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The greater antihypertensive responses to initial therapy with calcium channel blockers (CCBs) or thiazide-type diuretics than renin-angiotensin system blockers as initial therapy in non-Hispanic Black (NHB) adults was recognized in the US High BP guidelines from 1988 to 2003. The 2014 Report from Panel Members Appointed to the Eighth Joint National Committee (2014 aJNC8 Report) and the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline were the first to recommend CCBs or thiazide-type diuretics rather than renin-angiotensin system blockers as initial therapy in NHB. We assessed the temporal relationship of these recommendations on self-reported CCB or thiazide-type diuretics monotherapy by NHB and NHW adults with hypertension absent compelling indications for β-blockers or renin-angiotensin system blockers in National Health and Nutrition Examination Surveys 2015 to 2018 versus 2007 to 2012 (after versus before 2014 aJNC8 Report). CCB or thiazide-type diuretics monotherapy was unchanged in NHW adults (17.1% versus 18.1%, P =0.711) and insignificantly higher after 2014 among NHB adults (43.7% versus 38.2%, P =0.204), although CCB monotherapy increased (29.5% versus 21.0%, P =0.021) and renin-angiotensin system blocker monotherapy fell (44.5% versus 31.0%, P =0.008). Although evidence-based CCB monotherapy increased among NHB adults in 2015 to 2018, hypertension control declined as untreated hypertension and monotherapy increased. While a gap between recommended and actual monotherapy persists, evidence-based monotherapy appears insufficient to improve hypertension control in NHB adults, especially given evidence for worsening therapeutic inertia. Initiating treatment with single-pill combinations and timely therapeutic intensification when required to control hypertension are evidence-based, race-neutral options for improving hypertension control among NHB adults.

Recently published national data demonstrate inadequate and worsening control of high blood pressure (HBP) in the United States, outcomes that likely have been made even worse by the coronavirus disease 2019 (COVID-19) pandemic. This major public health crisis exposes shortcomings of the US health care delivery system and creates an urgent opportunity to reduce mortality, major cardiovascular events, and costs for 115 million Americans. Ending this crisis will require a more coherent and systemic change to traditional patterns of care. The authors present an evidence-based Blueprint for Change for comprehensive health delivery system redesign based on current national clinical practice guidelines and quality measures. This innovative model includes a systems-based approach to ensuring proper BP measurement, assessment of cardiovascular risk, effective patient-centered team-based care, addressing social determinants of health, and shared decision-making. The authors also propose building on current national quality improvement initiatives designed to better control HBP.

This review summarizes published findings of the beneficial and harmful effects on the heart, lungs, immune system, kidney, liver, and central nervous system of 47 drugs that have been proposed to treat COVID-19. Many of the repurposed drugs were chosen for their benefits to the pulmonary system, as well as immunosuppressive and anti-inflammatory effects. However, these drugs have mixed effects on the heart, liver, kidney, and central nervous system. Drug treatments are critical in the fight against COVID-19, along with vaccines and public health protocols. Drug treatments are particularly needed as variants of the SARS-Cov-2 virus emerge with some mutations that could diminish the efficacy of the vaccines. Patients with comorbidities are more likely to require hospitalization and greater interventions. The combination of treating severe COVID-19 symptoms in the presence of comorbidities underscores the importance of understanding the effects of potential COVID-19 treatments on other organs. Supplementary Information The online version contains supplementary material available at 10.1007/s42399-021-00874-8.

The Systolic Blood Pressure Intervention Trial (SPRINT) results have influenced clinical practice but have also generated discussion regarding the validity, generalizability and importance of the findings. Following the SPRINT primary results manuscript in 2015, additional results and analyses of the data have addressed these concerns. The primary objective of this manuscript is to respond to key questions that have been raised. The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated the effectiveness of treating SBP to levels well below those previously recommended in US and European BP guidelines.(1) The SPRINT results have informed guideline committees in recommending treatment to SBP targets lower than previously advised.(2–4) However, some of the SPRINT findings have generated discussion, and questions have been raised regarding their application in clinical practice. These include generalizability, validity of the outcome measures (especially heart failure), the methods used for event ascertainment, the effect size of the intervention benefit, and safety and tolerability of the

To explore aged care nurses' awareness and experience of unwanted sexual behaviour (USB) in residential aged care services (RACS).An anonymous online questionnaire was administered to an opportunistic sample of RACS nurses enrolled to complete an e-learning course in Australia. From the 167 participants who expressed interest to enrol, 129 were eligible and 53 returned completed consent forms.46/53 responded of which most were females (41/45, 91.1%). Few respondents reported resident-resident USB (35%) or staff-resident USB (22%) happened once a year. Most respondents had not been informed by a resident of USB (75%) or had personally reported USB within their internal reporting system (77%). Respondents were also unaware if their facility had lodged an incident report to the regulator or law enforcement authorities within the past 12 months (34/46, 73.9%). Finally, most considered there to be no barriers to reporting USB (35/46, 77.8%).Respondents' awareness and estimates of USB directed at residents were much lower than known national prevalence rates. This lack of awareness could be a substantive barrier to recognition and optimal management of this form of abuse.

Regenerative medicine, using cells as therapeutic agents for the repair or regeneration of tissues and organs, offers great hope for the future of medicine. Cell therapy for treating defects in articular cartilage has been an exemplar of translating this technology to the clinic, but it is not without its challenges. These include applying regulations, which were designed for pharmaceutical agents, to living cells. In addition, using autologous cells as the therapeutic agent brings additional costs and logistical challenges compared with using allogeneic cells. The main cell types used in treating chondral or osteochondral defects in joints to date are chondrocytes and mesenchymal stromal cells derived from various sources such as bone marrow, adipose tissue or umbilical cord. This review discusses some of their biology and pre-clinical studies before describing the most pertinent clinical trials in this area.

RATIONALE AND OBJECTIVE. While low estimated glomerular filtration rate (eGFR) is associated with cardiovascular disease (CVD) events and mortality, the clinical significance of variability in eGFR over time is uncertain. We aimed to evaluate the association between variability in eGFR and the risk of CVD events and all-cause mortality. STUDY DESIGN. Longitudinal analysis of clinical trial participants. SETTINGS AND PARTICIPANTS. 7,520 Systolic Blood Pressure Intervention Trial (SPRINT) participants aged ≥ 50 year with 1 or more CVD risk factors. PREDICTORS. eGFR variability, estimated by the coefficients of variation of eGFR measurements at the 6, 12, and 18-month study visits. OUTCOMES. SPRINT primary CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death) and all-cause mortality from month 18 to end of follow-up. ANALYTICAL APPROACH. Cox models evaluated associations between eGFR variability and CVD outcomes and all-cause mortality. Models were adjusted for demographics, randomization arm, CVD risk factors, albuminuria and month 18 eGFR. RESULTS. Mean age was 68±9 years, 65% were men, and 58% were white. The mean eGFR was 73±21 ml/min/1.73m(2) at 6 months. There were 370 CVD events and 154 deaths during a median follow-up of 2.4 years. Greater eGFR variability was associated with higher risk for all-cause mortality (hazard ratio (HR) per standard deviation (SD) greater variability, 1.29; 95% confidence interval (CI) 1.14 to 1.45) but not CVD events (HR 1.05; 95% CI 0.95 to 1.16) after adjusting for albuminuria at baseline, eGFR at month 18, and other CVD risk factors. Associations were similar when stratified by treatment arm and baseline CKD status, when accounting for concurrent systolic BP changes, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and diuretic medications during follow-up. LIMITATIONS. Persons with diabetes and proteinuria > 1 g/day were excluded. CONCLUSIONS. In trial participants at high risk for CVD with hypertension, greater eGFR variability was independently associated with all-cause mortality but not CVD events.

Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.

Background: Biomarkers are needed to predict clinical outcomes for microfracture and osteotomy surgeries to ensure patients can be better stratified to receive the most appropriate treatment. Purpose: To identify novel biomarker candidates and to investigate the potential of a panel of protein biomarkers for the prediction of clinical outcome after treatment with microfracture or osteotomy. Study Design: Descriptive laboratory study. Methods: To identify novel candidate biomarker proteins, we used label-free quantitation after liquid chromatography–tandem mass spectrometry of dynamic range-compressed synovial fluids (SFs) from individuals who responded excellently or poorly (based on change in Lysholm score) to microfracture (n = 6) or osteotomy (n = 7). Biomarkers that were identified in this proteomic analysis or that relate to osteoarthritis (OA) severity or have predictive value in another early OA therapy (autologous cell implantation) were measured in the SF of 19 and 13 patients before microfracture or osteotomy, respectively, using commercial immunoassays, and were normalized to urea. These were aggrecanase-1 (ADAMTS-4), cartilage oligomeric matrix protein (COMP), hyaluronan (HA), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), matrix metalloproteinase 1 and 3, soluble CD14, S100 calcium binding protein A13, and 14-3-3 protein theta (YWHAQ). Levels of COMP and HA were also measured in the plasma of these patients. To find predictors of postoperative function, multivariable regression analyses were performed. Results: Proteomic analyses highlighted YWHAQ and LYVE-1 as being differentially abundant between the clinical responders/improvers and nonresponders after microfracture. A linear regression model after backward variable selection could relate preoperative concentrations of SF proteins (HA, YWHAQ, LYVE-1), activity of ADAMTS-4, and patient demographic characteristics (smoker status and sex) with Lysholm score 12 months after microfracture. Further, a generalized linear model with elastic net penalization indicated that lower preoperative activity of ADAMTS-4 in SF, being a nonsmoker, and being younger at the time of operation were indicative of a higher postoperative Lysholm score (improved joint function) after osteotomy surgery. Conclusion: We have identified biomarkers and generated regression models with the potential to predict clinical outcome in patients treated with microfracture or osteotomy of the knee. Clinical Relevance: Candidate protein biomarkers identified in this study have the potential to help determine which patients will be best suited to treatment with microfracture or osteotomy.

Carolyn H Still,1 Chris Burant,1 Shirley Moore,1 Doug Einstadter,2,3 Cheryl Killion,1 Charles Modlin,4 Sophia Sundararajan,5,6 John D Thornton,3,7 Jackson T Wright Jr,5,6 Martha Sajatovic6,8 1Frances Payne Bolton, School of Nursing, Case Western Reserve University, Cleveland, OH, USA; 2Center for Health Care Research and Policy, Case Western Reserve University, Cleveland, OH, USA; 3The MetroHealth System, Cleveland, OH, USA; 4Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA; 5Case Western Reserve University, School of Medicine, Cleveland, OH, USA; 6University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 7Center for Reducing Health Disparities, Case Western Reserve University, Cleveland, OH, USA; 8Department of Psychiatry and of Neurology, Case Western Reserve University, School of Medicine, Cleveland, OH, USACorrespondence: Carolyn H StillFrances Payne Bolton, School of Nursing, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USATel: +1 216 368 6338Email cwh11@case.eduBackground: African American (AA) male survivors of strokes or transient ischemic attacks (TIA) have the highest risk of recurrent stroke when compared to other racial-ethnic men. However, there is a paucity of evidence-based strategies, including organizational, educational, or behavioral interventions, that targets secondary stroke risk reduction in AA men.Methods: Targeted Management for Reducing Stroke Risk (TEAM) is an ongoing, 6-month prospective, randomized controlled trial that will determine whether a curriculum-guided self-management approach, using peer dyads (men who had a stroke or TIA and their care partners) will improve post-stroke care in AA men.Results: The study sample will consist of 160 AA men who have experienced a stroke or TIA within 5 years, randomized to TEAM or Wait-list control group. The primary outcome changes in systolic blood pressure (BP) and high-density lipoprotein (HDL), while secondary outcomes include diastolic BP, total cholesterol, low-density lipoprotein, triglycerides, and glycemic control for diabetics. We hypothesize that AA men in TEAM will have significantly lower systolic BP and higher HDL when compared to AA men in the Wait-list control group at 6-month.Conclusion: Persistent disparities for stroke burden in AA men highlight the need for novel interventions to promote secondary stroke-risk reduction. Building on promising pilot data, TEAM uses a group format, with a nurse and patient co-led intervention focused on AA men and family needs, practice in problem-solving, and attention to emotional and role management. In addition, the TEAM approach may help reduce stroke risk factors and health disparities in AA men.Clinicaltrials.gov Identifier: NCT04402125.Keywords: stroke, transient ischemic attack, stroke prevention, African-Americans, health disparities

Osteochondral lesions of the talus (OLTs) are a common complication following trauma, involving both the articular cartilage and the underlying subchondral bone, with variable aetiologies and often presenting with non-specific symptoms. Diagnosis of OLTs requires a combination of clinical assessment and imaging and despite many different treatment options, there is no generalised consensus regarding which option is the most effective. Left untreated, OLTs risk progressing to osteoarthritis. Acute non-displaced OLTs can be treated non-operatively. However, OLTs refractory to non-surgical care for three to six months may be suitable for surgical care. In these cases, conservative treatments are often unsuccessful, particularly for larger and more severe defects and so the majority require surgical intervention. Although bone marrow stimulation techniques remain the “gold standard” for lesions

As the highest level of cloud computing delivery model, Software-as-a-Service (SaaS) has gained considerable popularity in the industry as a new way of deploying IT solutions, due to its low cost and high elasticity. However, the new business model associated with SaaS highlights the importance for SaaS vendors to understand how to retain customers in a hyper-competitive market. In particular, increasing customer retention and preventing customers from replacing the adopted SaaS applications has become a crucial task for all SaaS vendors. In this study, using a mixed-methods approach, and drawing on the cognitive–affective–conative– action (CACA) framework, we investigate the IS replacement phenomenon in the context of SaaS-delivered applications. Our qualitative study allows us to develop an IS-centric view of customer commitment by differentiating between organizations’ commitment to the SaaS application and to the cloud computing technology in general, while the subsequent quantitative study validates the difference between the two types of commitment and helps understand how they together influence organizations’ intentions to replace a SaaS application. Our results generate important theoretical implications for research on IS replacement and clarifies the concept of customer commitment. We also offer practical guidelines to SaaS vendors on how to retain customers so as to survive/thrive in this competitive market.

Carolyn H Still,1 Seunghee Margevicius,2 Carla Harwell,3,4 Ming-Chun Huang,5 LaTonya Martin,6 Phuong B Dang,1 Jackson T Wright Jnr3,7 1Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH, USA; 2Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; 3Department of Internal Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; 4University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 5Department of Electrical Engineering and Computer Science, Case School of Engineering, Case Western Reserve University, Cleveland, OH, USA; 6Community Partners, Cleveland Council of Black Nurses, Cleveland, OH, USA; 7Department of Nephrology and Hypertension, Clinical Hypertension Program, University Hospitals Cleveland Medical Center, Cleveland, OH, USACorrespondence: Carolyn H StillFrances Payne Bolton School of Nursing, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106, USATel +1 216 368 6338Fax +1 216 368 3452Email cwh11@case.eduPurpose: Adoption of technology has increased to support self-managing chronic diseases. However, behavioral interventions evaluating such technology have been understudied in African Americans with hypertension. The aim of this study was to explore a community and technology-based intervention for hypertension self-management (COACHMAN) intervention on blood pressure (BP) control and health-related quality of life (HRQoL) in African Americans with hypertension.Methods: Sixty African Americans (mean age 60; 75% females) who were prescribed antihypertensive medications and owning a smartphone were randomized to the COACHMAN (n = 30) or enhanced usual care (n = 30) group for 12 weeks. COACHMAN is comprised of four components: web-based education, home BP monitoring, medication management application, and nurse counseling. Hypertension knowledge, self-efficacy, technology adoption/use, medication adherence, BP, and HRQoL scores were assessed.Results: Mean systolic and diastolic BP at baseline was 150.49 (SD = 13.89) and 86.80 (SD = 13.39), respectively. After completing the 3-month intervention to improve hypertension self-management, the groups did not significantly differ in BP control and HRQoL. Clinically relevant BP reduction was observed in the intervention group. Paired t-test showed that mean medication-taking adherence scores significantly improved in the intervention group (P = 0.023) compared to the control group (P = 0.075).Conclusion: Using technology may have a positive impact on supporting hypertension self-management, particularly in medication-taking adherence. Further research is warranted in a larger sample and should include standardization of medication management to isolate the effects of behavioral interventions on changes in BP.Clinicaltrials.gov Identifier: NCT03722667.Keywords: African Americans, hypertension, minority health, technology, self-management

Summary Background Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. Methods SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov , NCT01206062 . Findings From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7–5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of −0·005 (95% CI −0·010 to 0·001) in the intensive treatment group and −0·001 (–0·006 to 0·005) in the standard treatment group (between-group difference −0·004, 95% CI −0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference −0·010, 95% CI −0·017 to −0·002; p=0·02), with an annual decline of −0·025 (–0·030 to −0·019) for the intensive treatment group and −0·015 (–0·021 to 0·009) for the standard treatment group. Interpretation Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. Funding National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.

As the tidal energy industry looks to expand into commercial-scale array installations, uncertainty in methodology and outcome for environmental impact assessments can encumber tidal energy developments. Incorporating environmental monitoring measures into site characterisation campaigns can provide baseline information about biophysical relationships and help recognise potential impacts to the marine environment early in the development process. Concurrent measurements of fish and tidal currents were taken at a tidal energy candidate site in Australia over ∼2.5 months during its tidal resource assessment. Fish aggregation metrics (density, abundance, centre-of-mass (CM), dispersion, %-water column occupied, evenness, and relative aggregation) were investigated for their relation to environmental conditions (current speed, shear, temperature, diel stage, and tidal stage). Diel stage was the most significant indicator for fish density, abundance, and %-water column occupied. Fish density and abundance were elevated during strong currents, with vertical fish distribution (CM and dispersion) also influenced by current speed. Environmental conditions were able to explain up to 25% of variation in fish aggregation metrics using linear models. This study shows that early-stage environmental monitoring can successfully provide baseline information about fish aggregation responses to prevailing environmental conditions, thus reducing uncertainty risks for stakeholders of tidal energy developments.

Organisations face growing IT security risks with substantial consequences for missteps in business continuity, data loss, reputational harm, and future competitive advantage. To improve precaution...

BACKGROUND: This study examined the impact of age and sex of first-time donors who had not experienced an adverse event or deferral on their likelihood of and time to return. STUDY DESIGN AND METHODS: On behalf of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative, international blood collection agencies (BCAs) were invited to provide data on first-time whole blood donors in 2014, including initial presentation date, collection site type, age, sex, blood type, return to donate within 24 months (yes/no), and subsequent presentation date. RESULTS: Eight BCAs contributed 706,789 records. The overall odds of returning to donate were slightly lower in female versus male donors, and the overall age trend was U-shaped with younger and older donors having higher odds for returning relative to middle-aged donors. However, variations by BCA were observed. Specifically, in three BCAs, women had higher odds of returning to donate than men. Further, while across seven BCAs the smallest cohort of older first-time donors returned at a higher rate and returned more quickly than middle-aged first-time donors, the behavior of younger donors varied substantially between BCAs. CONCLUSION: While older first-time donors are more likely to return and return more quickly than middle-aged donors they make up only a small proportion of first-time donors, whereas the larger group of younger donors exhibits less clear patterns of return compared to middle-aged donors. Further research is needed to determine whether targeting the recruitment of older donors or bolstering retention of middle-aged donors would be most effective in maintaining the blood supply.

This paper critically comments on the state of affairs in the UK relating to the pandemic and explores how a focus on inequities experienced by marginalized and vulnerable groups is necessary for exposing the material realties of everyday life, but also how such a focus has been hijacked by center right politics to distract us from collective responsibilities and building alliances for systemic change. The paper critically reviews the impact of the COVID‐19 pandemic on the most marginalized and vulnerable in UK society and highlights the interconnected risk factors of COVID‐19 and its secondary impacts to demonstrate how these are linked to political ideology, policy, and practice. We conclude with recommendations informed through a looking back at the key tenants and purposes of universal healthcare to apprise what is needed in this moment of crisis and beyond.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Human umbilical cord (hUC)- or bone marrow (hBM)-derived mesenchymal stromal cells (MSCs) were evaluated as an allogeneic source of cells for cartilage repair. We aimed to determine if they could enhance healing of chondral defects with or without the recruitment of endogenous cells. hMSCs were applied into a focal joint surface injury in knees of adult mice expressing tdTomato fluorescent protein in cells descending from Gdf5-expressing embryonic joint interzone cells. Three experimental groups were used: (i) hUC-MSCs, (ii) hBM-MSCs and (iii) PBS (vehicle) without cells. Cartilage repair was assessed after 8 weeks and tdTomato-expressing cells were detected by immunostaining. Plasma levels of pro-inflammatory mediators and other markers were measured by electrochemiluminescence. Both hUC-MSC (n = 14, p = 0.009) and hBM-MSC (n = 13, p = 0.006) treatment groups had significantly improved cartilage repair compared to controls (n = 18). While hMSCs were not detectable in the repair tissue at 8 weeks post-implantation, increased endogenous Gdf5-lineage cells were detected in repair tissue of hUC-MSC-treated mice. This xenogeneic study indicates that hMSCs enhance intrinsic cartilage repair mechanisms in mice. Hence, hMSCs, particularly the more proliferative hUC-MSCs, could represent an attractive allogeneic cell population for treating patients with chondral defects and perhaps prevent the onset and progression of osteoarthritis.

Introduced predators currently threaten endemic animals on Madagascar through predation, facilitation of human-led hunts, competition, and disease transmission, but the antiquity and past consequences of these introductions are poorly known. We use directly radiocarbon dated bones of introduced dogs (Canis familiaris) to test whether dogs could have aided human-led hunts of the island’s extinct megafauna. We compare carbon and nitrogen isotope data from the bone collagen of dogs and endemic “fosa” (Cryptoprocta spp.) in central and southwestern Madagascar to test for competition between introduced and endemic predators. The distinct isotopic niches of dogs and fosa suggest that any past antagonistic relationship between these predators did not follow from predation or competition for shared prey. Radiocarbon dates confirm that dogs have been present on Madagascar for over a millennium and suggest that they at least briefly co-occurred with the island’s extinct megafauna, which included giant lemurs, elephant birds, and pygmy hippopotamuses. Today, dogs share a mutualism with pastoralists who also occasionally hunt endemic vertebrates, and similar behavior is reflected in deposits at several Malagasy paleontological sites that contain dog and livestock bones along with butchered bones of extinct megafauna and extant lemurs. Dogs on Madagascar have had a wide range of diets during the past millennium, but relatively high stable carbon isotope values suggest few individuals relied primarily on forest bushmeat. Our newly generated data suggest that dogs were part of a suite of animal introductions beginning over a millennium ago that coincided with widespread landscape transformation and megafaunal extinction. Introduction Materials and Methods - Specimen and Site Selection - 14C and Stable Isotope Analyses - Data Analysis Results - Chronological Data - Stable Isotope Data Discussion

Background: Funded by the Ohio Department of Medicaid, the Ohio Cardiovascular and Diabetes Health Collaborative (Cardi-OH) unites the 7 medical schools in Ohio to improve outcomes and reduce disparities in hypertension and type 2 diabetes (T2D). The purpose of this needs assessment was to identify high priority educational topics for the dissemination of evidenced-based best practices. Methods: Questions surveyed collaborative members’ familiarity with guidelines, educational topics, and barriers to care. Results: A total of 111 out of 123 members completed the needs assessment (90.2% response rate). Half (49.5%, n=55) were familiar with the 2017 ACC/AHA guidelines for hypertension, whereas only 36.9% (n=41) were familiar with the 2020 ADA guidelines. The 3 topics of most interest were: 1) social determinants of health (SDOH, 55.9%, n=62), 2) lifestyle approaches to T2D (40.5%, n=45), and 3) new therapies for T2D (32.4%, n=36). Fifty-nine members (53.2%) provided direct clinical care; the others worked in research and public health. Providers estimated 25% of their T2D patients had A1C values >9.0%. Providers listed the 3 most common patient self-care barriers as: 1) lack of patient motivation (65.5%, n=38), 2) lack of patient education (60.3%, n=35), and 3) limited formularies and prior authorizations (41.4%, n=24). The 3 most common reasons for clinical inertia were: 1) lack of patient education (50.0%, n=29), 2) competing priorities (46.6%, n=27), and 3) lack of patient motivation (44.8%, n=26). Providers felt payers could help them with: 1) transportation (61.0%, n=68), 2) coverage of diabetes self-management education and support (DSMES, 59.4%, n=66), and 3) obtaining glucose monitors (45.9%, n=51). Conclusions: Top priorities for future evidence-based best practices are SDOH, patient engagement, and addressing complexity of care. Payers should prioritize increased coverage for DSMES and simplification of ordering monitoring supplies. Disclosure E. A. Beverly: None. G. D. Solomon: None. M. B. Holliday: None. J. Lewis: None. A. Nevar: None. S. M. Swiatkowski: None. M. W. Konstan: None. S. D. Bolen: None. K. M. Dungan: Advisory Panel; Self; Eli Lilly and Company, Tolerion, Inc., Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Elsevier, Novo Nordisk, Other Relationship; Self; UpToDate, Research Support; Self; Abbott, Sanofi-Aventis, Viacyte, Inc. J. T. Wright: None. A. Caron: None. M. Clemons: None. S. Aldrich renner: None. K. Gawlik: None. M. Sajatovic: Consultant; Self; Alkermes, Janssen Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Other Relationship; Self; Springer Press, Johns Hopkins University Press, Oxford Press, UpToDate, Research Support; Self; Alkermes, Nuromate, Otsuka America Pharmaceutical, Inc. G. Rao: None. Funding Ohio Medicaid Technical Assistance and Policy Program (G-2021-05-0069)

Objectives The objectives are to (1) describe disability outcomes at 24 months after injury and (2) identify factors contributing to disability outcomes at 24 months after injury, for Māori and non-Māori who have been hospitalised for injury. Study design This is a prospective cohort study. Methods Prospective Outcomes of Injury Study participants were injured New Zealanders aged 18–64 years and recruited from New Zealand's no-fault injury insurer, the Accident Compensation Corporation's entitlement claims register. Data about a number of pre-injury, injury-related and early post-injury characteristics were collected from interviews held at 3 and 24 months after injury. Disability was measured using the World Health Organization Disability Assessment Schedule (WHODAS). Modified Poisson regression modelling was used to estimate relative risks (RRs) of disability for Māori and non-Māori who were hospitalised for injury. Results Analyses were restricted to 375 Māori and 1824 non-Māori participants for whom complete data were available. Of these, 105 (28%) Māori and 446 (24%) non-Māori were hospitalised for their injury. Of these hospitalised groups, 26% of Māori and 10% of non-Māori were experiencing disability (WHODAS ≥10) at 24 months after injury. Māori who were hospitalised for injury and who were not working for pay before their injury (RR = 2.7; 95% confidence interval [CI] 1.4–4.9), who were experiencing disability before their injury (RR = 3.1; 95% CI 1.6–5.8) or who reported trouble accessing healthcare services for their injury (RR = 2.6; 95% CI 1.3–5.2) were independently at increased risk of disability 24 months after injury. Non-Māori who were hospitalised for injury and who had inadequate household income before injury (RR = 2.4; 95% CI 1.4–4.1), less than the secondary school qualifications (RR = 2.0; 95% CI 1.1–3.8), were not working for pay before injury (RR = 2.8; 95% CI 1.5–5.1), were experiencing disability before their injury (RR = 3.0; 95% CI 1.7–5.2), had ≥2 chronic conditions (RR = 3.5; 95% CI 2.0–6.4) or had body mass index ≥30 kg/m2/undisclosed (RR = 2.4; 95% CI 1.3–4.4) were at increased risk of disability 24 months after injury. Conclusions Variables predicting disability 24 months after injury for Māori, also predict disability 24 months after injury for non-Māori, with one notable exception—trouble accessing healthcare services. Our findings show that having access to healthcare services for injury plays an important role after injury and must be focussed on to ensure that the burden of poor injury-related outcomes and injury-related inequities are reduced and ultimately eliminated.

A domestic rabbit was diagnosed with a grade III out of IV medial patellar luxation. A trochlear wedge recession and lateral imbrication were performed to replace and stabilize the patella in the trochlear groove. The rabbit recovered well from anesthesia and was held in strict confinement for 8 weeks after surgery to allow the surgical site to heal. At 8 weeks, the rabbit was deemed healed and released to normal activity. At four postoperative months, the patella was stable and maintained appropriate anatomical positioning. At 27 postoperative months, the joint had normal range of motion and the rabbit had normal activity level. This case report details a successful long-term surgical correction of a medially-luxated patella in a pet rabbit.

Background Low serum bicarbonate level is associated with increased mortality, but its role as a predictor of cardiovascular disease (CVD) is unclear. This study evaluates the association between serum bicarbonate concentration and CVD and whether the effect of intensive blood pressure (BP) lowering on CVD outcomes is modified by serum bicarbonate level. Methods The Systolic Blood Pressure Intervention Trial (SPRINT) randomized participants to a systolic BP target Results Over a median follow-up of 3.33 years (interquartile range 2.87–3.87 years), 618 (6.6%) participants experienced a primary CVD outcome. Participants with serum bicarbonate Conclusions In hypertensive individuals, serum bicarbonate level

The 2017 Hypertension Clinical Practice Guidelines recommend out-of-clinic BP monitoring to screen for white coat and masked hypertension among adults not taking antihypertensive medication and white coat effect and masked uncontrolled hypertension among adults taking antihypertensive medication. We estimated the percentage of US adults meeting criteria for out-of-clinic BP monitoring by the American College of Cardiology/American Heart Association guideline using the 2011 to 2014 National Health and Nutrition Examination Survey (n=9623). Among US adults not taking antihypertensive medication, 92.6% (95% CI, 90.7%–94.1%) with systolic/diastolic BP ≥130/80 mm Hg met criteria for out-of-clinic BP monitoring to screen for white coat hypertension and 32.8% (95% CI, 30.4%–35.3%) with systolic/diastolic BP

The Yiluo region in the middle Yellow River has been a core area of archaeological inquiry for understanding the origins of the first dynastic states in China. In order to investigate the social changes on a regional scale, a systematic full-coverage regional survey project was carried out from 1997 to 2018, covering an area of 1183 km2 in the Yiluo region. This paper analyzes the settlement patterns of 451 sites of the Neolithic and Bronze Ages (ca. 6000–200 cal. BC), providing the most comprehensive pictures yet, of the spatial and temporal relationships of settlement distribution during a nearly 6000-year time span. The paper demonstrates a developmental trajectory from a landscape dotted with scattered, small Neolithic villages to a highly centralized dynastic heartland in early Chinese civilization. The evolutionary pathways were not straightforward, but were characterized by episodic fluctuations in population density, and the rise and fall of complex societies. Holocene climatic fluctuations may have played significant roles affecting human activities, but it is the human responses to external challenges in various ways that ultimately determined the trajectories of social evolution.

BACKGROUND: Between February and June 2011, more than 300 horses with unexplained neurological disease were observed in New South Wales, Australia. A virulent strain of West Nile virus (WNVNSW₂₀₁₁), of Australian origin, was shown to be the cause of many of these cases. METHODS: We reviewed the clinical descriptions provided by veterinary practitioners and the associated laboratory results. Although there was a range of clinical signs described, ataxia was the only sign that was consistently described in laboratory‐confirmed cases. RESULTS: WNV was detected in brain samples by real‐time reverse transcription PCR assay and virus isolation. For serological confirmation of clinical cases, an equine IgM ELISA specific for WNV was shown to be the most effective tool. CONCLUSION: A state‐wide serological survey undertaken after the outbreak indicated that, contrary to expectation, although infection had been widespread, the seroprevalence of antibodies to WNV was very low, suggesting that there could be a significant risk of future disease outbreaks.

Apparent treatment-resistant hypertension (ATRH) is highly prevalent and associated with cardiovascular disease risk in patients with chronic kidney disease. We analyzed the association of inflammatory biomarkers with ATRH and its complications in patients with chronic kidney disease. ATRH was defined as blood pressure ≥140/90 mm Hg while taking ≥3 antihypertensive medications or blood pressure

The accurate measurement of blood pressure (BP) is essential for the diagnosis and management of hypertension. Restricted use of mercury devices, increased use of oscillometric devices, discrepancies between clinic and out-of-clinic BP, and concerns about measurement error with manual BP measurement techniques have resulted in uncertainty for clinicians and researchers. The National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health convened a working group of clinicians and researchers in October 2017 to review data on BP assessment among adults in clinical practice and clinic-based research. In this report, the authors review the topics discussed during a 2-day meeting including the current state of knowledge on BP assessment in clinical practice and clinic-based research, knowledge gaps pertaining to current BP assessment methods, research and clinical needs to improve BP assessment, and the strengths and limitations of using BP obtained in clinical practice for research and quality improvement activities.

Purpose The purpose of this paper is to scope out European and global policy documents focused on dementia with the purpose of providing a synthesis of the challenges the phenomenon poses and the gaps evident. Design/methodology/approach An adapted PESTEL framework as a data extraction tool resulted in an analysis of the political, economic, social, technological, environmental, organisational, educational and research aspects of dementia policy. Findings Policy documents showed variability of dementia strategy, plan and programme development. All documents recognised rapidly growing ageing populations, and increasing numbers of people living with dementia. Dementia as a public health priority is inconsistent in growth. Global policy documents stress the impact of dementia will be felt most by low- and middle-income countries. Main themes were: a need to raise awareness of dementia and action to reduce stigma around it, the need for early diagnosis and preventative person-centred approaches with integrated care, fiscal investment, further research, training and education for workforces, increased involvement of and support for people living with dementia and care and support close to home. Practical implications By identifying current dementia challenges and policy gap implications this analysis urges engagement with broader frames of reference as potential for enabling bolder and radically better dementia care models. Originality/value This paper offers a review of present global and European dementia policy, outlining the potential implications for the most marginalised in society if it fails to be critical of its own underpinning assumptions.

Periodontal disease is a chronic inflammatory disorder of the tissues surrounding the teeth, with evidence of systemic effects. Some studies showed the benefit of periodontal therapy on blood pressure (BP), but the impact of periodontitis on BP control is unknown. We retrospectively analyzed cross-sectional, nationally representative data from treated hypertensive adults aged ≥30 years with and without periodontitis. BP was examined as both continuous (mm Hg) and categorical (treatment goal achievement status according to guidelines: at goal and above goal) variable according to the presence or absence of periodontitis and its clinical parameters (probing depth, clinical attachment loss, and disease severity [mild, moderate, and severe]). Systolic BP means and odds ratios for uncontrolled BP according to the presence and severity of periodontitis were calculated using progressively adjusted models. Among treated hypertensive adults, mean systolic BP was about 2.3 to 3 mm Hg higher in the presence of periodontitis ( P

BACKGROUND: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected. METHODS: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure

IntroductionDirect-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.MethodsSeveral design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and disseminationDirect-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration numberClinicalTrials.gov Registry (NCT04358302).

To contribute to achieving local and global sustainability, we propose a novel educational methodology, called field environmental philosophy (FEP), which orients ecotourism practices to reconnect citizens and nature. FEP is based on the systemic approach of the biocultural ethic that values the vital links among the life habits of co-inhabitants (humans and other-than-humans) who share a common habitat. Based on this “3Hs” model (habitats, co-inhabitants, habits), FEP combines tourism with experiential education to reorient biocultural homogenization toward biocultural conservation. FEP’s methodological approach seeks to integrate social, economic, and environmental dimensions of sustainability by generating new links between biological and cultural diversity at different spatial and social scales. Ecotourism has an underutilized potential to link sciences with education and conservation practices at different scales. By incorporating a philosophical foundation, FEP broadens both understanding and practices of environmental education and sustainable tourism. FEP has been developed at the Omora Ethnobotanical Park in the Cape Horn Biosphere Reserve, Chile, at the southern end of the Americas since 2000, where it has oriented transdisciplinary work for the creation of new protected areas and ecotourism practices. FEP enables an integration of biophysical, cultural, and institutional dimensions into the design of ecotourism activities that transform and broaden the perceptions of tourists, local guides, students, and other participants to better appreciate local biological and cultural diversity. FEP’s methodology is starting to be adapted in other world regions, such as Germany, Japan, and Mexico, to integrate education and ecotourism for sustainability.

We outline specific steps that NASA and the space science community can take to advance collaboration and coordination between the communities represented by the four NASA Science Mission Directorate Divisions. It is important to note that the only way that this effort can succeed is if NASA initiates and supports it through directed resources.

The Habitable zone Planet Finder (HPF) is a fiber fed precise radial velocity spectrograph at the 10 m Hobby Eberly Telescope (HET). Due to its fixed altitude design, the HET pupil changes appreciably across a track, leading to significant changes of the fiber far-field illumination. HPF's fiber scrambler is designed to suppress the impact of these illumination changes on the radial velocities -- but the residual impact on the radial velocity measurements has yet to be probed on sky. We use GJ 411, a bright early type (M2) M dwarf to probe the effects of far-field input trends due to these pupil variations on HPF radial velocities (RVs). These large changes ($\sim$ 2x) in pupil area and centroid present a harsh test of HPF's far-field scrambling. Our results show that the RVs are effectively decoupled from these extreme far-field input changes due to pupil centroid offsets, attesting to the effectiveness of the scrambler design. This experiment allows us to test the impact of these changes with large pupil variation on-sky, something we would not easily be able to do at a conventional optical telescope. While the pupil and illumination changes expected at these other telescopes are small, scaling from our results enables us to estimate and bound these effects, and show that they are controllable even for the new and next generation of RV instruments in their quest to beat down instrumental noise sources towards the goal of a few cm/s., 16 pages. Published in The Astrophysical Journal

Neurological outcomes following spinal cord injury (SCI) are currently difficult to predict. While the initial American Spinal\udInjury Association Impairment Scale (AIS) grade can give an estimate of outcome, the high remaining degree of uncertainty\udhas stoked recent interest in biomarkers for SCI. This study aimed to assess the prognostic value of routinely measured blood\udbiomarkers by developing prognostic models of AIS scores at discharge and 12 months post-injury. Routine blood and clinical\uddata were collected from SCI patients (n = 417), and blood measures that had been assessed in less than 50% of patients were\udexcluded. Outcome neurology was obtained from AIS and Spinal Cord Independence Measure III (SCIM-III) scores at\uddischarge and 12 months post-injury, with motor (AIS) and sensory (AIS, touch and prick) abilities being assessed individually. Linear regression models with and without elastic net penalization were created for all outcome measures. Blood\udmeasures associated with liver function, such as alanine transaminase, were found to add value to predictions of SCIM-III at\uddischarge and 12 months post-injury. Further, components of a total blood count, including hemoglobin, were found to add\udvalue to predictions of AIS motor and sensory scores at discharge and 12 months post-injury. These findings corroborate the\udresults of our previous preliminary study and thus provide further evidence that routine blood measures can add prognostic\udvalue in SCI and that markers of liver function are of particular interest.

Background It is unclear whether faster progression of atherosclerosis explains the higher risk of cardiovascular events in CKD. The objectives of this study were to 1. Characterize the associations of CKD with presence and morphology of atherosclerotic plaques on carotid magnetic resonance imaging (MRI) and 2. Examine the associations of baseline CKD and carotid atherosclerotic plaques with subsequent cardiovascular events. Methods In a subgroup (N = 465) of Systolic Blood Pressure Intervention Trial. (SPRINT) participants, we measured carotid plaque presence and morphology at baseline and after 30-months with MRI. We examined the associations of CKD (baseline eGFR 2) with progression of carotid plaques and the SPRINT cardiovascular endpoint. Results One hundred and ninety six (42%) participants had CKD. Baseline eGFR in the non-CKD and CKD subgroups were 77 ± 14 and 49 ± 8 ml/min/1.73 m2, respectively. Lipid rich necrotic-core plaque was present in 137 (29.5%) participants. In 323 participants with both baseline and follow-up MRI measurements of maximum wall thickness, CKD was not associated with progression of maximum wall thickness (OR 0.62, 95% CI 0.36 to 1.07, p = 0.082). In 96 participants with necrotic core plaque at baseline and with a valid follow-up MRI, CKD was associated with lower odds of progression of necrotic core plaque (OR 0.41, 95% CI 0.17 to 0.95, p = 0.039). There were 28 cardiovascular events over 1764 person-years of follow-up. In separate Cox models, necrotic core plaque (HR 2.59, 95% CI 1.15 to 5.85) but not plaque defined by maximum wall thickness or presence of a plaque component (HR 1.79, 95% CI 0.73 to 4.43) was associated with cardiovascular events. Independent of necrotic core plaque, CKD (HR 3.35, 95% CI 1.40 to 7.99) was associated with cardiovascular events. Conclusions Presence of necrotic core in carotid plaque rather than the presence of plaque per se was associated with increased risk of cardiovascular events. We did not find CKD to be associated with faster progression of necrotic core plaques, although both were independently associated with cardiovascular events. Thus, CKD may contribute to cardiovascular disease principally via mechanisms other than atherosclerosis such as arterial media calcification or stiffening. Trial Registration NCT01475747, registered on November 21, 2011.

The α2a adrenoceptor is a medically relevant subtype of the G protein-coupled receptor family. Unfortunately, high-throughput techniques aimed at producing novel drug leads for this receptor have been largely unsuccessful because of the complex pharmacology of adrenergic receptors. As such, cutting-edge in silico ligand- and structure-based assessment and de novo deep learning methods are well positioned to provide new insights into protein-ligand interactions and potential active compounds. In this work, we (i) collect a dataset of α2a adrenoceptor agonists and provide it as a resource for the drug design community; (ii) use the dataset as a basis to generate candidate-active structures via deep learning; and (iii) apply computational ligand- and structure-based analysis techniques to gain new insights into α2a adrenoceptor agonists and assess the quality of the computer-generated compounds. We further describe how such assessment techniques can be applied to putative chemical probes with a case study involving proposed medetomidine-based probes.

Introduction Contemporary phase 2 TB disease treatment clinical trials have found that microbiologic treatment responses differ between African versus non-African regions, the reasons for which remain unclear. Understanding host and disease phenotypes that may vary by region is important for optimizing curative treatments. Methods We characterized clinical features and the serum proteome of phase 2 TB clinical trial participants undergoing treatment for smear positive, culture-confirmed TB, comparing host serum protein expression in clinical trial participants enrolled in African and Non-African regions. Serum samples were collected from 289 participants enrolled in the Centers for Disease Control and Prevention TBTC Study 29 (NCT00694629) at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). Results After a peptide level proteome analysis utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS) and subsequent statistical analysis, a total of 183 core proteins demonstrated significant differences at both baseline and at week 8 timepoints between participants enrolled from African and non-African regions. The majority of the differentially expressed proteins were upregulated in participants from the African region, and included acute phase proteins, mediators of inflammation, as well as coagulation and complement pathways. Downregulated proteins in the African population were primarily linked to nutritional status and lipid metabolism pathways. Conclusions We have identified differentially expressed nutrition and lipid pathway proteins by geographic region in TB patients undergoing treatment for pulmonary tuberculosis, which appear to be associated with differential treatment responses. Future TB clinical trials should collect expanded measures of nutritional status and further evaluate the relationship between nutrition and microbiologic treatment response.

The human colonization of eastern Africa's near- and offshore islands was accompanied by the translocation of several domestic, wild and commensal fauna, many of which had long-term impacts on local environments. To better understand the timing and nature of the introduction of domesticated caprines (sheep and goat) to these islands, this study applied collagen peptide fingerprinting (Zooarchaeology by Mass Spectrometry or ZooMS) to archaeological remains from eight Iron Age sites, dating between ca 300 and 1000 CE, in the Zanzibar, Mafia and Comoros archipelagos. Where previous zooarchaeological analyses had identified caprine remains at four of these sites, this study identified goat at seven sites and sheep at three, demonstrating that caprines were more widespread than previously known. The ZooMS results support an introduction of goats to island eastern Africa from at least the seventh century CE, while sheep in our sample arrived one–two centuries later. Goats may have been preferred because, as browsers, they were better adapted to the islands' environments. The results allow for a more accurate understanding of early caprine husbandry in the study region and provide a critical archaeological baseline for examining the potential long-term impacts of translocated fauna on island ecologies. 1. Introduction 2. Background 2.1. Island colonization and species translocations 2.2. Tracing the introduction of caprines to insular Eastern Africa 3. Methods 3.1. Sites 3.2. Sample selection 3.3. ZooMS protocol 3.3.1. Acid-insoluble protocol 3.3.2. Acid-soluble protocol 3.3.3. Lyophilized collagen for stable isotope analysis 3.3.4. C18 clean-up and MALDI-ToF analysis 4. Results 5. Discussion 5.1. Diachronic patterns in the introduction of caprines 5.2. Island herd compositions 5.3. Wild faunal extirpations and translocations 5.4. Long-term ecological impacts of caprines on Eastern Africa’s islands 6. Conclusion

To evaluate the outcomes of excision and primary anastomosis (EPA) for radiation-associated bulbomembranous stenoses using a multi-institutional analysis. The treatment of radiation-associated urethral stenosis is typically complex owing to the adverse impact of radiation on adjacent tissue.An IRB-approved multi-institutional retrospective review was performed on patients who underwent EPA for bulbomembranous urethral stenosis following prostate radiotherapy. Preoperative patient demographics, operative technique, and postoperative outcomes were abstracted from 1/2007-6/2018. Success was defined as voiding per urethra without the need for endoscopic treatment and a minimum follow-up of 12 months.One hundred and thirty-seven patients from 10 centers met study criteria with a mean age of 69.3 years (50-86), stenosis length of 2.3 cm (1-5) and an 86.9% (119/137) success rate at a mean follow-up 32.3 months (12-118). Univariate Cox regression analysis identified increasing patient age (P = .02), stricture length (P.0001) and combined modality radiotherapy (P = .004) as factors associated with stricture recurrence while body mass index (P = .79), diabetes (P = .93), smoking (P = .62), failed endoscopic treatment (P = .08) and gracilis muscle use (P = .25) were not. On multivariate analysis, increasing patient age (H.R.1.09, 95%CI 1.01-1.16; P = .02) and stenosis length (H.R.2.62, 95%CI 1.49-4.60; P = .001) remained associated with recurrence. Subsequent artificial urinary sphincter was performed in 30 men (21.9%), of which 25 required a transcorporal cuff and 5 developed cuff erosion.EPA for radiation-associated urethral stenosis effectively provides unobstructed instrumentation-free voiding. However, increasing stenosis length and age are independently associated with surgical failure. Patients should be counseled that further surgery for incontinence may be necessary.

Background Although intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH). Purpose To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults. Data sources MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions. Study selection Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing. Data extraction 2 investigators independently abstracted articles and rated risk of bias. Data synthesis 5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH (P for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged. Limitations Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available. Conclusion Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension. Primary funding source National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).