Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. METHODS: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. FINDINGS: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483). INTERPRETATION: SRT can reduce ranibizumab treatment burden without compromising vision. FUNDING: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Risk of diabetic retinopathy and diabetic macular oedema with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in type 2 diabetes: a real-world data study from a global federated database.

AIMS/HYPOTHESIS: A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin. METHODS: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed. RESULTS: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208). CONCLUSIONS/INTERPRETATION: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated  retinal imaging are required to determine the causal relationship with these therapies.

Distinct regulatory networks control toxin gene expression in elapid and viperid snakes.

BACKGROUND: Venom systems are ideal models to study genetic regulatory mechanisms that underpin evolutionary novelty. Snake venom glands are thought to share a common origin, but there are major distinctions between venom toxins from the medically significant snake families Elapidae and Viperidae, and toxin gene regulatory investigations in elapid snakes have been limited. Here, we used high-throughput RNA-sequencing to profile gene expression and microRNAs between active (milked) and resting (unmilked) venom glands in an elapid (Eastern Brown Snake, Pseudonaja textilis), in addition to comparative genomics, to identify cis- and trans-acting regulation of venom production in an elapid in comparison to viperids (Crotalus viridis and C. tigris). RESULTS: Although there is conservation in high-level mechanistic pathways regulating venom production (unfolded protein response, Notch signaling and cholesterol homeostasis), there are differences in the regulation of histone methylation enzymes, transcription factors, and microRNAs in venom glands from these two snake families. Histone methyltransferases and transcription factor (TF) specificity protein 1 (Sp1) were highly upregulated in the milked elapid venom gland in comparison to the viperids, whereas nuclear factor I (NFI) TFs were upregulated after viperid venom milking. Sp1 and NFI cis-regulatory elements were common to toxin gene promoter regions, but many unique elements were also present between elapid and viperid toxins. The presence of Sp1 binding sites across multiple elapid toxin gene promoter regions that have been experimentally determined to regulate expression, in addition to upregulation of Sp1 after venom milking, suggests this transcription factor is involved in elapid toxin expression. microRNA profiles were distinctive between milked and unmilked venom glands for both snake families, and microRNAs were predicted to target a diversity of toxin transcripts in the elapid P. textilis venom gland, but only snake venom metalloproteinase transcripts in the viperid C. viridis venom gland. These results suggest differences in toxin gene posttranscriptional regulation between the elapid P. textilis and viperid C. viridis. CONCLUSIONS: Our comparative transcriptomic and genomic analyses between toxin genes and isoforms in elapid and viperid snakes suggests independent toxin regulation between these two snake families, demonstrating multiple different regulatory mechanisms underpin a venomous phenotype.

LIVECell-A large-scale dataset for label-free live cell segmentation.

Light microscopy combined with well-established protocols of two-dimensional cell culture facilitates high-throughput quantitative imaging to study biological phenomena. Accurate segmentation of individual cells in images enables exploration of complex biological questions, but can require sophisticated imaging processing pipelines in cases of low contrast and high object density. Deep learning-based methods are considered state-of-the-art for image segmentation but typically require vast amounts of annotated data, for which there is no suitable resource available in the field of label-free cellular imaging. Here, we present LIVECell, a large, high-quality, manually annotated and expert-validated dataset of phase-contrast images, consisting of over 1.6 million cells from a diverse set of cell morphologies and culture densities. To further demonstrate its use, we train convolutional neural network-based models using LIVECell and evaluate model segmentation accuracy with a proposed a suite of benchmarks.

Assessment of guidelines for bariatric and metabolic surgery: a systematic review and evaluation using appraisal of guidelines for research and evaluation II (AGREE II).

BACKGROUND: In recent years, multiple guidelines on bariatric and metabolic surgery were published, however, their quality remains unknown, leaving providers with uncertainty when using them to make perioperative decisions. This study aims to evaluate the quality of existing guidelines for perioperative bariatric surgery care. METHODS: A comprehensive search of MEDLINE and EMBASE were conducted from January 2010 to October 2022 for bariatric clinical practice guidelines. Guideline evaluation was carried out using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. RESULTS: The initial search yielded 1483 citations, of which, 26 were included in final analysis. The overall median domain scores for guidelines were: (1) scope and purpose: 87.5% (IQR: 57-94%), (2) stakeholder involvement: 49% (IQR: 40-64%), (3) rigor of development: 42.5% (IQR: 22-68%), (4) clarity of presentation: 85% (IQR: 81-90%), (5) applicability: 6% (IQR: 3-16%), (6) editorial independence: 50% (IQR: 48-67%), (7) overall impressions: 48% (IQR: 33-67%). Only six guidelines achieved an overall score >70%. CONCLUSIONS: Bariatric surgery guidelines effectively outlined their aim and presented recommendations. However, many did not adequately seek patient input, state search criteria, use evidence rating tools, and consider resource implications. Future guidelines should reference the AGREE II framework in study design.

Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

Generation, Characterization and Reactivity of a High-Valent Mononuclear Cobalt(IV)-Diazide Complex.

High-valent Fe(IV)=O intermediates of metalloenzymes have inspired numerous efforts to generate synthetic analogs to mimic and understand their substrate oxidation reactivities. However, high-valent M(IV) complexes of late transition metals are rare. We have recently reported a novel Co(IV)-dinitrate complex (1-NO3) that activates sp3 C-H bonds up to 87 kcal/mol. In this work, we have shown that the nitrate ligands in 1-NO3 can be replaced by azide, a more basic coordinating base, resulting in the formation of a more potent Co(IV)-diazide species (1-N3) that reacts with substrates (hydrocarbons and phenols) at faster rate constants and activates stronger C-H bonds than the parent complex 1-NO3. We have characterized 1-N3 employing a combination of spectroscopic and computational approaches. Our results clearly show that the coordination of azide leads to the modulation of the Co(IV) electronic structure and the Co(IV/III) redox potential. Together with the higher basicity of azide, these thermodynamic parameters contribute to the higher driving forces of 1-N3 than 1-NO3 for C-H bond activation. Our discoveries are thus insightful for designing more reactive bio-inspired high-valent late transition metal complexes for activating inert aliphatic hydrocarbons.

Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients.

BACKGROUND AND AIMS: Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non-alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross-validation approach to assess this interaction in bariatric patients. METHODS: 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non-alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4. RESULTS: We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3-F4) versus F0 had lower abundance of anti-inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol-10 biosynthesis and Peptidoglycan biosynthesis IV. CONCLUSIONS: In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity.

C-H Bond Oxidation by MnIV-Oxo Complexes: Hydrogen-Atom Tunneling and Multistate Reactivity.

The reactivity of six MnIV-oxo complexes in C-H bond oxidation has been examined using a combination of kinetic experiments and computational methods. Variable-temperature studies of the oxidation of 9,10-dihydroanthracene (DHA) and ethylbenzene by these MnIV-oxo complexes yielded activation parameters suitable for evaluating electronic structure computations. Complementary kinetic experiments of the oxidation of deuterated DHA provided evidence for hydrogen-atom tunneling in C-H bond oxidation for all MnIV-oxo complexes. These results are in accordance with the Bell model, where tunneling occurs near the top of the transition-state barrier. Density functional theory (DFT) and DLPNO-CCSD(T1) computations were performed for three of the six MnIV-oxo complexes to probe a previously predicted multistate reactivity model. The DFT computations predicted a thermal crossing from the 4B1 ground state to a 4E state along the C-H bond oxidation reaction coordinate. DLPNO-CCSD(T1) calculations further confirm that the 4E transition state offers a lower energy barrier, reinforcing the multistate reactivity model for these complexes. We discuss how this multistate model can be reconciled with recent computations that revealed that the kinetics of C-H bond oxidation by this set of MnIV-oxo complexes can be well-predicted on the basis of the thermodynamic driving force for these reactions.

Trading HIV for sheep: Risky sexual behavior and the response of female sex workers to Tabaski in Senegal.

We use a cohort of female sex workers (FSWs) in Senegal to show how large anticipated economic shocks lead to increased risky sexual behavior. Exploiting the exogenous timing of interviews, we study the effect of Tabaski, the most important Islamic festival celebrated in Senegal, in which most households purchase an expensive animal for sacrifice. Condom use, measured robustly via the list experiment, falls by between 27.3 percentage points (pp) (65.5%) and 43.1 pp (22.7%) in the 9 days before Tabaski, or a maximum of 49.5 pp (76%) in the 7 day period preceding Tabaski. The evidence suggests the economic pressures from Tabaski are key to driving the behavior change observed through the price premium for condomless sex. Those most exposed to the economic pressure from Tabaski were unlikely to be using condoms at all in the week before the festival. Our findings show that Tabaski leads to increased risky behaviors for FSWs, a key population at high risk of HIV infection, for at least 1 week every year and has implications for FSWs in all countries celebrating Tabaski or similar festivals. Because of the scale, frequency, and size of the behavioral response to shocks of this type, policy should be carefully designed to protect vulnerable women against anticipated shocks.

Hospital volume-outcome relationships for robot-assisted surgeries: a population-based analysis.

BACKGROUND: Associations between procedure volumes and outcomes can inform minimum volume standards and the regionalization of health services. Robot-assisted surgery continues to expand globally; however, data are limited regarding which hospitals should be using the technology. STUDY DESIGN: Using administrative health data for all residents of Ontario, Canada, this retrospective cohort study included adult patients who underwent a robot-assisted radical prostatectomy (RARP), total robotic hysterectomy (TRH), robot-assisted partial nephrectomy (RAPN), or robotic portal lobectomy using 4 arms (RPL-4) between January 2010 and September 2021. Associations between yearly hospital volumes and 90-day major complications were evaluated using multivariable logistic regression models adjusted for patient characteristics and clustering at the level of the hospital. RESULTS: A total of 10,879 patients were included, with 7567, 1776, 724, and 812 undergoing a RARP, TRH, RAPN, and RPL-4, respectively. Yearly hospital volume was not associated with 90-day complications for any procedure. Doubling of yearly volume was associated with a 17-min decrease in operative time for RARP (95% confidence interval [CI] - 23 to - 10), 8-min decrease for RAPN (95% CI - 14 to - 2), 24-min decrease for RPL-4 (95% CI - 29 to - 19), and no significant change for TRH (- 7 min; 95% CI - 17 to 3). CONCLUSION: The risk of 90-day major complications does not appear to be higher in low volume hospitals; however, they may not be as efficient with operating room utilization. Careful case selection may have contributed to the lack of an observed association between volumes and complications.

Hospital learning curves for robot-assisted surgeries: a population-based analysis.

BACKGROUND: Robot-assisted surgery has been rapidly adopted. It is important to define the learning curve to inform credentialling requirements, training programs, identify fast and slow learners, and protect patients. This study aimed to characterize the hospital learning curve for common robot-assisted procedures. STUDY DESIGN: This cohort study, using administrative health data for Ontario, Canada, included adult patients who underwent a robot-assisted radical prostatectomy (RARP), total robotic hysterectomy (TRH), robot-assisted partial nephrectomy (RAPN), or robotic portal lobectomy using four arms (RPL-4) between 2010 and 2021. The association between cumulative hospital volume of a robot-assisted procedure and major complications was evaluated using multivariable logistic models adjusted for patient characteristics and clustering at the hospital level. RESULTS: A total of 6814 patients were included, with 5230, 543, 465, and 576 patients in the RARP, TRH, RAPN, and RPL-4 cohorts, respectively. There was no association between cumulative hospital volume and major complications. Visual inspection of learning curves demonstrated a transient worsening of outcomes followed by subsequent improvements with experience. Operative time decreased for all procedures with increasing volume and reached plateaus after approximately 300 RARPs, 75 TRHs, and 150 RPL-4s. The odds of a prolonged length of stay decreased with increasing volume for patients undergoing a RARP (OR 0.87; 95% CI 0.82-0.92) or RPL-4 (OR 0.77; 95% CI 0.68-0.87). CONCLUSION: Hospitals may adopt robot-assisted surgery without significantly increasing the risk of major complications for patients early in the learning curve and with an expectation of increasing efficiency.

Impact of Sugammadex Versus Neostigmine Reversal on Postoperative Recovery Time in Patients With Obstructive Sleep Apnea Undergoing Bariatric Surgery: A Double-Blind, Randomized Controlled Trial.

BACKGROUND: Residual neuromuscular blockade can be associated with serious postoperative complications. Sugammadex is a newer neuromuscular blocking drug (NMBD) reversal agent that rapidly and completely reverses rocuronium. Whether sugammadex has any advantages over neostigmine in morbidly obese patients with obstructive sleep apnea (OSA) is unclear. We investigated whether sugammadex would reduce discharge time from the operating room (OR) compared with neostigmine in morbidly obese patients with OSA undergoing bariatric surgery. METHODS: This was a prospective, double-blinded randomized controlled superiority trial with 2 parallel groups. Patients were randomized 1:1 into reversal of NMBD with sugammadex or neostigmine. Our inclusion criteria were morbidly obese adult patients with OSA undergoing elective bariatric surgery under general anesthesia. Our exclusion criteria were allergy to rocuronium, sugammadex or neostigmine, malignant hyperthermia, hepatic or renal insufficiency, neuromuscular diseases, and an inability to give consent. The primary outcome was the time from administration of the NMBD reversal agent to discharge from the OR. Secondary outcomes included the time from administration of the NMBD reversal agent to the time the patient opened eyes to command, and the time to extubation. The Mann-Whitney test was used to compare the outcomes between treatment groups. RESULTS: We randomized 120 patients into 2 groups of 60 patients. Overall median body mass index (BMI) was 48.1 kg/m2 ([interquartile range, IQR]) [43.0-53.5]. The time from drug administration to discharge from OR was 13.0 minutes [10.0-17.0] in the sugammadex group and 13.5 minutes [11.0-18.3] in the neostigmine group (P = .27). The treatment effect estimate with a bootstrapped 95% confidence interval [CI] for time from admission to discharge from OR was -0.5 [-2.5 to 3]. No differences were observed in postoperative complications and other secondary outcomes. CONCLUSIONS: No difference was observed in OR discharge time in morbidly obese patients with OSA when sugammadex was administered instead of neostigmine.

Health facility assessment of small and sick newborn care in low- and middle-income countries: systematic tool development and operationalisation with NEST360 and UNICEF.

BACKGROUND: Each year an estimated 2.3 million newborns die in the first 28 days of life. Most of these deaths are preventable, and high-quality neonatal care is fundamental for surviving and thriving. Service readiness is used to assess the capacity of hospitals to provide care, but current health facility assessment (HFA) tools do not fully evaluate inpatient small and sick newborn care (SSNC). METHODS: Health systems ingredients for SSNC were identified from international guidelines, notably World Health Organization (WHO), and other standards for SSNC. Existing global and national service readiness tools were identified and mapped against this ingredients list. A novel HFA tool was co-designed according to a priori considerations determined by policymakers from four African governments, including that the HFA be completed in one day and assess readiness across the health system. The tool was reviewed by > 150 global experts, and refined and operationalised in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania between September 2019 and March 2021. RESULTS: Eight hundred and sixty-six key health systems ingredients for service readiness for inpatient SSNC were identified and mapped against four global and eight national tools measuring SSNC service readiness. Tools revealed major content gaps particularly for devices and consumables, care guidelines, and facility infrastructure, with a mean of 13.2% (n = 866, range 2.2-34.4%) of ingredients included. Two tools covered 32.7% and 34.4% (n = 866) of ingredients and were used as inputs for the new HFA tool, which included ten modules organised by adapted WHO health system building blocks, including: infrastructure, pharmacy and laboratory, medical devices and supplies, biomedical technician workshop, human resources, information systems, leadership and governance, family-centred care, and infection prevention and control. This HFA tool can be conducted at a hospital by seven assessors in one day and has been used in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania. CONCLUSION: This HFA tool is available open-access to adapt for use to comprehensively measure service readiness for level-2 SSNC, including respiratory support. The resulting facility-level data enable comparable tracking for Every Newborn Action Plan coverage target four within and between countries, identifying facility and national-level health systems gaps for action.

Editorial Commentary: Capsule Repair Is Necessary at the Conclusion of Arthroscopy to Optimize Return to Full Activity.

Hip capsulotomy and capsule repair have minimal effect on joint kinematics during activities of daily living. With low demands placed on the hip, the hip capsule may provide little to no role on hip stability or microinstability. But the majority, if not all, patients undergoing hip arthroscopy are not content with only resuming basic activities of daily living. Seeking to optimize the hip joint to its maximum capacity should be the goal. Capsule repair is necessary in most to achieve that goal.

Editorial Commentary: Indications for Acetabular Labral Debridement Versus Repair and Reconstruction: There is Still a Role for Selective Labral Debridement.

Not all acetabular labral tears, tissue quality, and size are the same. There is still a role for selective debridement of the acetabular labrum when stable, functional labral tissue remains. An unstable labrum that appears very different than the rest of the labrum is an easy target for repair. Tears requiring resection require graft augmentation or reconstruction.

Editorial Commentary: Endoscopic Repair of Abductor Tendon Tears Results in Variable Patient Reported Outcomes and Generally Good to Excellent Results.

Abductor tendon pathology is fairly common, with up to a 25% incidence in patients having total hip arthroplasty and 30% having hip arthroscopy. A systematic review of endoscopic abductor tendon repair demonstrated that as few as 41% of patients with endoscopic repair of abductor tendon tears achieve a patient acceptable satisfactory state, but a major limitation of systematic reviews is extreme heterogeneity between included studies. Surgical techniques and skills differ, as do tear severity and confounding pathology such as labral tears. Another limitation is a focus on patient-reported outcome measures (PROMs). PROMs are important (we prefer happy patients with poor healing to unhappy patients with healed repairs), but PROMs are also "subjective," and different cohorts of patients in different studies from different locations may have different perceptions or goals with regard to pain and function. As surgeons, we are able to observe gait, strength, and, with advanced imaging when indicated or for research purposes, healing. These, combined with PROMs, influence overall assessment of outcome. Experience and review of the literature show that endoscopic surgical repair of abductor tendon tears generally shows good or excellent results. If a patient has significant pain improvement and objectively improved gait, a calculation of an outcome threshold based on a subjective survey may not tell the full story.

Prevalent bee venom genes evolved before the aculeate stinger and eusociality.

BACKGROUND: Venoms, which have evolved numerous times in animals, are ideal models of convergent trait evolution. However, detailed genomic studies of toxin-encoding genes exist for only a few animal groups. The hyper-diverse hymenopteran insects are the most speciose venomous clade, but investigation of the origin of their venom genes has been largely neglected. RESULTS: Utilizing a combination of genomic and proteo-transcriptomic data, we investigated the origin of 11 toxin genes in 29 published and 3 new hymenopteran genomes and compiled an up-to-date list of prevalent bee venom proteins. Observed patterns indicate that bee venom genes predominantly originate through single gene co-option with gene duplication contributing to subsequent diversification. CONCLUSIONS: Most Hymenoptera venom genes are shared by all members of the clade and only melittin and the new venom protein family anthophilin1 appear unique to the bee lineage. Most venom proteins thus predate the mega-radiation of hymenopterans and the evolution of the aculeate stinger.

Investigating Ligand Sphere Perturbations on MnIII-Alkylperoxo Complexes.

Manganese catalysts that activate hydrogen peroxide carry out several different hydrocarbon oxidation reactions with high stereoselectivity. The commonly proposed mechanism for these reactions involves a key manganese(III)-hydroperoxo intermediate, which decays via O-O bond heterolysis to generate a Mn(V)-oxo species that institutes substrate oxidation. Due to the scarcity of characterized MnIII-hydroperoxo complexes, MnIII-alkylperoxo complexes are employed to understand factors that affect the mechanism of the O-O cleavage. Herein, we report a series of novel complexes, including two room-temperature-stable MnIII-alkylperoxo species, supported by a new amide-containing pentadentate ligand (6Medpaq5NO2). We use a combination of spectroscopic methods and density functional theory computations to probe the effects of the electronic changes in the ligand sphere trans to the hydroxo and alkylperoxo units to thermal stability and reactivity. The structural characterizations for both MnII(OTf)(6Medpaq5NO2) and [MnIII(OH)(6Medpaq5NO2)](OTf) were obtained via single-crystal X-ray crystallography. A perturbation to the ligand sphere allowed for a marked increase in reactivity towards an organic substrate, a modest change in the distribution of the O-O cleavage products from homolytic and heterolytic pathways, and little change in thermal stability.

A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration.

PURPOSE: Neovascular (wet) age-related macular degeneration (nAMD) is driven by VEGFs A, C, and D, which promote angiogenesis and vascular permeability. Intravitreal injections of anti-VEGF-A drugs are the standard of care, but these do not inhibit VEGF-C and D, which may explain why many patients fail to respond fully. This trial aimed to test the safety and efficacy of OPT-302, a biologic inhibitor of VEGF-C and D, in combination with the anti-VEGF-A inhibitor ranibizumab. DESIGN: Dose-ranging, phase 2b, randomized, double-masked, sham-controlled trial. PARTICIPANTS: Participants with treatment-naive nAMD were enrolled from 109 sites across Europe, Israel, and the United States. METHODS: Participants were randomized to 6, 4-weekly, intravitreal injections of 0.5 mg OPT-302, 2.0 mg OPT-302, or sham, plus intravitreal 0.5 mg ranibizumab. MAIN OUTCOME MEASURES: The primary outcome was mean change in ETDRS best-corrected visual acuity (BCVA) at 24 weeks. Secondary outcomes (comparing baseline with week 24) were the proportion of participants gaining or losing ≥ 15 ETDRS BCVA letters; area under the ETDRS BCVA over time curve; change in spectral-domain OCT (SD-OCT) central subfield thickness; and change in intraretinal fluid and subretinal fluid on SD-OCT. RESULTS: Of 366 participants recruited from December 1, 2017, to November 30, 2018, 122, 123, and 121 were randomized to 0.5 mg OPT-302, 2.0 mg OPT-302, and sham, respectively. Mean (± standard deviation) visual acuity gain in the 2.0 mg OPT-302 group was significantly superior to sham (+14.2 ± 11.61 vs. +10.8 ± 11.52 letters; P = 0.01). The 0.5 mg OPT-302 group was not significantly different than the sham group (+9.44 ± 11.32 letters; P = 0.83). Compared with sham, the secondary BCVA outcomes favored the 2.0 mg OPT-302 group, with structural outcomes favoring both OPT-302 dosage groups. Adverse events (AEs) were similar across groups, with 16 (13.3%), 7 (5.6%), and 10 (8.3%) participants in the lower-dose, higher-dose, and sham groups, respectively, developing at least 1 serious AE. Two unrelated deaths both occurred in the sham arm. CONCLUSIONS: Significantly superior vision gain was observed with OPT-302 2.0 mg combination therapy, versus standard of care, with favorable safety (ClinicalTrials.gov identifier: NCT03345082). FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.