Domestication and Divergence of Saccharomyces cerevisiae Beer Yeasts.

Whereas domestication of livestock, pets, and crops is well documented, it is still unclear to what extent microbes associated with the production of food have also undergone human selection and where the plethora of industrial strains originates from. Here, we present the genomes and phenomes of 157 industrial Saccharomyces cerevisiae yeasts. Our analyses reveal that today's industrial yeasts can be divided into five sublineages that are genetically and phenotypically separated from wild strains and originate from only a few ancestors through complex patterns of domestication and local divergence. Large-scale phenotyping and genome analysis further show strong industry-specific selection for stress tolerance, sugar utilization, and flavor production, while the sexual cycle and other phenotypes related to survival in nature show decay, particularly in beer yeasts. Together, these results shed light on the origins, evolutionary history, and phenotypic diversity of industrial yeasts and provide a resource for further selection of superior strains. PAPERCLIP.

Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.

Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay.

Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.

Investigator attitudes on equipoise and practice patterns in the BEST-CLI trial.

OBJECTIVES: There has been significant variability in practice patterns and equipoise regarding treatment approach for chronic limb-threatening ischemia (CLTI). We aimed to assess treatment preferences of Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) investigators prior to and following the trial. METHODS: An electronic 60-question survey was sent to 1180 BEST-CLI investigators in 2022, after trial conclusion and before announcement of results. Investigators' preferences were assessed across clinical scenarios for both open (OPEN) and endovascular (ENDO) revascularization strategies. Vascular surgeon (VS) surgical and ENDO preferences were compared with a 2010 survey administered to prospective investigators before trial funding. RESULTS: For the 2022 survey, the response rate was 20.2% and was comprised of VSs (76.3%), interventional cardiologists (11.4%) and interventional radiologists (11.6%). The majority (72.6%) were in academic practice and 39.1% were in practice for >20 years. During initial CLTI work-up, 65.8%, 42.6%, and 55.9% of respondents always or usually ordered an arterial duplex, computed tomography angiography, and vein mapping, respectively. The most common practice distribution between ENDO and OPEN procedures was 70/30. Postoperatively, a majority reported performing routine duplex surveillance of vein bypass (99%), prosthetic bypass (81.9%), and ENDO interventions (86%). A minority reported always or usually using the wound, ischemia, and foot infection (WIfI) criteria (25.8%), GLASS (8.3%), and a risk calculator (14.8%). More than one-half (52.9%) agreed that the statement "no bridges are burned with an ENDO-first approach" was false. Intervention choice was influenced by availability of the operating room or ENDO suite, personal schedule, and personal skill set in 30.1%, 18.0%, and 45.9% of respondents, respectively. Most respondents reported routinely using paclitaxel-coated balloons (88.1%) and stents (67.5%); however, 73.3% altered practice when safety concerns were raised. Among surgeons, 17.8%, 2.9%, and 10.3% reported performing >10 annual alternative autogenous vein bypasses, composite vein composite vein bypasses, and bypasses to pedal targets, respectively. Among all interventionalists, 8%, 24%, and 8% reported performing >10 annual radial access procedures, pedal or tibial access procedures, and pedal loop revascularizations. The majority (89.1%) of respondents felt that CLTI teams improved care; however, only 23.2% had a defined team. The effectiveness of the teamwork at institutions was characterized as highly effective in 42.5%. When comparing responses by VSs to the 2010 survey, there were no changes in preferred treatment based on Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) II classification or conduit preference. In 2022, OPEN surgery was preferred more for a popliteal occlusion. For clinical scenarios, there were no differences except a decreased proportion of respondents who felt there was equipoise for major tissue loss for major tissue loss (43.8% vs 31.2%) and increased ENDO choice for minor tissue loss (17.6% vs 30.8%) (P < .05). CONCLUSIONS: There is a wide range of practice patterns among vascular specialists treating CLTI. The majority of investigators in BEST-CLI had experience in both advanced OPEN and ENDO techniques and represent a real-world sample of technical expertise. Over the course of the decade of the BEST-CLI trial, there was overall similar equipoise among VSs.

Recent advances and controversial issues in the optimal management of asymptomatic carotid stenosis.

OBJECTIVE: The optimal management of patients with asymptomatic carotid stenosis (AsxCS) is enduringly controversial. We updated our 2021 Expert Review and Position Statement, focusing on recent advances in the diagnosis and management of patients with AsxCS. METHODS: A systematic review of the literature was performed up to August 1, 2023, using PubMed/PubMed Central, EMBASE and Scopus. The following keywords were used in various combinations: "asymptomatic carotid stenosis," "carotid endarterectomy" (CEA), "carotid artery stenting" (CAS), and "transcarotid artery revascularization" (TCAR). Areas covered included (i) improvements in best medical treatment (BMT) for patients with AsxCS and declining stroke risk, (ii) technological advances in surgical/endovascular skills/techniques and outcomes, (iii) risk factors, clinical/imaging characteristics and risk prediction models for the identification of high-risk AsxCS patient subgroups, and (iv) the association between cognitive dysfunction and AsxCS. RESULTS: BMT is essential for all patients with AsxCS, regardless of whether they will eventually be offered CEA, CAS, or TCAR. Specific patient subgroups at high risk for stroke despite BMT should be considered for a carotid revascularization procedure. These patients include those with severe (≥80%) AsxCS, transcranial Doppler-detected microemboli, plaque echolucency on Duplex ultrasound examination, silent infarcts on brain computed tomography or magnetic resonance angiography scans, decreased cerebrovascular reserve, increased size of juxtaluminal hypoechoic area, AsxCS progression, carotid plaque ulceration, and intraplaque hemorrhage. Treatment of patients with AsxCS should be individualized, taking into consideration individual patient preferences and needs, clinical and imaging characteristics, and cultural, ethnic, and social factors. Solid evidence supporting or refuting an association between AsxCS and cognitive dysfunction is lacking. CONCLUSIONS: The optimal management of patients with AsxCS should include BMT for all individuals and a prophylactic carotid revascularization procedure (CEA, CAS, or TCAR) for some asymptomatic patient subgroups, additionally taking into consideration individual patient needs and preference, clinical and imaging characteristics, social and cultural factors, and the available stroke risk prediction models. Future studies should investigate the association between AsxCS with cognitive function and the role of carotid revascularization procedures in the progression or reversal of cognitive dysfunction.

Environmental plastics in the context of UV radiation, climate change, and the Montreal Protocol.

There are close links between solar UV radiation, climate change, and plastic pollution. UV-driven weathering is a key process leading to the degradation of plastics in the environment but also the formation of potentially harmful plastic fragments such as micro- and nanoplastic particles. Estimates of the environmental persistence of plastic pollution, and the formation of fragments, will need to take in account plastic dispersal around the globe, as well as projected UV radiation levels and climate change factors.

Plastics in the environment in the context of UV radiation, climate change and the Montreal Protocol: UNEP Environmental Effects Assessment Panel, Update 2023.

This Assessment Update by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) considers the interactive effects of solar UV radiation, global warming, and other weathering factors on plastics. The Assessment illustrates the significance of solar UV radiation in decreasing the durability of plastic materials, degradation of plastic debris, formation of micro- and nanoplastic particles and accompanying leaching of potential toxic compounds. Micro- and nanoplastics have been found in all ecosystems, the atmosphere, and in humans. While the potential biological risks are not yet well-established, the widespread and increasing occurrence of plastic pollution is reason for continuing research and monitoring. Plastic debris persists after its intended life in soils, water bodies and the atmosphere as well as in living organisms. To counteract accumulation of plastics in the environment, the lifetime of novel plastics or plastic alternatives should better match the functional life of products, with eventual breakdown releasing harmless substances to the environment.

The Public Health and Economic Impact of Drug Overdose Out-of-Hospital Cardiac Arrest in the United States.

OBJECTIVE: To calculate disability-adjusted life years (DALY) and labor productivity loss due to drug overdose out-of-hospital cardiac arrest (DO-OHCA) and compare its contribution to the burden of disease and economic impact of all-cause nontraumatic out-of-hospital cardiac arrest (OHCA) in the US. METHODS: We performed a retrospective observational cohort analysis of all adult (age ≥18 years) nontraumatic emergency medical services-treated OHCA events, including those due to DO-OHCA, from the national Cardiac Arrest Registry to Enhance Survival (CARES) database from January 1, 2017 and December 31, 2020. The main outcome measures of interest were disability-adjusted life years, annual, and lifetime labor productivity loss over the 4-year study period. The findings for the study population were extrapolated to a national level using the CARES population catchment and U.S. population estimates by year. RESULTS: A total of 378,088 adult OHCA events, including 23,252 DO-OHCA (6.2%) met study inclusion criteria. The DO-OHCA DALY increased from 156,707 in 2017 to 265,692 in 2020. Per year, DO-OHCA contributed to 11.4%, 12.0%, 10.5%, and 11.4% of all OHCA DALY lost from 2017-2020, respectively. The mean annual and lifetime productivity losses for all OHCA were stable over time (annual: $47K in 2017 to $50K in 2020; lifetime: $647K in 2017 to $692K in 2020). The CARES population catchment increased by 39.8% over the study period (102.6 M in 2017 to 143.4 M in 2020). For DO-OHCA, the mean annual productivity loss was approximately 30% higher than non-DO-OHCA ($64K vs. $49K in 2020, respectively). The mean lifetime productivity loss for DO-OHCA was 2.5 times higher than non-DO-OHCA ($1.6 M vs. $630K in 2020, respectively). CONCLUSIONS: The DALY due to DO-OHCA has increased over time with expansion of the CARES dataset, but its relative contribution to total OHCA DALY (all non-traumatic etiologies) remained fairly stable. The DO-OHCAs represent approximately 6% of all adult non-traumatic EMS-treated OHCA events but has a disproportionately greater economic impact. Continued efforts to reduce DO-OHCA through public health initiatives are warranted to lessen the societal impact of OHCA in the U.S.

Subacromial Balloon Spacer Implantation Is a Promising Alternative for Patients With Massive Irreparable Rotator Cuff Tears: A Systematic Review.

PURPOSE: To provide an overview of the existing literature on subacromial balloon spacers for the treatment of massive irreparable rotator cuff tears, in an effort to inform surgeons of the procedure's clinical effectiveness. METHODS: The PubMed, Scopus, and Ovid EMBASE databases were queried to identify studies evaluating the clinical, radiographic, and patient-reported outcomes of patients indicated for subacromial balloon spacer implantation. The following datapoints were extracted: study demographics, patient baseline characteristics, and postoperative outcomes of interest. Outcomes were evaluated at baseline and at the longest available follow-up period. RESULTS: A total 766 patients were included among 22 included studies, with an average follow-up of 27.54 months. Improvements were seen for all clinical and patient-reported outcomes: forward elevation (ranging from 9.20 to 90.00° improvement), external rotation (ranging from 2.00 to 22.00°), abduction (ranging from 14.00 to 95.00°), Total Constant Score (ranging from 7.70 to 50.00), American Shoulder and Elbow Surgeons score (ranging from 24.60 to 59.84), Oxford Shoulder Score (ranging from 7.20 to 22.20), and pain score (ranging from 3.57 to 6.50). Minimal differences were seen in acromiohumeral interval (ranging from -2.00 to 1.27). Reoperation and complication rates ranged from 0% to 33% and 0% to 19.64%, respectively. CONCLUSIONS: The short-term results of subacromial balloon spacers for management of massive rotator cuff tears demonstrate clinically relevant improvements in shoulder range of motion and substantial improvements in patient-reported outcome measures. Of note, minimal change in acromiohumeral interval was seen on postoperative radiography, and wide variations in complication and reoperation rates were reported across studies. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies.

Cemented vs. press-fit humeral stems: a matched cohort analysis at a mean follow-up of 10 years.

BACKGROUND: Although cementation of humeral stems has long been considered the gold standard for anatomic shoulder arthroplasty (aTSA), cementless, or press-fit, fixation offers a relatively cheaper and less demanding alternative, particularly in the setting of a revision procedure. However, this approach has been accompanied by concerns of implant loosening and high rates of radiolucency. In the present study, we performed a propensity-matched comparison of clinical and patient-reported outcomes between cemented and cementless fixation techniques for aTSA. We hypothesized that cemented fixation of the humeral component would have significantly better implant survival while providing comparable functional outcomes at final follow-up. METHODS: This study was a retrospective comparison of 50 shoulders undergoing aTSA: 25 using cemented humeral fixation vs. 25 using press-fit humeral fixation. Patients in the 2 groups were propensity matched according to age, sex, and preoperative American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score. Primary outcome measures included range of motion (ROM) (forward elevation, external rotation, internal rotation), patient-reported outcomes (ASES, Simple Shoulder Test [SST], visual analog scale [VAS]), and implant survival. RESULTS: At baseline, the 2 fixation groups were similar in regard to age, sex, body mass index, preoperative ASES score, and surgical indication. Mean follow-up was 11.7 ± 4.95 years in the cemented cohort and 9.13 ± 3.77 years in the press-fit cohort (P = .045). Both groups demonstrated significant improvements postoperatively in all included ROM and patient-reported outcomes. However, press-fit patients reported significantly better VAS, ASES, and SST scores. Mean VAS pain score was 1.1 ± 1.8 in press-fit patients and 3.2 ± 3.0 in cemented patients (P = .005). The mean ASES score was 87.7 ± 12.4 in press-fit patients and 69.5 ± 22.7 in cemented patients (P = .002). Lastly, the mean SST score was 9.8 ± 3.1 in press-fit patients and 7.7 ± 3.7 in cemented patients (P = .040). Both fixation techniques provided lasting implant survivorship with only a single revision operation in each of the cohorts. CONCLUSION: Herein, we provide a propensity-matched, long-term comparison of patients receiving anatomic shoulder arthroplasty stratified according to humeral stem fixation technique. The results of this analysis illustrate that both types of humeral fixation techniques yield durable and significant improvements in shoulder function with similar rates of survival at 10 years of follow-up.

Osteoporosis screening in Australian community pharmacies: A mixed methods study.

ISSUES ADDRESSED: Osteoporosis and poor bone health impact a large proportion of the Australian population, but is drastically underdiagnosed and undertreated. Community pharmacies are a strategic location for osteoporosis screening services due to their accessibility and the demographic profile of customers. The aim of this study was to develop, implement and evaluate a community pharmacy health promotion service centred on encouraging consumers to complete an anonymous osteoporosis screening survey called Know Your Bones. METHODS: The implementation process was documented using the REAIM (reach, effectiveness, adoption, implementation, maintenance) framework. Uptake of the Know Your Bones screening tool was monitored anonymously with website traffic. Surveys and interviews were designed to capture consumer outcomes after screening. Semi-structured interviews were conducted with Australian community pharmacy stakeholders during design and implementation phases to explore their perspectives of the barriers and facilitators. RESULTS: The service was implemented in 27 community pharmacies. There were 448 visits to the screening website. Interviews were conducted with 41 stakeholders. There were a range of factors that appeared to influence implementation of the service. Perceived acceptability was critical, which depended on staff training, pharmacists' altruism, and remuneration. Staff relied heavily on their existing close relationships with consumers. No consumers completed non-anonymous surveys or agreed to participate in interviews post-screening. CONCLUSION: Using an implementation science approach, a community pharmacy osteoporosis screening service for the Australian context was designed and found to be acceptable to pharmacy staff and effective in reaching the target population. SO WHAT?: This low-cost and non-invasive health promotion has potential to sustainably increase national screening rates for osteoporosis.

Mid-term outcomes following reverse total shoulder arthroplasty.

PURPOSE: The utilization of reverse total shoulder arthroplasty now exceeds the incidence of anatomic shoulder arthroplasty. Previous mid-to-long-term studies on rTSA have reported a decrease in shoulder function as follow-up increased. The purpose of this study was to provide data on mid-term outcomes and implant survival in a series focusing on reverse total shoulder arthroplasty. MATERIALS AND METHODS: Demographic information such as age at surgery, revision surgery status, BMI, and smoking status were recorded. The clinical endpoints measured in this study were range of motion scores (forward elevation, external rotation, internal rotation) and patient reported outcomes (VAS, ASES, SST). Radiographic variables captured included preoperative glenoid morphology, humeral lucency, and glenoid loosening. RESULTS: Fifty-six shoulders were included in this study. The overall mean age at surgery was 72.5 ± 7.2 years with an average follow-up time of 6.8 ± 3.5 years. The mean BMI was 28.1 ± 5.5. All measurements of range of motion saw significant and sustained improvements. Overall, forward elevation improved from 82° preoperatively to 133° postoperatively (p < 0.01). External rotation improved from 23° preoperatively to 36° (p < 0.01), while internal rotation improved from L3 to L1 (p = 0.05). ASES scores improved from 31 preoperatively to 70 postoperatively (p < 0.01). SST scores improved from 2 preoperatively to 7 (p < 0.01). VAS pain index scores improved from 6 to 2 following surgery (p < 0.01). Postoperative scapular notching was seen in 18 patients at final follow-up. Glenoid loosening was seen in 3 shoulders. Humeral loosening was seen in 18 shoulders. Tuberosity resorption was seen in 8 shoulders. The 5 year survival estimate was 98%, and the 10 year survival estimate was 83%. CONCLUSION: In this series, we found that rTSA provides mid-term improvements in range of motion in patients while reducing pain levels. When considered together, this demonstrates that most patients undergoing rTSA can have excellent use of their shoulder from age at surgery to end-of-life.

Relationship between WIfI stage and quality of life at revascularization in the BEST-CLI trial.

OBJECTIVE: The WIfI (Wound, Ischemia, foot Infection) stage measures the extent of wounds, ischemia, and foot infection in patients with chronic limb threatening ischemia (CLTI) and has been associated with the risk of major amputation. Patients with CLTI have impaired health-related quality of life (HRQoL), which can be multifactorial. We hypothesized that the severity of the limb threat (WIfI stage) would be associated with poor HRQoL among patients with CLTI presenting for revascularization. METHODS: The dataset of the BEST-CLI (best endovascular versus best surgical therapy in patients with CLTI) trial, a prospective, randomized trial comparing open and endovascular revascularization strategies, was queried for HRQoL assessments at patient enrollment. The HRQoL assessments included (1) Vascular Quality of Life; (2) 12-item short form survey (SF-12), containing the utility index score (short-form six-dimension R2 utility index, incorporating physical, emotional, and mental well-being) and mental and physical components; and (3) the EQ-5D. Multivariable regression analysis was used to identify the independent associations with the baseline HRQoL assessments. RESULTS: A total of 1568 patients with complete WIfI data were analyzed, of whom 71.5% were men. The WIfI distribution was 35.5% with stage 4, 29.6% with stage 3, 28.6% with stage 2, and 6.3% with stage 1. Patients presenting with WIfI stage 4, compared with stage 1 to 3, were more often men (74.9% vs 69.6%) and current smokers (25.4% vs. 17.6%), had had end-stage renal disease (13.3% vs 8.5%) and diabetes (83.6% vs 60.2%), were not independently ambulatory (56.8% vs 38.5%), and had had higher median morbidity scores (4 vs 3; P < .05 for all). On multivariable analysis, WIfI stage 4, compared with stage 1 to 3, was associated with lower SF-12 mental component scale scores (estimate, -2.43; 95% confidence interval, -3.73 to -1.13; P < .001) and short-form six-dimension R2 utility index scores (estimate, -0.02; 95% confidence interval, -0.03 to 0.001; P = .04). The WIfI stage was not independently associated with the baseline Vascular Quality of Life, SF-12 physical component scale, or EQ-5D assessments. CONCLUSIONS: WIfI stage was independently associated with poorer quality of life because of mental, rather than physical, health for patients with CLTI. Clinicians should be aware of the burden of mental stress borne by those with the greatest limb impairment.

Baseline modern medical management in the BEST-CLI trial.

OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Reinforcement Motor Learning After Cerebellar Damage Is Related to State Estimation.

Recent work showed that individuals with cerebellar degeneration could leverage intact reinforcement learning (RL) to alter their movement. However, there was marked inter-individual variability in learning, and the factors underlying it were unclear. Cerebellum-dependent sensory prediction may contribute to RL in motor contexts by enhancing body state estimates, which are necessary to solve the credit-assignment problem. The objective of this study was to test the relationship between the predictive component of state estimation and RL in individuals with cerebellar degeneration. Individuals with cerebellar degeneration and neurotypical control participants completed two tasks: an RL task that required them to alter the angle of reaching movements and a state estimation task that tested the somatosensory perception of active and passive movement. The state estimation task permitted the calculation of the active benefit shown by each participant, which is thought to reflect the cerebellum-dependent predictive component of state estimation. We found that the cerebellar and control groups showed similar magnitudes of learning with reinforcement and active benefit on average, but there was substantial variability across individuals. Using multiple regression, we assessed potential predictors of RL. Our analysis included active benefit, somatosensory acuity, clinical ataxia severity, movement variability, movement speed, and age. We found a significant relationship in which greater active benefit predicted better learning with reinforcement in the cerebellar, but not the control group. No other variables showed significant relationships with learning. Overall, our results support the hypothesis that the integrity of sensory prediction is a strong predictor of RL after cerebellar damage.

Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies.

INTRODUCTION/AIMS: Up to 25% of patients with myasthenia gravis (MG) have refractory disease despite trials of multiple immunosuppressants. Several case series describe acetylcholine receptor antibody-positive (AChR) MG patients treated with autologous hematopoietic stem cell transplant (HSCT). In this report, we describe three patients with anti-muscle-specific kinase (MuSK) MG treated with HSCT. METHODS: We included all patients who had undergone HSCT with anti-MuSK myasthenia gravis identified through the records of the Alberta Blood and Marrow Transplant Program. We collected demographic and clinical data including validated MG scales as well as questionnaire data. RESULTS: All 3 patients had severe disease (Myasthenia Gravis Foundation of America score IVb-V) and were refractory to multiple treatments, including rituximab. All patients improved with no clinical manifestations or mild symptoms and remained as such for 2, 3.5, and 5.5 y. Adverse events ranged from treatable infections and transient dyspnea to persistent fatigue and premature menopause. The average worst Myasthenia Gravis Activities of Daily Living (MG-ADL) scores improved from 14.7 before to 0.3 after HSCT. The mean worst Myasthenia Gravis Quality of Life Questionnaire (MG-QoL15) scores improved from 26.7 to 0. All patients reported they would undergo transplant again for their MG. DISCUSSION: We describe three patients with anti-MuSK MG treated with HSCT, all of whom became symptom free from MG with a tolerable side effect profile. In patients with severe refractory anti-MuSK MG, it may be reasonable to consider HSCT.

Robust prediction of nonhome discharge following elective anterior cervical discectomy and fusion using explainable machine learning.

PURPOSE: Predict nonhome discharge (NHD) following elective anterior cervical discectomy and fusion (ACDF) using an explainable machine learning model. METHODS: 2227 patients undergoing elective ACDF from 2008 to 2019 were identified from a single institutional database. A machine learning model was trained on preoperative variables, including demographics, comorbidity indices, and levels fused. The validation technique was repeated stratified K-Fold cross validation with the area under the receiver operating curve (AUROC) statistic as the performance metric. Shapley Additive Explanation (SHAP) values were calculated to provide further explainability regarding the model's decision making. RESULTS: The preoperative model performed with an AUROC of 0.83 ± 0.05. SHAP scores revealed the most pertinent risk factors to be age, medicare insurance, and American Society of Anesthesiology (ASA) score. Interaction analysis demonstrated that female patients over 65 with greater fusion levels were more likely to undergo NHD. Likewise, ASA demonstrated positive interaction effects with female sex, levels fused and BMI. CONCLUSION: We validated an explainable machine learning model for the prediction of NHD using common preoperative variables. Adding transparency is a key step towards clinical application because it demonstrates that our model's "thinking" aligns with clinical reasoning. Interactive analysis demonstrated that those of age over 65, female sex, higher ASA score, and greater fusion levels were more predisposed to NHD. Age and ASA score were similar in their predictive ability. Machine learning may be used to predict NHD, and can assist surgeons with patient counseling or early discharge planning.

Does body mass index influence long-term outcomes after anatomic total shoulder arthroplasty?

BACKGROUND: As of 2018, upwards of 42% of the US adult population was considered obese based on body mass index (BMI) scales. With the annual number of total joint replacements increasing, this study aimed to evaluate the impact BMI has on anatomic total shoulder arthroplasty (aTSA) outcomes. METHODS: This was a retrospective analysis of 128 shoulders requiring primary aTSA. Patients were stratified into 3 cohorts based on their BMI at surgery: underweight/normal weight (U/NW; BMI ≤25.0), overweight (25.0 < BMI ≤ 30.0), and obese (BMI >30.0). BMI was separately analyzed as a continuous variable. Clinical endpoints were range of motion scores, including forward elevation, external rotation, and internal rotation, and patient-reported outcomes, including visual analog scale (VAS) scores, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores, and the Simple Shoulder Test (SST). Survivorship curves were calculated using Kaplan-Meier analysis. RESULTS: Forty-four, 50, and 34 patient shoulders were in the U/NW, overweight, and obese cohorts, respectively. The mean follow-up time was 11.4 years. The U/NW cohort had more females (73%) compared with the overweight (34%; P = .0030) and obese (35%; P = .0015) groups; no differences were seen in revision rates. BMI was negatively correlated with age at surgery (r = -0.19, P = .014); it was not correlated with any of the 6 postoperative clinical endpoints. All 3 cohorts saw significant improvements in forward elevation, external rotation, internal rotation and VAS, ASES, and SST scores when compared preoperatively to postoperatively (P < .001). There were no significant differences between the 3 cohorts with respect to postoperative range of motion. Postoperative ASES scores were higher for the overweight cohort (82.6 ± 18.6) compared with both the U/NW (63.0 ± 25.1) and obese cohorts (70.5 ± 26.8) (P < .001). The overweight cohort also had higher SST (P = .0012) postoperative scores compared with the U/NW and obese cohorts; VAS scores were comparable between groups (P = .12). The nonobese (BMI <30) group (n = 94) showed 5-, 10-, and 15-year implant survival of 98.9%, 94.9%, and 83.9%, respectively compared to 97.1%, 93.7%, and 87.0% in the obese (BMI ≥30) group (n = 34). The log rank test revealed no significant difference in survival curves (P = .82). CONCLUSION: To our knowledge, this is the longest follow-up study analyzing clinical endpoints stratified by BMI for aTSA. We saw that patients with a higher BMI required shoulder replacement at a significantly younger age. However, we also report that regardless of BMI, all patients saw significant improvements in patient-reported outcomes and range of motion scores postoperatively.