Clinical Outcomes After Acute Coronary Syndromes or Revascularization Among People Living With HIV: A Systematic Review and Meta-Analysis.

Importance: Clinical outcomes after acute coronary syndromes (ACS) or percutaneous coronary interventions (PCIs) in people living with HIV have not been characterized in sufficient detail, and extant data have not been synthesized adequately. Objective: To better characterize clinical outcomes and postdischarge treatment of patients living with HIV after ACS or PCIs compared with patients in an HIV-negative control group. Data Sources: Ovid MEDLINE, Embase, and Web of Science were searched for all available longitudinal studies of patients living with HIV after ACS or PCIs from inception until August 2023. Study Selection: Included studies met the following criteria: patients living with HIV and HIV-negative comparator group included, patients presenting with ACS or undergoing PCI included, and longitudinal follow-up data collected after the initial event. Data Extraction and Synthesis: Data extraction was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Clinical outcome data were pooled using a random-effects model meta-analysis. Main Outcome and Measures: The following clinical outcomes were studied: all-cause mortality, major adverse cardiovascular events, cardiovascular death, recurrent ACS, stroke, new heart failure, total lesion revascularization, and total vessel revascularization. The maximally adjusted relative risk (RR) of clinical outcomes on follow-up comparing patients living with HIV with patients in control groups was taken as the main outcome measure. Results: A total of 15 studies including 9499 patients living with HIV (pooled proportion [range], 76.4% [64.3%-100%] male; pooled mean [range] age, 56.2 [47.0-63.0] years) and 1 531 117 patients without HIV in a control group (pooled proportion [range], 61.7% [59.7%-100%] male; pooled mean [range] age, 67.7 [42.0-69.4] years) were included; both populations were predominantly male, but patients living with HIV were younger by approximately 11 years. Patients living with HIV were also significantly more likely to be current smokers (pooled proportion [range], 59.1% [24.0%-75.0%] smokers vs 42.8% [26.0%-64.1%] smokers) and engage in illicit drug use (pooled proportion [range], 31.2% [2.0%-33.7%] drug use vs 6.8% [0%-11.5%] drug use) and had higher triglyceride (pooled mean [range], 233 [167-268] vs 171 [148-220] mg/dL) and lower high-density lipoprotein-cholesterol (pooled mean [range], 40 [26-43] vs 46 [29-46] mg/dL) levels. Populations with and without HIV were followed up for a pooled mean (range) of 16.2 (3.0-60.8) months and 11.9 (3.0-60.8) months, respectively. On postdischarge follow-up, patients living with HIV had lower prevalence of statin (pooled proportion [range], 53.3% [45.8%-96.1%] vs 59.9% [58.4%-99.0%]) and ß-blocker (pooled proportion [range], 54.0% [51.3%-90.0%] vs 60.6% [59.6%-93.6%]) prescriptions compared with those in the control group, but these differences were not statistically significant. There was a significantly increased risk among patients living with HIV vs those without HIV for all-cause mortality (RR, 1.64; 95% CI, 1.32-2.04), major adverse cardiovascular events (RR, 1.11; 95% CI, 1.01-1.22), recurrent ACS (RR, 1.83; 95% CI, 1.12-2.97), and admissions for new heart failure (RR, 3.39; 95% CI, 1.73-6.62). Conclusions and Relevance: These findings suggest the need for attention toward secondary prevention strategies to address poor outcomes of cardiovascular disease among patients living with HIV.

A Prospective, Randomized Controlled Multicenter Trial Comparing the Bard Inlay Optima and the Cook Universa Soft Stent.

OBJECTIVE: To determine if the Bard Inlay Optima with its anti-inflammatory pHreecoat stent coating had reduced stent-related symptoms at Week 1 (W1) and Week 3 (W3) post insertion compared to the Cook Universa Soft (CUS) using the validated Ureteral Stent Symptoms Questionnaire (USSQ). METHODS: A prospective, double-blinded, randomized controlled trial was performed on patients receiving unilateral retrograde double-J stents for urolithiasis or pelviureteric junction obstruction at three public Urology services. One hundred forty patients that met inclusion criteria were randomized in a 1:1 ratio to each stent. Primary endpoints were the mean USSQ index scores for the urinary, pain, general, and sexual health domains at W1 and W3. Secondary endpoints were responses to individual USSQ questions, early stent removal, and postoperative opioid use. RESULTS: No significant difference was found between the two stents in terms of index scores for all USSQ domains, early stent removal or postoperative opioid use. The CUS had worse symptom scores at W1 relating to self-reported urinary tract infection symptoms (3.1 ± 1.3 vs 2.6 ± 1.3, P = .05). The CUS was also associated with higher rate of representation to hospital at W1 (n = 10, 16% vs n = 1, 2%, P < .001) and W3 (n = 15, 25% vs n = 3, 5%, P < .001). This did not remain significant when adjusted to site of recruitment (W1 P = .27; W3 P = .22). CONCLUSION: The Bard Inlay Optima's anti-inflammatory pHreecoat stent coating did not translate to any significant difference in overall postoperative symptoms across urinary, pain, general, and sexual health domains.

Performance of Cardiovascular Risk Prediction Models Among People Living With HIV: A Systematic Review and Meta-analysis.

Importance: Extant data on the performance of cardiovascular disease (CVD) risk score models in people living with HIV have not been synthesized. Objective: To synthesize available data on the performance of the various CVD risk scores in people living with HIV. Data Sources: PubMed and Embase were searched from inception through January 31, 2021. Study Selection: Selected studies (1) were chosen based on cohort design, (2) included adults with a diagnosis of HIV, (3) assessed CVD outcomes, and (4) had available data on a minimum of 1 CVD risk score. Data Extraction and Synthesis: Relevant data related to study characteristics, CVD outcome, and risk prediction models were extracted in duplicate. Measures of calibration and discrimination are presented in tables and qualitatively summarized. Additionally, where possible, estimates of discrimination and calibration measures were combined and stratified by type of risk model. Main Outcomes and Measures: Measures of calibration and discrimination. Results: Nine unique observational studies involving 75 304 people (weighted average age, 42 years; 59 490 male individuals [79%]) living with HIV were included. In the studies reporting these data, 86% were receiving antiretroviral therapy and had a weighted average CD4+ count of 449 cells/µL. Included in the study were current smokers (50%), patients with diabetes (5%), and patients with hypertension (25%). Ten risk prediction scores (6 in the general population and 4 in the HIV-specific population) were analyzed. Most risk scores had a moderate performance in discrimination (C statistic: 0.7-0.8), without a significant difference in performance between the risk scores of the general and HIV-specific populations. One of the HIV-specific risk models (Data Collection on Adverse Effects of Anti-HIV Drugs Cohort 2016) and 2 of the general population risk models (Framingham Risk Score [FRS] and Pooled Cohort Equation [PCE] 10 year) had the highest performance in discrimination. In general, models tended to underpredict CVD risk, except for FRS and PCE 10-year scores, which were better calibrated. There was substantial heterogeneity across the studies, with only a few studies contributing data for each risk score. Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that general population and HIV-specific CVD risk models had comparable, moderate discrimination ability in people living with HIV, with a general tendency to underpredict risk. These results reinforce the current recommendations provided by the American College of Cardiology/American Heart Association guidelines to consider HIV as a risk-enhancing factor when estimating CVD risk.

A Rare Case of Haemophilus Influenzae Serotype F Endocarditis Complicated by Concurrent Cardiogenic and Septic Shock: A Case of Challenging Management.

H. Influenza is a rare cause of endocarditis. We report a case of H. Influenza endocarditis that was complicated by cardiogenic and septic shock, active myocardial ischemia and aortic insufficiency. The goal of this report is to help recognize the signs and symptoms of endocarditis and to discuss management strategies in patients with concomitant cardiogenic and septic shock complicated by aortic insufficiency.

Mineral content variations between Australian tap and bottled water in the context of urolithiasis.

Objectives: The objective of this study is to investigate the variations in mineral content of tap drinking water across major Australian cities, compared with bottled still and sparkling water, and discuss the possible implications on kidney stone disease (KSD). Materials and Methods: The mineral composition of public tap water from 10 metropolitan and regional Australian cities was compared using the drinking water quality reports published from 2019 to 2021 by the respective water service utilities providers. Specifically, average levels of calcium, bicarbonate, magnesium, sodium, potassium, and sulphates were compared with published mineral content data from bottled still and sparkling drinking water in Australia. Results: The median or mean (depending on report output) mineral composition was highly variable for calcium (range 1.3 to 20.33 mg/L), magnesium (range 1.1 to 11.2 mg/L), bicarbonate (range 12 to 79 mg/L), sodium (range 3 to 47.1 mg/L), potassium (range 0.4 to 3.23 mg/L) and (sulphates range <1 to 37.4 mg/L). Calcium, magnesium and bicarbonate levels in tap water were lower than in bottled sparkling water. Consumption of 3 L/day of the most calcium rich tap water would fulfil 4.7% of the RDI, compared with 8.7% with bottled sparkling water. Consumption of 3 L of the most magnesium rich tap water would fulfil 8% of the RDI, compared with 13.6% with bottled sparkling water. Conclusion: The mineral content of tap drinking water varied substantially across major Australian city centres. Bottled sparkling water on average provided higher levels of calcium, bicarbonate and magnesium and may be preferred for prevention of calcium oxalate stones. These findings may assist counselling of patients with KSD depending on geographic location in the context of other modifiable risk factors and 24-h urine analysis results.

Prevalence and sequelae of penile lichen sclerosus in males presenting for circumcision in regional Australia: a multicentre retrospective cohort study.

Background: Lichen sclerosus (LS) in men commonly involves the external genitalia, with up to 20% of these patients developing urethral stricture disease, and a small group developing malignant transformation to penile squamous cell carcinoma (SCC). The objective of this study was to determine the prevalence of LS and its sequelae in males presenting for circumcision. Methods: A multicentre retrospective cohort study was conducted at 8 hospitals within 3 Australian regional centres. We identified males who underwent circumcision between January 2004 and November 2018 and obtained histological and clinical data. Histopathological confirmation of LS was the primary outcome. Development of urethral stricture disease and penile cancer were secondary outcomes. Results: Six hundred and eleven patients underwent circumcision, of which 313 (51.2%) had a specimen sent for histology. Of these, 199 (63.6%) had confirmed LS where the median age at diagnosis was 65 years [interquartile range (IQR), 40-77]. Even if the remainder of unsent specimens were free of LS, the prevalence would still be 32.6%. Amongst the patients with LS, 44 (22.1%) developed urethral strictures, 1 penile SCC (0.5%), and 1 penile intraepithelial neoplasia (0.5%). Conclusions: The prevalence of LS in patients undergoing circumcision where the foreskin was sent for histopathological review was 63.6%. In those with LS, the prevalence of urethral stricture disease was 22.1%.

Guideline of guidelines: management of recurrent urinary tract infections in women.

OBJECTIVE: To compare recurrent urinary tract infection (rUTI) guidelines from major urological and non-urological organisations internationally and identify areas of consensus and discrepancy. METHODS: PubMed, Google Scholar and the official webpages of major urological, gynaecological, infectious diseases and general practice organisations were searched for rUTI guidelines in March 2022. Nine guidelines were included for review: European Association of Urology, National Institute for Health and Care Excellence (NICE), Society of Obstetricians and Gynaecologists of Canada, American Academy of Family Physicians, Mexican College of Gynaecology and Obstetrics Specialists, Swiss Society of Gynaecology and Obstetrics, Spanish Society of Infectious Diseases and Clinical Microbiology, German Association of Scientific Medical Societies, and the combined American Urological Association/Canadian Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction. RESULTS: The definition and evaluation of rUTIs, and antibiotic prophylaxis strategies, were mostly consistent across guidelines, and emphasised the importance of obtaining urine cultures and limiting cystoscopy and upper tract imaging in women without risk factors. Variable recommendations were noted for symptomatic treatment, self-initiated antibiotics, and antibiotic-sparing preventative strategies such as cranberry, vaginal oestrogen, immunoactive prophylaxis with OM-89, intravesical glycosaminoglycan instillation, and phytotherapeutics. Recent randomised evidence supports the use of methenamine hippurate. Either continuous or post-coital prophylactic antibiotics were supported by all guidelines. None of the guidelines were tailored to the management recurrent complicated UTI. CONCLUSION: Multiple rUTI guidelines were identified and mostly limited their recommendations to otherwise healthy non-pregnant women with uncomplicated cystitis. Variation was noted, particularly in antibiotic-sparing preventative strategies. Some conflicting recommendations are due to more recent guidelines including updated evidence. Future guidelines should consider recommendations to assist management of complex patient groups, such as recurrent complicated UTI.

Endovascular Intravascular Lithotripsy in the Treatment of Calcific Common Femoral Artery Disease: A Case Series With an 18-Month Follow-Up.

BACKGROUND: Intravascular lithotripsy (IVL) is a novel endovascular treatment for calcified common femoral artery disease (CFA). Data on midterm effectiveness for clinically driven target lesions revascularization (CD-TLR) is lacking. This study investigated CD-TLR during 18-month follow-up in patients requiring IVL for CFA disease treatment. METHODS: In a single-center retrospective cohort study, electronic medical record of patients undergoing IVL for CFA disease from January 2018 to March 2020 were reviewed. Primary outcome was CD-TLR estimated by Kaplan-Meier method during 18-month follow-up. Univariate logistic regression was used to compare differences in CD-TLR by the type of adjunct therapy used. RESULTS: Among 54 CFA lesions in 50 patients, mean age (SD) was 75(8) years, gender and race were predominantly male (74%, n = 37) and white (94%, n = 47), respectively. Rutherford class III claudication was most common (70%, n = 35) with mean ABI of 0.66 (0.26) and mean angiographic stenosis of 77% (13%). Adjunct use of drug-coated balloon (DCB) angioplasty was 83% (n = 45) and atherectomy was 39% (n = 21). Residual angiographic stenosis was <30% in all cases. Complications included dissection requiring stent placement (2%, n = 1). After 18-months, 18% (n = 9) died unrelated to procedural complications and 6% (n = 3) were lost to follow-up. 18-month cumulative freedom from CD-TLR was 80.6% (95% CI: 69.1%, 92%). Univariate logistic regression did not reveal a statistically significant difference in CD-TLR with type of adjunct therapy used (p > 0.05). CONCLUSION: IVL with adjunct use of DCB and/or atherectomy is safe and effective in treatment of calcified CFA disease. Randomized studies are required to confirm these findings.

The role of dual tracer PSMA and FDG PET/CT in renal cell carcinoma (RCC) compared to conventional imaging: A multi-institutional case series with intra-individual comparison.

PURPOSE: The objective of this study was to perform an intra-individual dual tracer comparison of Fluorodeoxyglucose (FDG) and Prostate Specific Membrane Antigen (PSMA) computed tomography (CT)/Positron Emission Tomography (PET) against standard of care (SOC) imaging for the characterisation, staging and restaging of renal cell carcinoma (RCC). METHODS: A multicentre retrospective cohort study was performed at 3 major tertiary referral institutions in Brisbane, Australia between 2015 and 2020. All patients who underwent both PSMA and FDG PET/CT following SOC imaging for investigation of RCC were identified. Clinical details, imaging characteristics and histopathology were collected prior to univariate statistical analysis. RESULTS: Eleven patients who underwent dual tracer PET/CT were included. Mean age was 65.5 years (SD 8.8). Most patients were male (64%) with clear cell morphology (91%). The indication for dual tracer PET was staging (36%) and restaging after radical/partial nephrectomy (64%). Primary tumour assessment showed mixed avidity patterns (concordant 40%, discordant favouring PSMA 20%, and FDG 40%). Metastatic disease assessment showed concordant avidity in 6 patients (55%), concordant negative in 3 (27%), and discordant uptake favouring PSMA. PET outperformed SOC imaging for assessment of metastatic disease in 5 patients (45%) and equivalent for the remainder. A change in management was noted in three cases (27%). CONCLUSION: Dual tracer FDG and PSMA PET/CT for assessment of primary and metastatic RCC were mostly concordant. PET imaging outperformed conventional imaging and led to a change in management for 1 in 4 patients. Further studies with larger samples sizes are required to validate these findings and identify characteristics to guide patient selection for selective or dual tracer use.

Intravascular Lithotripsy in Calcified Subclavian and Innominate Peripheral Artery Disease: A Single-Centre Experience.

BACKGROUND: Intravascular lithotripsy (IVL) is a novel tool for the treatment of calcified vascular stenosis. Recently, IVL has been successfully used for modification of calcified plaque in coronary and lower extremity peripheral arteries with promising results. However, experience in subclavian and innominate peripheral arterial disease is limited. This study aims to report our initial experience of IVL use in calcified subclavian and innominate vasculature. METHODS: This was a retrospective review of all the cases of IVL performed in subclavian and innominate arteries at the Miriam Hospital, Providence, between January 2019 and May 2020. Data on the baseline and procedural characteristics were collected. The primary endpoint was procedural success defined as residual stenosis of <20% after stenting. Other endpoints of interest were; 1) procedural complications, including dissections, perforations, abrupt closure, slow or no-reflow, thrombosis, and distal embolization; 2) in-hospital major adverse cardiac events (MACE) defined as a composite of death, myocardial infarction, or stroke/transient ischemic attack. RESULTS: A total of 7 patients with 13 lesions undergoing IVL were included. Of these, 5 (71%) were women, the mean age was 74.6 ± 12.9, and the mean BMI was 25.1 ± 6.7. IVL was successfully delivered to all the target lesions with a mean 252.9 ± 54.4 pulses delivered per patient. Procedural success was achieved in 100% of the treated lesions. No procedure-related complications or in-hospital MACE occurred in any of the patients. CONCLUSIONS: In this single-center retrospective analysis, IVL facilitated acute procedural success without any procedural complications in severely calcified stenoses of the subclavian and innominate vasculature. Larger studies with an active comparator and longer follow-up are needed to establish the relative efficacy and safety of IVL use in this vascular bed.

Dual-Tracer Positron-Emission Tomography Using Prostate-Specific Membrane Antigen and Fluorodeoxyglucose for Staging of Prostate Cancer: A Systematic Review.

PSMA PET is more accurate than conventional imaging (CT/bone scan) for staging of intermediate- or high-risk prostate cancer (PCa), but 5-10% of primary tumours have low PSMA ligand uptake. FDG PET has been used to further define disease extent in end-stage castrate-resistant PCa and may be beneficial earlier in the disease course for more accurate staging. The objective of this study was to review the available evidence for patients undergoing both FDG and PSMA PET for PCa staging at initial diagnosis and in recurrent disease. A systematic literature review was performed for studies with direct, intraindividual comparison of PSMA and FDG PET for staging of PCa. Assessment for radioligand therapy eligibility was not considered. Risk of bias was assessed. 543 citations were screened and assessed. 13 case reports, three retrospective studies, and one prospective study were included. FDG after PSMA PET improved the detection of metastases from 65% to 73% in high-risk early castration-resistant PCa with negative conventional imaging (M0). Positive FDG PET was found in 17% of men with negative PSMA PET for postprostatectomy biochemical recurrence. Gleason score ≥8 and higher PSA levels predicted FDG-avid metastases in BCR and primary staging. Variant histology (ductal and neuroendocrine) was common in case reports, resulting in PSMA-negative FDG-positive imaging for 3 patients. Dual-tracer PET for PCa may assist in characterising high-risk disease during primary staging and restaging. Further studies are required to determine the additive benefit of FDG PET and if the FDG-positive phenotype may indicate a poorer prognosis.

A young man with irregularly irregular narrow complex tachycardia.

Pulmonary vein atrial tachycardia (PVAT) is a rare arrhythmia that accounts for 3% of all atrial tachycardia types. On electrocardiogram, fast PVATs may be misinterpreted as atrial fibrillation at first glance. We present a case of PVAT refractory to pharmacological intervention in a 31-year-old, requiring ablation to terminate the arrhythmia.

Spontaneous Termination of Ventricular Fibrillation: Is Organization Required?

Ventricular fibrillation is a life-threatening arrhythmia that can result in sudden cardiac death and almost always requires emergency electrical defibrillation. This paper presents a unique case of a 74-year-old woman with spontaneous termination of a 2-min 13-s ventricular fibrillation episode without organization before termination. (Level of Difficulty: Advanced.).

Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease.

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.

Dual expandable interbody cage utilization for enhanced stability in vertebral column reconstruction following thoracolumbar corpectomy: A report of two cases.

BACKGROUND: Thoracolumbar corpectomies require adequate anterior column spinal reconstruction, often achieved through a single static or expandable cage. Patients with larger vertebrae, or those who require a larger footprint of reconstruction placed via a posterior approach are technically challenging. The aim of this report was to describe a novel approach for reconstruction using two smaller expandable cages following corpectomy, in the setting of tumor and trauma. METHODS: These technical reports illustrate a novel intraoperative technique with reconstruction via dual expandable cages implanted posteriorly from a bilateral costotransversectomy and transpedicular approaches. Due to the smaller size of each cage, implantation in the vertebral column was achieved with minimal retraction of the spinal cord. RESULTS: Two patients underwent urgent corpectomy in the thoracolumbar spine using this technique. Clinical improvement was evident post-surgery and adequate spine stabilization was confirmed radiographically without cage migration or subsidence, at up to one year of clinical follow up. No iatrogenic neurological deficits were reported in each case as well. CONCLUSION: To the authors' knowledge, this is the first report of a corpectomy where this surgical technique was implemented in the thoracolumbar spine. This technique created a large footprint of reconstruction with less retraction on the spinal cord during surgery, reducing the potential for neurological complications. An alternative strategy is to place a larger footprint reconstruction through an anterior or lateral approach; however, these techniques also have potential morbidity which require consideration.

Massive Hemothorax from Bronchial Artery Bleeding after Endobronchial Ultrasound Transbronchial Needle Aspiration.

Endobronchial Ultrasound (EBUS) with Transbronchial Needle Aspiration (TBNA) is performed with a very low complication rate. We present a unique case of massive life-threatening hemothorax from bronchial artery bleeding after EBUS-TBNA, presenting in a delayed fashion and requiring operative intervention. Although exceedingly rare, along with the unusual delayed timing of the presentation, practitioners should be aware of this complication. It may be helpful to perform EBUS with color doppler examination of the subcarinal space to identify and avoid bronchial arteries prior to TBNA of subcarinal lymph nodes.

For the future and possible ensuing waves of COVID-19: A perspective to consider when disseminating data.

During the COVID-19 pandemic, most citizens in North America receive daily updates, which highlight the number of new cases per day in a specified region. However, as this data metric is often presented alone on media and news platforms, the spread of the novel coronavirus may often be misinterpreted. Among these daily updates which are critical to informing the public, the authors emphasize the importance of controlling for variation attributed to changes in surveillance. The number of test results that have been analyzed each day along with the total number of tests being conducted in a region have a significant impact on capturing virus spread and should always be included in widespread data. Presenting these variables may help to differentiate increases or decreases of new cases attributed to the expansion of surveillance and testing, or rather other environmental and behavioral factors. Overall, to best inform politicians, healthcare workers, and all citizens of the progress against COVID-19, there is a need to constantly improve analyses and reporting of data.

Revision gastric bypass after laparoscopic adjustable gastric band: a 10-year experience at a public teaching hospital.

BACKGROUND: In Australia, there is limited access to public revisional bariatric procedures. However, the need for such procedures is rising. We investigated the safety and efficacy of band-to-bypass procedures in our experience at a public teaching hospital over a period of 10 years. METHODS: Using a prospectively maintained bariatric surgical database, we analysed 91 consecutive planned band-to-bypass procedures from 2007 to November 2016. All patients had prior laparoscopic adjustable gastric bands removed and formation of Roux-en-Y gastric bypass, in one or two stages. Primary outcomes were 30-day complication rate and excess weight loss from 12 months. The impact of fellows as primary operators on these outcomes was assessed. RESULTS: Eighty-two patients met the inclusion criteria. Seventy-one (84.5%) were females. Mean age was 48.8 years (SD: 8.85). Immediate post-operative complications included six (7.3%) patients with gastrojejunostomy leak, three of whom required conversion to laparotomy, with one mortality (1.22%). Fifty-two patients had follow-up of 1 year or more (median: 2.36, range: 1-9.24). Mean excess weight loss at the end of follow-up was 52.79% (SD: 46.46). Twenty-eight (34.14%) cases were performed primarily by a fellow under the guidance of an experienced bariatric surgeon, with equivalent results. CONCLUSION: Revisional band-to-bypass in the public setting is an effective but complex procedure associated with morbidity. Some risk may be ameliorated by development of selection criteria to exclude certain high-risk groups. We hope discussion amongst other bariatric groups will further refine this approach.

USP7 small-molecule inhibitors interfere with ubiquitin binding.

The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival. However, developing selective deubiquitinase inhibitors has been challenging and no co-crystal structures have been solved with small-molecule inhibitors. Here, using nuclear magnetic resonance-based screening and structure-based design, we describe the development of selective USP7 inhibitors GNE-6640 and GNE-6776. These compounds induce tumour cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors. Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12 Å distant from the catalytic cysteine. The compounds attenuate ubiquitin binding and thus inhibit USP7 deubiquitinase activity. GNE-6640 and GNE-6776 interact with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain, suggesting that USP7 preferentially interacts with and cleaves ubiquitin moieties that have free Lys48 side chains. We investigated this idea by engineering di-ubiquitin chains containing differential proximal and distal isotopic labels and measuring USP7 binding by nuclear magnetic resonance. This preferential binding protracted the depolymerization kinetics of Lys48-linked ubiquitin chains relative to Lys63-linked chains. In summary, engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly applicable to inhibiting proteins that require ubiquitin binding for full functional activity.