Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2.

The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

A TOG Protein Confers Tension Sensitivity to Kinetochore-Microtubule Attachments.

The development and survival of all organisms depends on equal partitioning of their genomes during cell division. Accurate chromosome segregation requires selective stabilization of kinetochore-microtubule attachments that come under tension due to opposing pulling forces exerted on sister kinetochores by dynamic microtubule tips. Here, we show that the XMAP215 family member, Stu2, makes a major contribution to kinetochore-microtubule coupling. Stu2 and its human ortholog, ch-TOG, exhibit a conserved interaction with the Ndc80 kinetochore complex that strengthens its attachment to microtubule tips. Strikingly, Stu2 can either stabilize or destabilize kinetochore attachments, depending on the level of kinetochore tension and whether the microtubule tip is assembling or disassembling. These dichotomous effects of Stu2 are independent of its previously studied regulation of microtubule dynamics. Altogether, our results demonstrate how a kinetochore-associated factor can confer opposing, tension-dependent effects to selectively stabilize tension-bearing attachments, providing mechanistic insight into the basis for accuracy during chromosome segregation.

Peering into the crystal ball: influenza pandemics and vaccine efficacy.

The looming threat of a new influenza virus pandemic has fueled ambitious efforts to devise more predictive parameters for assessing the risks associated with emergent virus strains. At the same time, a comprehensive understanding of critical factors that can accurately predict the outcome of vaccination is sorely needed in order to improve the effectiveness of influenza virus vaccines. Will new studies aimed at identifying adaptations required for virus transmissibility and systems-level analyses of influenza virus vaccine responses provide an improved framework for predictive models of viral adaptation and vaccine efficacy?

Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis.

The human helicase senataxin (SETX) has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2). Here we identified a role for SETX in controlling the antiviral response. Cells that had undergone depletion of SETX and SETX-deficient cells derived from patients with AOA2 had higher expression of antiviral mediators in response to infection than did wild-type cells. Mechanistically, we propose a model whereby SETX attenuates the activity of RNA polymerase II (RNAPII) at genes stimulated after a virus is sensed and thus controls the magnitude of the host response to pathogens and the biogenesis of various RNA viruses (e.g., influenza A virus and West Nile virus). Our data indicate a potentially causal link among inborn errors in SETX, susceptibility to infection and the development of neurologic disorders.

Targeting the MR1-MAIT cell axis improves vaccine efficacy and affords protection against viral pathogens.

Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. Additionally, MAIT cells sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unclear. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster virus-specific CD8+ T cell responses, and potentiate heterosubtypic anti-influenza protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency and Toll-like receptor 3 and type I interferon receptor signaling. The observed phenomenon was reproducible in female and male mice, and in both young and old animals. It could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses.

An integrative systems genetic analysis of mammalian lipid metabolism.

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.

Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians.

DESCRIPTION: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs. METHODS: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE. AUDIENCE AND PATIENT POPULATION: The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes. RECOMMENDATION 1: ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). • Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure. • Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. RECOMMENDATION 2: ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

Pathology and Monkeypox virus Localization in Tissues From Immunocompromised Patients With Severe or Fatal Mpox.

BACKGROUND: Pathology and Monkeypox virus (MPXV) tissue tropism in severe and fatal human mpox is not thoroughly described but can help elucidate the disease pathogenesis and the role of coinfections in immunocompromised patients. METHODS: We analyzed biopsy and autopsy tissues from 22 patients with severe or fatal outcomes to characterize pathology and viral antigen and DNA distribution in tissues by immunohistochemistry and in situ hybridization. Tissue-based testing for coinfections was also performed. RESULTS: Mucocutaneous lesions showed necrotizing and proliferative epithelial changes. Deceased patients with autopsy tissues evaluated had digestive tract lesions, and half had systemic tissue necrosis with thrombotic vasculopathy in lymphoid tissues, lung, or other solid organs. Half also had bronchopneumonia, and one-third had acute lung injury. All cases had MPXV antigen and DNA detected in tissues. Coinfections were identified in 5 of 16 (31%) biopsy and 4 of 6 (67%) autopsy cases. CONCLUSIONS: Severe mpox in immunocompromised patients is characterized by extensive viral infection of tissues and viremic dissemination that can progress despite available therapeutics. Digestive tract and lung involvement are common and associated with prominent histopathological and clinical manifestations. Coinfections may complicate mpox diagnosis and treatment. Significant viral DNA (likely correlating to infectious virus) in tissues necessitates enhanced biosafety measures in healthcare and autopsy settings.

Toward a clearer understanding of what works to reduce gun violence: the role of falsification strategies.

Strong epidemiologic evidence from ecological and individual-level studies in the United States supports the claim that access to firearms substantially increases the risk of dying by suicide, homicide, and firearm accidents. Less certain is how well particular interventions work to prevent these deaths and other firearm-related harms. Given the limits of existing data to study firearm violence and the infeasibility of conducting randomized trials of firearm access, it is important to do the best we can with the data we already have. We argue that falsification strategies are a critical-yet underutilized-component of any such analytical approach. The falsification strategies we focus on are versions of "negative controls" analyses in which we expect that an analysis should yield a null causal effect, and thus where not obtaining a null effect estimate raises questions about the assumptions underlying causal interpretation of a study's findings. We illustrate the saliency of this issue today with examples drawn from studies published in leading peer-reviewed journals within the last 5 years. Collecting rich, high-quality data always takes time, urgent as the need may be. On the other hand, doing better with the data we already have can start right now.

Confounder selection in firearm policy research: A scoping review.

Legislative firearm policies are often proposed as a way of preventing firearm-related harm. Confounding is a substantial threat to accurately estimating the causal effects of firearm policies. This scoping review characterizes selection of potential confounders in US firearm policy evaluations in the health sciences literature. We identified empirical research articles indexed in PubMed from 1/1/2000-9/1/2021 that examined any of 18 pre-specified firearm policies and extracted key study elements, including the exposure (firearm policy), outcomes, potential confounders adjusted for in analyses, and study approach (i.e., static, uncontrolled pre-post, and controlled pre-post). There was wide variation in potential confounders within study approach-policy-outcome combinations. The most common potential confounders included sociodemographic and economic variables, rurality/urbanicity, violent crime, law enforcement-related variables, alcohol use, and firearm access (mostly measured via proxies for firearm ownership). Firearm policies other than the policy being evaluated were included in the adjustment set in 23-44% of studies, depending on the study approach. Confounder selection was most often said to be based on prior research (n=49, 40%) or not explicitly stated (n=48, 39%). This scoping review provides a comprehensive resource for critically appraising the firearm policy literature and offers considerations to support more rigorous confounding control in future firearm policy research.

Associations of Resilience, Perceived Control of Health, and Depression with Geriatric Outcomes after Surgery.

OBJECTIVE: To identify if depression, resilience, and perceived control of health are related to 2.5-year mortality and instrumental activities of daily living (IADL) decline among older adults after surgery. SUMMARY BACKGROUND DATA: The relationships of psychosocial factors with postoperative mortality and IADL decline among older adults are understudied. METHODS: We identified 3778 community-dwelling older adults in the Health and Retirement Study (HRS) with Medicare claims for surgery (mean [SD] age: 75.4 [7.8] years, 53.9% women, and 86.0% non-Hispanic White). We assessed associations of depression, resilience, and perceived control of health with 2.5-year postoperative mortality and IADL decline using cox and modified Poisson regression analyses, adjusting for sociodemographic and health variables. RESULTS: The incidence of 2.5-year postoperative mortality was 18.5% and IADL decline was 9.4%. Depression was associated with a higher incidence and adjusted hazard [95% CI] of mortality (26% vs. 16%, aHR:1.2[0.9, 1.5]), but high resilience was associated with a lower incidence and adjusted hazard of mortality (9% vs. 21%, aHR:0.6[0.5, 0.8]). Those with depression had higher incidence and adjusted relative risk [95% CI] of IADL decline (17% vs. 7%, aRR:1.6[1.2, 2.2]), but lower incidence and adjusted relative risk of IADL decline was identified for those with high resilience (4% vs. 11%, aRR:0.6[0.4, 1.0]) and high perceived control of health (7% vs. 10%, aRR:0.6[0.4, 1.0]). CONCLUSION: While depression confers greater risk of mortality and IADL decline, higher resilience and perceived control of health may be protective. Addressing psychosocial factors in the peri-operative period may improve outcomes among older adults.

PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

Type I interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection.

The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28-2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.

Reporting and Description of Research Methodology in Studies Estimating Effects of Firearm Policies.

BACKGROUND: Evidence about which firearm policies work, to what extent, and for whom is hotly debated, perhaps partly because variation in research methodology has produced mixed and inconclusive effect estimates. We conducted a scoping review of firearm policy research in the health sciences in the United States, focusing on methodological considerations for causal inference. METHODS: We identified original, empirical articles indexed in PubMed from 1 January 2000 to 1 September 2021 that examined any of 18 prespecified firearm policies. We extracted key study components, including policy type(s) examined, policy operationalization, outcomes, study setting and population, study approach and design, causal language, and whether and how authors acknowledged potential sources of bias. RESULTS: We screened 7733 articles and included 124. A plurality of studies used a legislative score as their primary exposure (n = 39; 32%) and did not examine change in policies over time (n = 47; 38%). Most examined firearm homicide (n = 51; 41%) or firearm suicide (n = 40; 32%) as outcomes. One-third adjusted for other firearm policies (n = 41; 33%). Three studies (2%) explicitly mentioned that their goal was to estimate causal effects, but over half used language implying causality (n = 72; 58%). Most acknowledged causal identification assumptions of temporality (n = 91; 73%) and exchangeability (n = 111; 90%); other assumptions were less often acknowledged. One-third of studies included bias analyses (n = 42; 34%). CONCLUSIONS: We identified a range of methodologic approaches in firearm policy research in the health sciences. Acknowledging the imitations of data availability and quality, we identify opportunities to improve causal inferences about and reporting on the effects of firearm policies on population health.

eConsultation for Deprescribing Among Older Adults: Clinician Perspectives on Implementation Barriers and Facilitators.

BACKGROUND: Electronic consultations (eConsults) enable asynchronous consultation between primary care providers (PCPs) and specialists. eConsults have been used successfully to manage a variety of conditions and have the potential to help PCPs manage polypharmacy and promote deprescribing. OBJECTIVE: To elicit clinician perspectives on barriers/facilitators of using eConsults for deprescribing among older adults within a university health network. DESIGN: Semi-structured interviews. PARTICIPANTS: PCPs, geriatricians, and pharmacists. APPROACH: We used the COM-B (Capability, Opportunity, Motivation, and Behavior) model to structure the interview guide and qualitative analysis methods to identify barriers/facilitators of (1) deprescribing and (2) use of eConsults for deprescribing. KEY RESULTS: Of 28 participants, 19 were PCPs (13 physicians, 4 residents, 2 nurse practitioners), 7 were geriatricians, and 2 were pharmacists. Barriers and facilitators to deprescribing: PCPs considered deprescribing important but identified myriad barriers (e.g., time constraints, fragmented clinical care, lack of pharmacist integration, and patient/family resistance). Use of eConsults for deprescribing: Both PCPs and geriatricians highlighted the limits of contextual information available through electronic health record (vs. face-to-face) to render specific and actionable eConsults (e.g., knowledge of prior deprescribing attempts). Participants from all groups expressed interest in a targeted process whereby eConsults could be offered for select patients based on key factors (e.g., polypharmacy or certain comorbidities) and accepted or declined by PCPs, with pithy recommendations delivered in a timely manner relative to patient appointments. This was encapsulated by one PCP: "they need to be crisp and to the point to be helpful, with specific suggestions of something that could be discontinued or switched…not, 'hey, did you know your patient is on over 12 medicines?'". CONCLUSIONS: Clinicians identified multifaceted factors influencing the utility of eConsults for deprescribing among older adults in primary care. Deprescribing eConsult interventions should be timely, actionable, and mindful of limitations of electronic chart review.

iSDAsoil: The first continent-scale soil property map at 30 m resolution provides a soil information revolution for Africa.

Open access, high-resolution soil property maps have been created for Africa at 30 m resolution, using machine learning trained on over 100,000 analysed soil samples. Combined with other field-level information, iSDAsoil enables the possibility of site-specific agronomy advisory for smallholder farmers.

Combat-related peripheral nerve injuries.

Active-duty service members (ADSM) and military Veterans represent a population with increased occupational risk for nerve injuries sustained both during training operations and wartime. Mechanisms of war-related nerve injuries have evolved over time, from the musket ball-related traumas described by S.W. Mitchell to complex blast injuries and toxic exposures sustained during Middle East conflicts in the 21st century. Commonly encountered nerve injury etiologies in this population currently include compression, direct trauma, nutritional deficits, traumatic limb amputation, toxic chemical exposures, or blast-related injuries. Expeditious identification and comprehensive, interdisciplinary treatment of combat-associated neuropathies, as well as prevention of these injuries whenever possible is critical to reduce chronic morbidity and disability for service members and to maintain a well-prepared military. However, diagnosis of a combat-associated nerve injury may be particularly challenging due to comorbid battlefield injuries or delayed presentation of neuropathy from military toxic exposures. Advances in imaging for nerve injury, including MRI and ultrasound, provide useful tools to compliment EMG in establishing a diagnosis of combat-associated nerve injury, particularly in the setting of anatomic disruption or edema. Surgical techniques can improve pain control or restoration of function. In all cases, comprehensive interdisciplinary rehabilitation provides the best framework for optimization of recovery. Further work is needed to prevent combat-associated nerve injuries and promote nerve recovery following injury.

Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease.

BACKGROUND & AIMS: Ferritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis. METHODS: This was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration-controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut-off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver-related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis. RESULTS: Of 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35-2.09], p < .001) and incident liver-related events (HR 1.92 [1.11-3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis-promoting alleles including PNPLA3-rs738409-G allele (p = .0068) and TM6SF2-rs58542926-T allele (p = 0.0083) but not with common HFE mutations. CONCLUSIONS: In MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver-related events, and cirrhosis-promoting alleles but not with iron overload-promoting HFE mutations.

The dual timescales of gait adaptation: Initial stability adjustments followed by subsequent energetic cost adjustments.

Gait adaptation during bipedal walking allows people to adjust their walking patterns to maintain balance, avoid obstacles, and avoid injury. Adaptation involves complex processes that function to maintain stability and reduce energy expenditure. However, the processes that influence walking patterns during different points in the adaptation period remain to be investigated. We recruited seventeen young adults ages 19-35 to assess split-belt adaptation. We also assessed individual aerobic capacity to understand how aerobic capacity influences adaptation. We analyzed step lengths, step length asymmetry (SLA), mediolateral margins of stability, positive, negative, and net mechanical work rates, as well as metabolic rate during adaptation. We used dual-rate exponential mixed-effects regressions to estimate the adaptation of each measure over two timescales. Our results indicate that mediolateral stability adapts over a single timescale in under 1 minute, while mechanical work rates, metabolic rate, step lengths, and step length asymmetry adapt over two distinct timescales, ranging from 3.5 to 11.2 minutes. We then regressed mediolateral margins of stability, net mechanical work rate, and metabolic rate on step length asymmetry during early and late adaptation phases to determine if stability drives early adaptation and energetic cost drives late adaptation. Stability predicted SLA during the initial rapid onset of adaptation, and mechanical work rate predicted SLA during the latter part of adaptation. These findings suggest that stability optimization may contribute to early gait changes and that mechanical work contributes to later changes during adaptation. A final sub-analysis assessed the effect of aerobic capacity on step length asymmetry adaptation. Aerobic capacity levels below 36 and above 43 ml/kg/min resulted in greater adaptation, underscoring the metabolic influences on gait adaptation. This study illuminates the complex interplay between biomechanical and metabolic factors in gait adaptation, shedding light on fundamental mechanisms underlying human locomotion.

Oritavancin as sequential therapy for Gram-positive bloodstream infections.

BACKGROUND: Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE). METHODS: We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance. RESULTS: Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5-17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient). CONCLUSIONS: The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance.