Search

Introduction: Cannabis use is common in the setting of inflammatory bowel disease (IBD). Patients frequently use cannabis to treat IBD-associated symptoms, and there is evidence that cannabis and its derivatives are helpful for this purpose. However, it is unclear how the symptom profiles of active IBD cannabis users and nonusers compare and how these symptoms may relate to their underlying disease state and/or complications. Materials and Methods: We performed a retrospective cohort study using a consented IBD natural history registry from a single tertiary care referral center between January 1, 2015 and August 31, 2020. We asked patients about current cannabis use and frequency. We also abstracted demographic and clinical characteristic information, including endoscopic severity, and totals and subscores of surveys assessing IBD characteristics, presence of anxiety/depression, and IBD-associated symptoms. We compared clinical and demographic factors of cannabis users and nonusers and developed a logistic regression model to evaluate for independent associations with cannabis use. Results: Three hundred eighty-three IBD patients met the inclusion criteria (206 females, 177 males; 258 Crohn's disease [CD], 118 ulcerative colitis, and 7 indeterminate colitis). Thirty patients (7.8%) were active cannabis users, consuming it for an average of 2.7 times per week. Cannabis users were more likely to report abdominal pain (83.3% vs. 61.7%), gas (66.7% vs. 45.6%), tenesmus (70.0% vs. 47.6%), and arthralgias (53.3% vs. 20.3%) compared to those that did not use cannabis (p

Nasal chondromesenchymal hamartoma (NCMH) is an extremely rare benign tumour of the nasal cavity predominantly described in infants. We report a case involving a 48-year-old woman who had been diagnosed with NCMH a year earlier and now re-presented with a short history of progressive nasal blockage, recurrent epistaxis and orbital apex syndrome. Histopathology was suggestive of malignant transformation into sinonasal sarcoma. However, following multidisciplinary team (MDT) discussions, including second and third opinions from external departments, the histological diagnosis was revised to ‘NCMH with bizarre stromal cells’. Despite this, the lesion demonstrated malignant features of rapid, invasive growth and was treated with palliative radiotherapy. The patient later developed radiological evidence of lung and liver metastases with subsequent pulmonary emboli. Shortly after this, she passed away. This case is unique in its diagnostic challenge, with ambiguous histopathological findings, and highlights the importance of an MDT approach when managing complex sinonasal tumours.

A 67-year-old man presented with 5 months of worsening memory impairment and sensory gait ataxia on the background of symptomatic anaemia. He experienced falls, agitation and became socially withdrawn over 3 weeks, resulting in hospital admission. On examination, he had sensory gait ataxia consistent with a dorsal column syndrome. He scored 13/30 on the Montreal Cognitive Assessment. Serum analysis showed normocytic anaemia and leucopenia, severe hypocupraemia, reduced caeruloplasmin and normal zinc levels. Overuse of zinc-containing denture cream was the cause of excess zinc ingestion and resultant copper deficiency, leading to blood dyscrasia and myelopathy. The cream was withdrawn and intravenous and then oral copper supplementation was implemented. Direct questions with regard to excess zinc in the diet and serological testing of copper and zinc should be considered in any patient with a dorsal column syndrome, particularly with concurrent anaemia. Copper deficiency may also have a role in exacerbating pre-existing cognitive impairment.

BACKGROUND: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 10 9 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. OBJECTIVE: To estimate the long-term risk difference for cancer with the immediate ART strategy.DESIGN: Multinational prospective cohort study.SETTING: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.PARTICIPANTS: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).MEASUREMENTS: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts RESULTS: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 10 9 cells/L and less than 350 × 10 9 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. LIMITATION: Potential residual confounding due to observational study design.CONCLUSION: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.PRIMARY FUNDING SOURCE: Highly Active Antiretroviral Therapy Oversight Committee.

Background The relationship between low oxygen delivery (DO2) on cardiopulmonary bypass and morbidity and mortality following cardiac surgery remains unexamined. Methods We reviewed patients undergoing Society of Thoracic Surgeons index procedures from March 2019 to July 2020, coincident with implementation of a new electronic perfusion record that provides for continuous recording of DO2 and flow parameters. Continuous perfusion variables were analyzed using area-over-the-curve (AOC) calculations below predefined thresholds (DO2 24 hours, stroke, sternal wound infection, and reoperation). Results Eight hundred thirty-four patients were included; 42.7% (356) underwent isolated coronary artery bypass grafting (CABG), whereas 57.3% underwent nonisolated CABG (eg, valvular or combined CABG/valvular operations). DO2 24 hours (P = .04), an effect again most pronounced in nonisolated-CABG cases (P = .002), as well as acute kidney injury Conclusions Low DO2 on bypass may be associated with morbidity/mortality following cardiac surgery, particularly in patients undergoing nonisolated CABG. These results underscore the importance of goal-directed perfusion strategies.

Objective: Understanding the relationship between attachment and mental health has an important role in informing management of perinatal mental disorders and for infant mental health. It has been suggested that experiences of attachment are transmitted from one generation to the next. Maternal sensitivity has been proposed as a mediator, although findings have not been as strong as hypothesised. A meta-analysis suggested that this intergenerational transmission of attachment may vary across populations with lower concordance between parent and infant attachment classifications in clinical compared to community samples. However, no previous study has examined major depression and adult attachment in pregnancy as predictors of infant–parent attachment classification at 12 months postpartum. Methods: Data were obtained on 52 first-time mothers recruited in early pregnancy, which included 22 women who met diagnostic criteria for current major depression using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. The Adult Attachment Interview was also administered before 20 weeks of pregnancy. A history of early trauma was measured using the Childhood Trauma Questionnaire and maternal sensitivity was measured at 6 months postpartum using the observational measure of the Emotional Availability Scales. Infant–parent attachment was measured using the Strange Situation Procedure at 12 months. Results: Overall, we found no significant association between the Adult Attachment Interview and the Strange Situation Procedure classifications. However, a combination of maternal non-autonomous attachment on the Adult Attachment Interview and major depression was a significant predictor of insecure attachment on the Strange Situation Procedure. We did not find that maternal sensitivity mediated parental and infant attachment security in this sample. Conclusion: While previous meta-analyses identified lower concordance in clinical samples, our findings suggest women with major depression and non-autonomous attachment have a greater concordance with insecure attachment on the Strange Situation Procedure. These findings can guide future research and suggest a focus on depression in pregnancy may be important for subsequent infant attachment.

The initial description of robotic tracheobronchoplasty for the treatment of tracheobronchomalacia demonstrated feasibility, safety, and short-term symptomatic and functional improvement. The purpose of the current study was to demonstrate intermediate outcomes in postoperative pulmonary function and quality of life after robotic tracheobronchoplasty.We retrospectively reviewed prospectively collected clinical data from 42 patients who underwent robotic tracheobronchoplasty from May 2016 to December 2017. The Institutional Review Board or equivalent ethics committee of the Northwell Health approved the study protocol and publication of data. Patient written consent for the publication of the study data was waived by the Institutional Review Board.A total of 42 patients underwent robotic tracheobronchoplasty during the study period. Median total follow-up is 40 months. There was 1 death since surgery from an unrelated disease. Significant decreases in St George's Respiratory Questionnaire total score (preoperative mean: 64.01, postoperative mean: 38.91, P = .002), St George's Respiratory Questionnaire symptom score (preoperative median: 82.6, postoperative median: 43.99, P .001), and St George's Respiratory Questionnaire impact score (preoperative median: 55.78, postoperative median: 25.95, P .001) were apparent at a median follow-up of 13 months. Comparison of preoperative and postoperative pulmonary function tests revealed a significant increase in percent predicted forced expiratory volume in 1 second (preoperative median: 74% vs postoperative median: 82%, P = .001), forced vital capacity (preoperative median: 68.5% vs postoperative median: 80.63%, P .001), and peak expiratory flow (preoperative median: 61.5% vs postoperative median: 75%, P = .02) measured at a median follow-up of 29 months.Robotic tracheobronchoplasty is associated with low intermediate-term mortality. Robotic tracheobronchoplasty results in significant improvement in quality of life and postoperative pulmonary function. Longer-term follow-up is necessary to continue to elucidate the effect of robotic tracheobronchoplasty on halting pathologic progression of tracheobronchomalacia and to determine the long-term impact of tracheobronchoplasty on symptomatic and functional improvement.

Background The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.

Objectives Endovascular Aneurysm Repair is an established treatment for abdominal aortic aneurysm which requires arterial access via the groin. Most centres perform percutaneous ultrasound-guided access into the common femoral artery for delivery of the stent graft. The profile of endovascular devices necessitates large sheath sizes, therefore formal closure of the arterial puncture site is required. Various percutaneous devices are available, with data lacking on efficacy and mid-term safety profile. We present outcomes from a single centre with the Perclose ProGlide™ (Abbott Vascular Devices, CA, USA) suture-mediated system, using the well described “pre-close” technique. Materials & methods Data were collected from operative records and electronic medical records. Patients undergoing standard (EVAR) or complex (F/B-EVAR) aneurysm repair between March 2015 and September 2019 were included. Complications were recorded per-patient and per-groin procedure. Results 266 patients were included; 182 (68.4%) standard infrarenal EVAR, 84 (31.6%) F/B-EVAR. There were a total of 484 groin procedures performed. Intraoperative Perclose ProGlide™ success was 98.1% (per patient) or 99.0% (per groin procedure). 30-day groin complication rate was 6.1% (per patient) or 3.1% (per groin procedure). There were no pre- or peri-operative factors which predicted the occurrence of groin complications. The rate of groin complications was not related to sheath size. Conclusions Our data support the use of percutaneous access with a pre-close technique for a variety of endovascular aneurysm repair procedures with both large- and small-bore access. The Perclose ProGlide™ system provides excellent mid-term complication-free and reintervention-free outcomes for groin procedures.

Small bowel cancers are rare gastrointestinal malignancies and tumor location impact on outcomes is unclear.A retrospective review was performed on stage I to IV small bowel cancer cases from 2000 to 2017 in British Columbia, Canada. Baseline patient characteristics, disease-free survival (DFS) and overall survival (OS) were evaluated by tumor location and systemic therapy use patterns were summarized.Of 340 patients included, primary tumor distribution was: duodenum (51.2%), ileum (19.1%), jejunum (18.5%), and unspecified (11.2%). Median DFS for stage I to III disease was 37.7, 49.1, and 26.7 months for duodenal, jejunal, and ileal tumors (P = .018). Median OS was 9.6, 35.2, and 20.1 months for duodenal, jejunal, and ileal tumors (P.0001). Compared to duodenal primaries, both jejunal and ileal tumors were associated with significantly improved OS (HR 0.43, P.001 for jejunal; HR 0.71, P = .035 for ileal). Adjuvant therapy was given to 21.6% of stage II and 50.6% of stage III cancers. Among patients with metastatic disease, median OS was 4.2, 11.4, and 6.9 months for duodenal, jejunal, and ileal tumors (P = .0019). Jejunal tumors had the best prognosis (HR 0.48, P = .001 vs. duodenum).Survival differences exist when small bowel cancers were assessed by tumor location, and jejunal tumors portended better prognosis overall.

The aim of this study is to use tibial Hounsfield unit measurements from preoperative computed tomography scans of ankle fractures to predict delayed union and nonunion. We hypothesize that patients with lower Hounsfield unit averages, an indirect measure of lower bone mineral density, in the distal tibia are more likely to develop delayed union and nonunion complications after ankle fracture surgery. Patient data from January 2010 to January 2020 were retrospectively analyzed from 2 institutions. Exposure cases of delayed union or nonunion that had preoperative computed tomography were compared to 5 controls matched for sex, age, and classification. 3 measurements were taken from the tibia on axial computed tomography and averaged to create a summative measure for overall bone health. Statistical analysis was used to analyze the relationship between the groups. 19 exposure patients were compared to 95 control patients. There were 16 females and 3 males in the exposure group aged from 30 to 88 years. Average follow-up was 1.6 years. The average exposure and control Hounsfield measurements were 186 (161-210) and 258 (248-269), respectively. Significant differences were found for all measured averages. This is the first study to our knowledge relating preoperative tibial Hounsfield measurements to healing rates of ankle fractures. Measurements taken from any of the 3 sites or the average could be an indicator of overall bone health. Using this technique on preoperative imaging will help surgeons adjust their perioperative planning for patients at higher risk for delayed union and nonunion.

OBJECTIVES This study sought to evaluate the long-term differences in survival between multiple arterial grafts (MAG) and single arterial grafts (SAG) in patients who underwent coronary artery bypass grafting (CABG) in the SYNTAX study. METHODS The present analysis included the randomized and registry-treated CABG patients (n = 1509) from the SYNTAX Extended Survival study (SYNTAXES). Patients with only venous (n = 42) or synthetic grafts (n = 1) were excluded. The primary end point was all-cause death at the longest follow-up. Multivariable Cox regression was used to adjust for differences in baseline characteristics. Sensitivity analysis using propensity matching with inverse probability for treatment weights was performed. RESULTS Of the 1466 included patients, 465 (31.7%) received MAG and 1001 (68.3%) SAG. Patients receiving MAG were younger and at lower risk. At the longest follow-up of 12.6 years, all-cause death occurred in 23.6% of MAG and 40.0% of SAG patients [adjusted hazard ratio (HR) 0.74, 95% confidence interval (CI) (0.55–0.98); P = 0.038], which was confirmed by sensitivity analysis. MAG in patients with the three-vessel disease was associated with significant lower unadjusted and adjusted all-cause death at 12.6 years [adjusted HR 0.65, 95% CI (0.44–0.97); P = 0.033]. In contrast, no significance was observed after risk adjustment in patients with the left main disease, with and without diabetes, or among SYNTAX score tertiles. CONCLUSIONS In the present post hoc analysis of all-comers patients from the SYNTAX trial, MAG resulted in markedly lower all-cause death at 12.6-year follow-up compared to a SAG strategy. Hence, this striking long-term survival benefit of MAG over SAG encourages more extensive use of multiple arterial grafting in selected patients with reasonable life expectancy. Trial registration SYNTAXES ClinicalTrials.gov reference: NCT03417050; SYNTAX ClinicalTrials.gov reference: NCT00114972.

Rationale: The objective was to assess the cost-effectiveness of staging positron emission tomography/computed tomography (PET/CT) in early-stage follicular lymphoma from the Canadian health care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding a staging PET/CT vs. using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a non-curative approach, or no change in RT treatment as planned. Subsequent disease course was described using a state-transition cohort model over a 30-year time horizon. Diagnostic characteristics, probabilities, utilities and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars, CAD$) and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs), and was cost-effective in 89% of simulations (i.e., either cost-saving or with an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis shows that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT prior to curative-intent RT.

Introduction Studies have shown that osteoporotic patients are more likely to have medical or surgical complications postoperatively. In this study, we determine the predictive value of various comorbidities on the likelihood of postoperative complications, mortality, and 30-day readmission following cement augmentation for osteoporotic vertebral compression fractures (OVCFs). Materials and Methods A retrospective analysis of the American College of Surgeons National Surgery Quality Improvement Project (ACS-NSQIP) database from 2007 to 2014 identified 1979 patients who met inclusion criteria. A multivariate logistic regression analysis was utilized to determine the relationship between various comorbidities and perioperative mortality, postoperative complications, and 30-day readmission rates. Results A history of cerebrovascular accident (CVA), coagulopathy, diminished preoperative functional status, and/or an American Society of Anesthesiologists (ASA) class > 2 were statistical predictors of postoperative complications. CVA generated the highest odds ratio among these comorbidities (OR = 5.36, p = 0.02 for minor complications; OR = 4.60 p = 0.05 for major complications). Among the 15 comorbidities considered, steroid use (OR =1.81; p = 0.03) and an ASA class > 2 (OR = 14.65; p = 0.01) were the only ones that were correlated with mortality; an ASA class > 2 had a particularly strong effect on the likelihood of mortality (OR = 14.65). Chronic obstructive pulmonary disorder (COPD), obesity, significant weight loss, and an ASA class > 2 were correlated with 30-day readmissions. Congestive heart failure (CHF), diabetes, dialysis, hypertension, or smoking was not correlated with adverse postoperative outcomes. Conclusion Of the 15 comorbidities considered in this study, four were statistically associated with increased rates of postoperative complications, two were associated with increased mortality, and four were associated with increased rates of readmission at 30 days. The presence of CHF, diabetes mellitus (DM), hypertension, ascites, renal failure, or smoking were not associated with the adverse outcomes studied. Level of Evidence III.

PURPOSE: To determine the change in intraocular pressure (IOP), ocular hypotensive medication use after cataract extraction in the Medication Group of the Ocular Hypertension Treatment Study (OHTS). DESIGN: Secondary analysis of randomized clinical trial data METHODS: We included 92 participants (n=149 eyes) of the OHTS Medication Group who underwent cataract surgery in at least one eye during the study, and 531 participants (n=1004 eyes) of the Medication Group who did not undergo cataract surgery. We defined the “split date” as the first study visit that cataract surgery was reported for the cataract surgery group, and the 15(th) visit in the control group to equalize the median number of visits. We then compared the two groups at visits relative to this split date. • MAIN OUTCOME MEASURES: Difference in preoperative and postoperative IOP, and number of classes of ocular hypotensive medications between the cataract and control group over a 72 month period. RESULTS: Cataract surgery significantly decreased the number of ocular hypotensive medications at all postoperative visits (mean −0.4 medications, p

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Introduction: Numerous classifications have been developed to assess tibial plateau fractures (TPF). Of these, the Schatzker system is the most widely reported in the literature yet this system is limited in its characterisation of morphological fracture features underlying the fracture location. The purpose of this study was to compare 3D morphological features of TPFs across different Schatzker types. Methods: This study retrospectively analysed preoperative TPF imaging data to reconstruct 3D models of the fractures. Ninety-one fractures (29 female, 62 male) were analysed and classified using Schatzker. Fracture location across Schatzker types was compared based on division of the articular surface into six ‘zones’. Additionally, morphological characteristics of the fractures were compared based on fracture type, including; the number, volume and shape of the fragments. Results: Schatzker II, IV and VI fractures were most common, making up 41%, 16% and 20%, respectively. Type II fractures commonly involved both the lateral and central aspect of the tibial plateau, similarly, type IV fractures incorporated the lateral condyle in most cases. Considering the morphological metrics, statistically significant differences were observed between Schatzker types for the number of; total, articular, cortical and volumetrically significant (all P < 0.001) fragments along with the volume of both primary (P < 0.001) and secondary (P = 0.02) fragments. Discussion: Assessment of underlying fracture characteristics in addition to fracture location can serve to provide greater detail relating to fracture morphology, which has the potential to assist with both surgical decision making and assessment of postoperative outcomes. Incorporating this information as part of a hierarchical or multifactorial framework for classifying fractures may help distinguish subtle differences between fracture types that are classifiable using the most current systems. Refereed/Peer-reviewed

Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.

Purpose Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. Design Cross-sectional study. Participants Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019. Methods Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age. Main Outcome Measures Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP. Results Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4–7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61–4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3–23.6; P = 0.023). Conclusions A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.

BACKGROUND: African Americans living with dementia are considered less likely to seek formal institutionalized elder care and more likely to be managed in the home by family-member caregivers. Assistive technologies (the use of smart visual devices like tablets and phones) can be used effectively to guide memory-impaired individuals with a sequence of pictures showing steps to complete activities of daily living, e.g., bathing, toileting, dressing. Assistive technology so far has not been generally embraced in African American communities. OBJECTIVES: Determine, if African American family caregivers, given the opportunity, would embrace the use of assistive technology and if they would perceive its use beneficial. METHODS: We assessed a group of eight family caregivers’ overall care-burden scores, and their user-satisfaction scores after using assistive technology for three months. RESULTS: We found significant reduction in caregiver burden, positive changes in behavior and emotion scores, and high ratings on user satisfaction. CONCLUSIONS: The findings reported here comprise the first systematic study of the use of assistive technology by caregivers in an underserved population. They set the stage for exploring meaningful strategies and variables that will better engage underserved populations to take advantage of assistive technologies available in healthcare.

Bronchiectasis refers to both a clinical disease and a radiological appearance that has multiple causes and can be associated with a range of conditions. Disease heterogeneity and the absence of standardised definitions have hampered clinical trials of treatments for bronchiectasis and are important challenges in clinical practice. In view of the need for new therapies for non-cystic fibrosis bronchiectasis to reduce the disease burden, we established an international taskforce of experts to develop recommendations and definitions for clinically significant bronchiectasis in adults to facilitate the standardisation of terminology for clinical trials. Systematic reviews were used to inform discussions, and Delphi processes were used to achieve expert consensus. We prioritised criteria for the radiological diagnosis of bronchiectasis and suggest recommendations on the use and central reading of chest CT scans to confirm the presence of bronchiectasis for clinical trials. Furthermore, we developed a set of consensus statements concerning the definitions of clinical bronchiectasis and its specific signs and symptoms, as well as definitions for chronic bacterial infection and sustained culture conversion. The diagnosis of clinically significant bronchiectasis requires both clinical and radiological criteria, and these expert recommendations and proposals should help to optimise patient recruitment into clinical trials and allow reliable comparisons of treatment effects among different interventions for bronchiectasis. Our consensus proposals should also provide a framework for future research to further refine definitions and establish definitive guidance on the diagnosis of bronchiectasis.

Background The impact of packed Red Blood Cell (pRBC) transfusion on oncological outcomes after liver transplantation (LT) for Hepatocellular Carcinoma (HCC) remains controversial. We evaluated the impact of pRBC transfusion on HCC recurrence and overall survival (OS) after LT for HCC. Methods Patients with HCC transplanted between 2000 and 2018 were included and stratified by receipt of pRBC transfusion. Outcomes were HCC recurrence and OS. Propensity score matching was performed to account for confounders. Results Of the 795 patients, 234 (29.4%) did not receive pRBC transfusion. After matching the 1-, 3-, and 5-year cumulative incidence of recurrence was 6.6%, 12.5% and 14.8% for no-pRBC transfusion, and 8.6%, 18.8% and 21.3% (p = 0.61) for pRBC transfusion. The OS at 1-, 3-, 5-year was 93.0%, 84.6% and 75.8% vs 92.0%, 79.7% and 73.5% (p = 0.83) for no-pRBC transfusion and pRBC transfusion, respectively. There were no differences in recurrence (HR 1.13, 95%CI 0.71–1.78, p = 0.61) or OS (HR 1.04, 95%CI 0.71–1.54, p = 0.83). Conclusion Perioperative administration of pRBC in liver transplant recipients for HCC resulted in a nonsignificant increase of HCC recurrence and death after accounting for confounder. Surgeons should continue to exercise cation and optimize patients iron stores medically preoperatively.

BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin.OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD).METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts.RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor.CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is considered to be an important risk factor for the development of cardiovascular disease (CVD). This study aimed to develop and evaluate a machine learning approach with a set of features for assessing the 10-year CVD mortality risk of the OSA population. METHODS: This study included 2,464 patients with OSA who met study inclusion criteria and were selected from the Sleep Heart Health Study. We evaluated the importance of potential features by mutual information. The top 9 features were selected to develop a random forest model. RESULTS: We evaluated the model performance on a test set (n = 493) using the area under the receiver operating curve with 95% confidence interval and confusion matrix. A random forest model awarded the highest area under the receiver operating curve of 0.84 (95% confidence interval: 0.78–0.89). The specificity and sensitivity were 73.94% and 81.82%, respectively. Sixty-three years old was a threshold for increased risk of 10-year CVD mortality. Persons with severe OSA had higher risk than those with mild OSA. CONCLUSIONS: This study demonstrated that a random forest model can provide a quick assessment of the risk of 10-year CVD mortality. Our model may be more informative for patients with OSA in determining their future CVD mortality risk. CITATION: Li A, Roveda JM, Powers LS, Quan SF. Obstructive sleep apnea predicts 10-year cardiovascular disease–related mortality in the Sleep Heart Health Study: a machine learning approach. J Clin Sleep Med. 2022;18(2):497–504.

PURPOSE Lung cancer screening (LCS) decreases lung cancer mortality; however, that reduction depends upon screening adherence. The purpose of this study was to determine factors associated with adherence rate for LCS among patients with negative baseline CT results in a multi-integrated health care network. METHODS A retrospective analysis was conducted among patients with negative baseline CT results in a multi-integrated health care network LCS program between January 2015 and January 2020. The two outcomes were adherence for the first and second subsequent LCS studies. Negative baseline result was defined as a Lung CT Screening Reporting and Data System score 0, 1, or 2. Adherence was defined as undergoing a follow-up study within 11 to 15 months of a prior scan. Multivariable logistic regression was used to determine significant predictors of adherence, adjusting for patient demographics, median household income (on the basis of geocoding ZIP codes from the US Census Bureau), smoking history, screening sites, and provider specialty. RESULTS A total of 30.7% (512 of 1,668) and 16.3% (270 of 1,660) of patients were adherent for the first two annual subsequent screens, respectively. First-year adherence was higher among former smokers and varied by site and provider specialty. Second-year adherence was higher among former smokers and varied by site, provider specialty, and pack-years smoked. CONCLUSIONS Adherence to LCS in a multihospital integrated health care network was poor and even lower at year 2. The identified factors associated with adherence may serve as targets to increase LCS adherence and decrease lung cancer mortality.

Completion lymph node dissection (CLND) following positive sentinel lymph node biopsy (SLNB) for cutaneous melanoma is a topic of controversy. The second Multicenter Selective Lymphadenectomy Trial (MSLT-II) suggested no survival benefit with CLND over observation amongst patients with a positive SLNB. The findings of the MSLT-II may have limited applicability to our high-risk population where nodal ultrasound and non-surgical melanoma treatment is rationed. In this regional, retrospective study, we reviewed primary melanoma, SLNB and CLND histopathological reports in the Bay of Plenty District Health Board (BOPDHB) across a 10-year period. The primary outcomes measured were size of sentinel lymph node metastases and non-sentinel node (NSN) positivity on CLND for patients with a positive SLNB. In the 157 SLNB identified, the mean sentinel lymph node metastatic deposit size was larger in BOPDHB compared with MSLT-II (3.53 vs 1.07/1.11mm). A greater proportion of BOPDHB patients (54.8%) had metastatic deposits larger than 1mm compared with MSLT-II (33.2/34.5%) and the rate of NSN involvement on CLND was also higher (23.8% vs 11.5%). These findings indicate that the BOPDHB is a high-risk population for nodal melanoma metastases. Forgoing CLND in the context of a positive SLNB may place these patients at risk.

Background: Individuals with chronic kidney disease (CKD) have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI). Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age-and sex matched healthy volunteers. Among COMBINE participants, we examined the associations of estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline (N=140) and 12-month change (N=112) in cMRI parameters. Results: Mean (standard deviation [SD]) age of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years. The mean (SD) baseline eGFR in COMBINE participants was 32.1 (8.0) and 85.9 (16.0) ml/ min/1.73m2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3 - 540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared to healthy volunteers (β estimate -0.13 CKD vs. non-CKD, 95% confidence interval [CI] -0.24, -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio (β-estimate per 1 unit increase in natural log UACR -0.06, 95% CI -0.09, -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses. Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction assessed by mitral valve E/A ratio in individuals with CKD with and without clinical CVD, but was not associated with change in any cMRI parameter.

Randomized clinical trials have shown that transcatheter aortic valve replacement is noninferior to surgery in low surgical risk patients. We compared outcomes in patients treated with a sutured (stented or stentless) or sutureless surgical valve from the Evolut Low Risk Trial.The Evolut Low Risk Trial enrolled patients with severe aortic stenosis and low surgical risk. Patients were randomized to self-expanding transcatheter aortic valve replacement or surgery. Use of sutureless or sutured valves was at the surgeons' discretion.Six hundred eighty patients underwent surgical aortic valve implantation (205 sutureless, 475 sutured). The Valve Academic Research Consortium-2 30-day safety composite endpoint was similar in the sutureless and sutured group (10.8% vs 11.0%, P = .93). All-cause mortality between groups was similar at 30 days (0.5% vs 1.5%, P = .28) and 1 year (3.3% vs 2.6%, P = .74). Disabling stroke was also similar at 30 days (2.0% vs 1.5%, P = .65) and 1 year (2.6% vs 2.2%, P = .76). Permanent pacemaker implantation at 30 days was significantly higher in the sutureless compared with the sutured group (14.4% vs 2.9%, P.001). Aortic valve-related hospitalizations occurred more often at 1 year with sutureless valves (9.1% vs 5.1%, P = .04). Mean gradients 1 year after sutureless and sutured aortic valve replacement were 9.9 ± 4.2 versus 11.7 ± 4.7 mm Hg (P.001).Among low-risk patients, sutureless versus sutured valve use did not demonstrate a benefit in terms of 30-day complications and produced marginally better hemodynamics but with an increased rate of pacemaker implantation and valve-related hospitalizations.

Understanding if maternal depression is a predictor of infant-parent attachment classification is important to furthering knowledge about the early pathways and predictors of socio-emotional development. Yet few studies that have utilised the Strange Situation Procedure, the gold standard for measurement of infant-parent attachment, have examined antenatal depression as a predictor of attachment, and none has also included a measure of maternal trauma. This study uses data on 224 women recruited in early pregnancy and followed up until 12 months postpartum. Maternal depression was measured in pregnancy using the Structured Clinical Interview for the DSM and repeat Edinburgh Postnatal Depression Scale as well as Stressful Life Events scale across pregnancy and postpartum including items on domestic violence. A past history of trauma was measured using the Childhood Trauma Questionnaire. Attachment was measured using the Strange Situation Procedure (SSP) at 12 months postpartum. We found that maternal depression was not associated with insecure or disorganized attachment. However, a maternal history of childhood trauma and current domestic violence both predicted insecure-avoidant attachment at 12 months, whereas increased number of stressful life events prior to conception and in pregnancy was associated with insecure-resistant attachment. Neither trauma, past or current, nor depression predicted disorganized attachment. In the first study to have included measures of antenatal depression, maternal childhood trauma, and current stressful events as predictors of infant attachment measured using the SSP, we found maternal experiences of past and current trauma but not depression were significant predictors of infant-parent attachment security.

Background: Heart failure (HF) patients with atrial fibrillation (AF) often have conduction system disorders, which may be worsened by β-blocker therapy.Objective: In a post hoc analysis we examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF trial.Methods: Patients randomized to metoprolol (n = 125) or bucindolol (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated. Bradycardia was defined as an electrocardiogram (ECG) heart rate (HR) Results: Mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for bucindolol (P < .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Episodes per patient for bucindolol vs metoprolol were 0.82 vs 2.08 (P < .001) for bradycardia and 0.24 vs 0.57 for severe bradycardia (P < .001), with 98.9% of the episodes occurring in SR. Patients experiencing bradycardia had a 4.15-fold higher prevalence of study medication dose reduction (P Conclusion: In AF-prone HF patients bradycardia may limit the effectiveness of β blockers, and this property is agent-dependent.

OBJECTIVES To examine the efficacy and safety of radiotherapy for the prevention of heterotopic ossification (HO) about the elbow. DESIGN Retrospective chart review. SETTING Level 1 Trauma Center. PATIENTS/PARTICIPANTS Two hundred and twenty-nine patients who received prophylactic radiotherapy (XRT) over a 15 year period were identified. Patients were included if they received XRT to the elbow joint and had at least 12 weeks of follow up after XRT. Fifty-four patients were ultimately included. INTERVENTION All patients were treated with a single dose of 7 Gy. 98% of patients received XRT within 24 hours after surgery, and all patients received XRT within 72 hours after surgery. MAIN OUTCOMES MEASUREMENTS The primary study measures evaluated were the presence or absence of clinically symptomatic HO and the presence of radiographic HO after XRT to the elbow joint. RESULTS Eighteen patients were treated with XRT after a traumatic injury requiring surgery (primary prophylaxis), and 36 were treated with XRT after excision surgery to remove HO which had already formed (secondary prophylaxis). In the primary cohort, 16.7% developed symptomatic HO after XRT, and 11.1% required surgery to resect heterotopic bone. In the secondary cohort, 11.1% developed symptomatic HO after surgery and XRT, and 5.5% required resection surgery. No secondary malignancies were identified. CONCLUSIONS Our findings suggest that XRT for elbow HO may be safe and effective for both primary and secondary HO. XRT for HO was not shown to be associated with radiation-induced sarcoma in this series, at least in the short term. Further study in a large patient population with extended follow up is required to better characterize populations at high risk for development of HO and secondary malignancy. [ZERO WIDTH SPACE]. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Summary Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of inflammatory bowel disease in patients with pouches are similar to those in patients without pouches.

BACKGROUND: Older adults are under-represented in cancer clinical trials. However, it remains unclear which types of trials under-enroll aging patients. We aimed to identify associations between trial characteristics and disparate enrollment of older adults onto trials sponsored by the Alliance for Clinical Trials in Oncology (Alliance). METHODS: Actual age ≥ 65 percentage and trial data were extracted from the Alliance closed study list. Each trial, based on its cancer type and years of enrollment, was assigned an expected age ≥ 65 percentage extracted from the Surveillance, Epidemiology, and End Results (SEER) US population-based database. Enrollment disparity difference (EDD), the difference between the expected age ≥ 65 percentage and the actual age ≥ 65 percentage, was calculated for each trial. Linear regression determined trial variables associated with larger EDDs and variables with an overall association p-value < 0.20 were included in a multivariable fixed-effects linear model. RESULTS: The median age of 66,708 patients across 237 trials was 60 years (range 18-102). The average actual age ≥ 65 percentage enrolled per trial was lower than each trial’s expected age ≥ 65 percentage average (39% vs. 58%; EDD 19, 95% CI 17.1-21.3%, p

Introduction The U.S. Affordable Care Act Medicaid expansion, which allowed states to expand Medicaid coverage to low-income adults beginning in 2014, has reduced the risk factors for child neglect and physical abuse, including parental financial insecurity, substance use, and untreated mental illness. This study examines the associations between Medicaid expansion and the rates of overall, first-time, and repeat reports of child neglect and physical abuse incidents per 100,000 children aged 0–5, 6–12, and 13–17 years. Methods The 2008–2018 National Child Abuse and Neglect Data System was analyzed using an extension of the difference-in-differences approach that accounts for staggered policy implementation across time. Owing to evidence of nonparallel preperiod trends in the 6 states that expanded Medicaid from 2015 to 2017, the main analyses included 20 states that newly expanded Medicaid in 2014 and 18 states that did not expand Medicaid from 2008 to 2018. Analyses were conducted in 2020–2021. Results Medicaid expansion states were associated with reductions of 13.4% (95% CI= −24.2, −9.6), 14.8% (95% CI= −26.4, −1.4), and 16.0% (−27.6, −2.6) in the average rate of child neglect reports per 100,000 children aged 0–5, 6–12, and 13–17 years, per state-year, relative to control states. Expansion was associated with a 17.3% (95% CI= −28.9, −3.8) reduction in the rate of first-time neglect reports among children aged 0–5 years and with 16.6% (95% CI= −29.3, −1.6) and 18.7% (95% CI= −32.5, −2.1) reductions in the rates of repeat neglect reports among children aged 6–12 and 13–17 years, respectively. There were no statistically significant associations between Medicaid expansion and the rates of physical abuse among children in any age group. Conclusions Insurance expansions for low-income adults may reduce child neglect.

Background The UK has one of the highest rates of recreational drug use and consequent deaths in Europe. Scotland is the “Drug deaths capital of Europe.” Intravenous drug use can result in limb- and life-threatening pathology. This study aimed to characterise limb-related admissions associated with intravenous drug use, outcomes and healthcare expenditure. Methods Retrospective data collection between December 2011 and August 2018. Patients were identified through discharge codes. Admission details were extracted from electronic records and a database compiled. Statistical analyses were performed using Statistical Package for the Social Science, P Results There were 558 admissions for 330 patients (1–9 admissions/patient), mean age 37 years (+/-7.6 SD) and 196 (59.2%; 319 admissions, 57.2%) were male. Three hundred forty-eight (62.4%) admissions were to surgical specialties, predominantly Vascular Surgery (247). Including onward referrals, Vascular ultimately managed 54.8% of admissions. Patients presented with multiple pathologies: 249 groin abscesses; 38 other abscesses; 74 pseudoaneurysms; 102 necrotising soft tissue infections (NSTI); 85 cellulitis; 138 deep venous thrombosis (DVTs); 28 infected DVTs and 70 other diagnoses. Two hundred and seventy-seven admissions (220 patients) required operations, with 361 procedures performed (1–7 operations/admission). There were 24 major limb amputations and 74 arterial ligations. Eleven amputations were due to NSTI and 13 followed ligation (17.6% of ligations). During follow-up 50 (15.2%) patients died, of which 6 (12%) had amputations (OR 3.2, 95% CI 1.04–9.61, P = 0.043). Cumulative cost of acute care was £4,783,241. Conclusions Limb-related sequalae of intravenous drug use represents a substantial surgical workload, especially for Vascular. These are complex, high-risk patients with poor outcomes and high healthcare costs.

We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).

Delivery of a peptide (APP96-110), derived from amyloid precursor protein (APP), has been shown to elicit neuroprotective effects following cerebral stroke and traumatic brain injury. In this study, the effect of APP96-110 or a mutant version of this peptide (mAPP96-110) was assessed following moderate (200 kdyn, (2 N)) thoracic contusive spinal cord injury (SCI) in adult Nude rats. Animals received a single tail vein injection of APP96-110 or mAPP96-110 at 30 minutes post-SCI and were then assessed for functional improvements over the next 8 weeks. A cohort of animals also received transplants of either viable or non-viable human mesenchymal stromal cells (hMSCs) into the SC lesion site at one week post-injury to assess the effect of combining intravenous APP96-110 delivery with hMSC treatment. Rats were perfused 8 weeks post-SCI and longitudinal sections of spinal cord analyzed for a number of factors including hMSC viability, cyst size, axonal regrowth, glial reactivity and macrophage activation. Analysis of sensorimotor function revealed occasional significant differences between groups using Ladderwalk or Ratwalk tests, however there were no consistent improvements in functional outcome after any of the treatments. mAPP96-110 alone, and APP96-110 in combination with both viable and non-viable hMSCs significantly reduced cyst size compared to SCI alone. Combined treatments with donor hMSCs also significantly increased βIII tubulin+, glial fibrillary acidic protein (GFAP+) and laminin+ expression, and decreased ED1+ expression in tissues. This preliminary study demonstrates that intravenous delivery of APP96-110 peptide has selective, modest neuroprotective effects following SCI, which may be enhanced when combined with hMSC transplantation. However, the effects are less pronounced and less consistent compared to the protective morphological and cognitive impact that this same peptide has on neuronal survival and behaviour after stroke and traumatic brain injury. Thus while the efficacy of a particular therapeutic approach in one CNS injury model may provide justification for its use in other neurotrauma models, similar outcomes may not necessarily occur and more targeted approaches suited to location and severity are required. All animal experiments were approved by The University of Western Australia Animal Ethics Committee (RA3/100/1460) on April 12, 2016.

Background We aimed to investigate the prescription pattern of pregabalin augmentation of antidepressants in major depressive disorder (MDD) and to explore variables associated with add-on pregabalin treatment. Methods 1410 MDD patients participated in this naturalistic European multicenter study with retrospective assessment of treatment response. Analyses of covariance, chi-squared tests, and binary logistic regressions were accomplished to determine differences in socio-demographic and clinical characteristics between MDD patients with and without pregabalin augmentation. Results Add-on pregabalin was established in 102 (7.23%) MDD patients. Compared to those without receiving pregabalin, pregabalin-treated patients were characterized by a significantly higher likelihood for older age (mean: 54.74 ± 13.08 vs 49.93 ± 14.13 years), unemployment (78.43% vs 51.23%), melancholic features (83.33% vs 58.94%), inpatient treatment (72.55% vs 31.65%), previous psychiatric hospitalizations (13.52 ± 24.82 vs 4.96 ± 19.93 weeks), any somatic comorbidity (68.63% vs 44.57%), comorbid hypertension (37.25% vs 17.51%), more severe depressive symptom severity at the onset of the current episode (mean MADRS: 37.55 ± 9.00 vs 33.79 ± 7.52), receiving augmentation/combination treatment strategies in general (mean number of psychotropic drugs: 3.64 ± 0.92 vs 2.07 ± 1.17), and with antidepressants (50.00% vs 27.91%) and antipsychotics (46.08% vs 24.08%) in particular. Limitations Due to its observational cross-sectional study design, our patient sample might not be fully representative for MDD patients in primary care settings. Conclusions Our findings suggest that add-on pregabalin is particularly administered in more severe/difficult-to-treat MDD conditions, whereas no association between the prescription of adjunctive pregabalin and comorbid anxiety symptoms could be determined.

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p = 0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11–1.98, p = 0.007). Nominal associations were also found between MDD-PRS and non-response (p = 0.013), as well as between SCZ-PRS and non-remission (p = 0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.

Background: Moringa oleifera Lam. (Moringaceae) leaves are commonly used for diabetes in Mali. This pilot clinical study aimed to evaluate its effect on post-prandial blood glucose in preparation for a larger trial. Methods: Diabetic patients and non-diabetic healthy volunteers (35 each) were asked to fast for 13 hours on three occasions. Blood glucose was measured before and after eating 100g of white bread (at 30, 60, 90, 120, 150 and 180 minutes). On their second and third study visits, they were given 1g and 2g respectively, of M. oleifera leaf powder, 30 minutes after eating the bread. The mean paired reduction in blood glucose at each time interval and the incremental area under the curve were calculated. Results: Ingestion of Moringa powder had no effect on blood glucose in non-diabetic participants, but in diabetic patients, it lowered blood glucose at 90 minutes. There was a trend towards lower incremental area under the curve when diabetic patients took 2g of Moringa. No side-effects were reported by any participant. Conclusions: Moringa oleifera leaf powder reduced post-prandial glycaemia in diabetic patients. A larger study is needed to define the optimal dose and to assess whether this translates into longer-term benefits.

Background Bovine Digital Dermatitis (BDD) is a prevalent infectious disease, causing painful foot skin lesions and lameness in cattle. We describe herein the bovine foot skin microbiota and its associations with BDD using 16S rRNA gene amplicon and shotgun metagenomic sequencing on samples from 259 dairy cows from three UK dairy farms. Results We show evidence of dysbiosis, and differences in taxonomy and functional profiles in the bovine foot skin microbiome of clinically healthy animals that subsequently develop BDD lesions, compared to those that do not. Our results suggest that taxonomical and functional differences together with alterations in ecological interactions between bacteria in the normal foot skin microbiome may predispose an animal to develop BDD lesions. Using genome-wide association and regional heritability mapping approaches, we provide first evidence for interactions between host genotype and certain members of the foot skin microbiota. We show the existence of significant genetic variation in the relative abundance of Treponema spp. and Peptoclostridium spp. and identify regions in the bovine genome that explain a significant proportion of this variation. Conclusions Collectively this work shows early changes in taxonomic and functional profiles of the bovine foot-skin microbiota in clinically healthy animals which are associated with subsequent development of BDD and could be relevant to prevention of disease. The description of host genetic control of members of the foot skin microbiota, combined with the association of the latter with BDD development offer new insights into a complex relationship that can be exploited in selective breeding programmes.

Background: Traumatic injuries are physical insults to the body that are prevalent worldwide. Many individuals involved in accidents suffer injuries affecting a number of extremities and organs, otherwise known as multitrauma or polytrauma. Traumatic brain injury is one of the most serious forms of the trauma-induced injuries and is a leading cause of death and long-term disability. Despite over dozens of phase III clinical trials, there are currently no specific treatments known to improve traumatic brain injury outcomes. These failures are in part due to our still poor understanding of the heterogeneous and evolving pathophysiology of traumatic brain injury and how factors such as concomitant extracranial injuries can impact these processes. Main body: Here, we review the available clinical and pre-clinical studies that have investigated the possible impact of concomitant injuries on traumatic brain injury pathobiology and outcomes. We then list the pathophysiological processes that may interact and affect outcomes and discuss promising areas for future research. Taken together, many of the clinical multitrauma/polytrauma studies discussed in this review suggest that concomitant peripheral injuries may increase the risk of mortality and functional deficits following traumatic brain injury, particularly when severe extracranial injuries are combined with mild to moderate brain injury. In addition, recent animal studies have provided strong evidence that concomitant injuries may increase both peripheral and central inflammatory responses and that structural and functional deficits associated with traumatic brain injury may be exacerbated in multiply injured animals. Conclusions: The findings of this review suggest that concomitant extracranial injuries are capable of modifying the outcomes and pathobiology of traumatic brain injury, in particular neuroinflammation. Though additional studies are needed to further identify the factors and mechanisms involved in central and peripheral injury interactions following multitrauma and polytrauma, concomitant injuries should be recognized and accounted for in future pre-clinical and clinical traumatic brain injury studies.

Objective Mild traumatic brain injury (mTBI) is a serious health concern in the adolescent population. Repeated mTBI may result in more pronounced deficits, and has been associated with long‐term neurological consequences including neurodegeneration. As such, there is a critical need for the development of objective mTBI biomarkers to help guide medical management. Diffusion‐weighted imaging (DWI) is an advanced magnetic resonance imaging (MRI) technique that may detect brain abnormalities after mTBI. Diffusion tensor imaging (DTI) is the most commonly applied DWI method, and initial studies have reported DTI changes in mTBI patients. Furthermore, new DWI methods (e.g., track‐weighted imaging; TWI) are being developed that may also be sensitive to mTBIs, but remain to be comprehensively studied. Methods This study utilized the Awake Closed Head Injury (ACHI) model of mTBI to investigate changes in DTI and TWI following repeated mTBI in adolescent male and female rats. A total of four ACHI impacts, two/day over two consecutive days, were delivered beginning on postnatal day 25. At 1 day and 7 days postinjury, rats were euthanized and brains were collected for DWI analyses. Results Rats given repeated mTBI displayed changes in fractional anisotropy and radial diffusivity (i.e., DTI measures), as well as track density (i.e., TWI). Interpretation These findings are consistent with initial DTI findings in mTBI patients, suggest that TWI may complement DTI, support the utility of DWI measures as biomarkers in mTBI, and further validate the ACHI rat model of mTBI.

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Aims: \ud Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevated myocardial infarction (STEMI) to heart failure. Here we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.\ud \ud Methods and Results: \ud We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 hour post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies, demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.\ud \ud Conclusion: \ud Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.\ud \ud Translational perspective: \ud New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.

Olorinab—a highly selective, full agonist of the cannabinoid receptor 2—significantly reduces visceral hypersensitivity and colonic nociceptor firing in inflammatory bowel disease–like and irritable bowel syndrome–like rodent models., Abdominal pain is a key symptom of inflammatory bowel disease and irritable bowel syndrome, for which there are inadequate therapeutic options. We tested whether olorinab—a highly selective, full agonist of the cannabinoid receptor 2 (CB2)—reduced visceral hypersensitivity in models of colitis and chronic visceral hypersensitivity (CVH). In rodents, colitis was induced by intrarectal administration of nitrobenzene sulfonic acid derivatives. Control or colitis animals were administered vehicle or olorinab (3 or 30 mg/kg) twice daily by oral gavage for 5 days, starting 1 day before colitis induction. Chronic visceral hypersensitivity mice were administered olorinab (1, 3, 10, or 30 mg/kg) twice daily by oral gavage for 5 days, starting 24 days after colitis induction. Visceral mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs) to colorectal distension. Ex vivo afferent recordings determined colonic nociceptor firing evoked by mechanical stimuli. Colitis and CVH animals displayed significantly elevated VMRs to colorectal distension and colonic nociceptor hypersensitivity. Olorinab treatment significantly reduced VMRs to control levels in colitis and CVH animals. In addition, olorinab reduced nociceptor hypersensitivity in colitis and CVH states in a concentration- and CB2-dependent manner. By contrast, olorinab did not alter VMRs nor nociceptor responsiveness in control animals. Cannabinoid receptor 2 mRNA was detected in colonic tissue, particularly within epithelial cells, and dorsal root ganglia, with no significant differences between healthy, colitis, and CVH states. These results demonstrate that olorinab reduces visceral hypersensitivity through CB2 agonism in animal models, suggesting that olorinab may provide a novel therapy for inflammatory bowel disease– and irritable bowel syndrome–associated abdominal pain.

The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population‐based Cervix Screening Program in British Columbia, Canada. We conducted a cost‐effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high‐grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid‐based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co‐testing at the 48‐month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of ‐$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC‐based testing every 2 years for cervical cancer screening at a lower cost., The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing primary HPV testing to liquid‐based cytology for cervical cancer screening. We conducted a cost‐effectiveness analysis alongside the HPV FOCAL trial. Results showed the intervention group yielded a higher rate of detected cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+) at a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of −$773. Findings suggest that primary HPV testing is cost‐effective compared to liquid‐based cytology.