Disease (CD) subjects and 88 Ulcerative Colitis (UC) subjects) as well as 15 healthy control subjects, and linked protein variability to patient age (all cohorts) and genetic components (genotype data generated from CD patients). We discovered new, previously unreported aging-associated proteomic traits (such as serum Albumin level), confirmed previously reported results from different tissues (i.e., upregulation of APOE with aging), and found loss of regulation of MMP7 in CD patients. In carrying out a genome wide genotype-protein association study (proteomic Quantitative Trait Loci, pQTL) within the CD patients, we identified 41 distinct proteomic traits influenced by cis pQTLs (underlying SNPs are referred to as pSNPs). Significant overlaps between pQTLs and cis eQTLs corresponding to the same gene were observed and in some cases the QTL were related to inflammatory disease susceptibility. Importantly, we discovered that serum protein levels of MST1 (Macrophage Stimulating 1) were regulated by SNP rs3197999 (p = 5.96E-10, FDR<5%), an accepted GWAS locus for IBD. Filling the knowledge gap of molecular mechanisms between GWAS hits and disease susceptibility requires systematically dissecting the impact of the locus at the cell, mRNA expression, and protein levels. The technology and analysis tools that are now available for large-scale molecular studies can elucidate how alterations in the proteome driven by genetic polymorphisms cause or provide protection against disease. Herein, we demonstrated this directly by integrating proteomic and pQTLs with existing GWAS, mRNA expression, and eQTL datasets to provide insights into the biological processes underlying IBD and pinpoint causal genetic variants along with their downstream molecular consequences.

Complications Following Transosseous Repair of Zone I Flexor Tendon Injuries.

PURPOSE: Multiple techniques are described for repair of zone I flexor tendon injuries, many of which are fraught with complications. This study evaluated the clinical complications after a transosseous repair technique. METHODS: A retrospective review of a single institutional database identified all zone I flexor digitorum profundus (FDP) injuries repaired using a transosseous technique. In this technique, 2 nonabsorbable sutures were passed from volar to dorsal through transosseous tunnels and tied dorsally over the distal phalanx proximal to the germinal matrix. Demographics, injury characteristics, operative details, and complications were reviewed. RESULTS: Eight patients met the inclusion criteria. Average age was 31 years (range, 15-66 years) and all patients were male. Eight fingers were included: ring (4), small (3), and middle (1). Seven injuries were closed and one was open. Average time between injury and surgery was 13 days (range, 4-34 days). Five patients experienced complications, including osteomyelitis, chronic draining granuloma, and abnormal nail growth. Three patients required an additional operative procedure for management of complications. CONCLUSIONS: Transosseous repair of zone I flexor digitorum profundus injuries with a buried dorsal suture is associated with a high rate of clinical complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Gene Expression Signature for Prediction of Golimumab Response in a Phase 2a Open-Label Trial of Patients With Ulcerative Colitis.

Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to-severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUCROC) of 0.688 (P = .002) and at week 30 with an AUCROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti-tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961.

Abnormal Small Intestinal Epithelial Microvilli in Patients With Crohn's Disease.

BACKGROUND & AIMS: Crohn disease (CD) presents as chronic and often progressive intestinal inflammation, but the contributing pathogenic mechanisms are unclear. We aimed to identify alterations in intestinal cells that could contribute to the chronic and progressive course of CD. METHODS: We took an unbiased system-wide approach by performing sequence analysis of RNA extracted from formalin-fixed paraffin-embedded ileal tissue sections from patients with CD (n = 36) and without CD (controls; n = 32). We selected relatively uninflamed samples, based on histology, before gene expression profiling; validation studies were performed using adjacent serial tissue sections. A separate set of samples (3 control and 4 CD samples) was analyzed by transmission electron microscopy. We developed methods to visualize an overlapping modular network of genes dysregulated in the CD samples. We validated our findings using biopsy samples (110 CD samples for gene expression analysis and 54 for histologic analysis) from the UNITI-2 phase 3 trial of ustekinumab for patients with CD and healthy individuals (26 samples used in gene expression analysis). RESULTS: We identified gene clusters that were altered in nearly all CD samples. One cluster encoded genes associated with the enterocyte brush border, leading us to investigate microvilli. In ileal tissues from patients with CD, the microvilli were of decreased length and had ultrastructural defects compared with tissues from controls. Microvilli length correlated with expression of genes that regulate microvilli structure and function. Network analysis linked the microvilli cluster to several other down-regulated clusters associated with altered intracellular trafficking and cellular metabolism. Enrichment of a core microvilli gene set also was lower in the UNITI-2 trial CD samples compared with controls; expression of microvilli genes was correlated with microvilli length and endoscopy score and was associated with response to treatment. CONCLUSIONS: In a transcriptome analysis of formalin-fixed and paraffin-embedded ileal tissues from patients with CD and controls, we associated transcriptional alterations with histologic alterations, such as differences in microvilli length. Decreased microvilli length and decreased expression of the microvilli gene set might contribute to epithelial malfunction and the chronic and progressive disease course in patients with CD.