Compositionally complex doping for zero-strain zero-cobalt layered cathodes.

The high volatility of the price of cobalt and the geopolitical limitations of cobalt mining have made the elimination of Co a pressing need for the automotive industry1. Owing to their high energy density and low-cost advantages, high-Ni and low-Co or Co-free (zero-Co) layered cathodes have become the most promising cathodes for next-generation lithium-ion batteries2,3. However, current high-Ni cathode materials, without exception, suffer severely from their intrinsic thermal and chemo-mechanical instabilities and insufficient cycle life. Here, by using a new compositionally complex (high-entropy) doping strategy, we successfully fabricate a high-Ni, zero-Co layered cathode that has extremely high thermal and cycling stability. Combining X-ray diffraction, transmission electron microscopy and nanotomography, we find that the cathode exhibits nearly zero volumetric change over a wide electrochemical window, resulting in greatly reduced lattice defects and local strain-induced cracks. In-situ heating experiments reveal that the thermal stability of the new cathode is significantly improved, reaching the level of the ultra-stable NMC-532. Owing to the considerably increased thermal stability and the zero volumetric change, it exhibits greatly improved capacity retention. This work, by resolving the long-standing safety and stability concerns for high-Ni, zero-Co cathode materials, offers a commercially viable cathode for safe, long-life lithium-ion batteries and a universal strategy for suppressing strain and phase transformation in intercalation electrodes.

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Prevalence of vision zero action plans or strategies: USA, 2021.

BACKGROUND: Vision Zero is a strategy to eliminate traffic fatalities and to promote equitable mobility options for all road users. Using a nationally representative survey, we aimed to estimate the prevalence of Vision Zero action plans or strategies in the USA. METHODS: Municipal officials were surveyed in 2021. In this cross-sectional study, we calculated the prevalence of Vision Zero plans or strategies and compared municipalities with adjusted prevalence ratios (PR) to account for region and sociodemographic characteristics. RESULTS: Among 1955 municipalities participating in the survey (question-specific response rate: 44.3%), the prevalence of a Vision Zero action plan or strategy was 7.7%; 70.5% responded no and 21.8% don't know. Prevalence was 4.8% in small municipalities (1000-2499 residents), 20.3% in medium-large municipalities (50 000-124 999 residents; PR=4.1), and 37.8% in large municipalities (≥125 000 residents; PR=7.6). CONCLUSION: The prevalence of Vision Zero plans and strategies across the USA is low. Additional adoption of Vision Zero plans and strategies could help address traffic fatalities.

Radiation Oncology Resident Education: Is Change Needed?

Leading successful change efforts first requires assessment of the "before change" environment and culture. At our institution, the radiation oncology (RO) residents follow a longitudinal didactic learning program consisting of weekly 1-h lectures, case conferences, and journal clubs. The resident didactic education series format has not changed since its inception over 10 years ago. We evaluated the perceptions of current residents and faculty about the effectiveness of the curriculum in its present form. Two parallel surveys were designed, one each for residents and attendings, to assess current attitudes regarding the effectiveness and need for change in the RO residency curriculum, specifically the traditional didactic lectures, the journal club sessions, and the case conferences. We also investigated perceived levels of engagement among residents and faculty, whether self-assessments would be useful to increase material retention, and how often the content of didactic lectures is updated. Surveys were distributed individually to each resident (N = 10) and attending (N = 24) either in-person or via Zoom. Following completion of the survey, respondents were informally interviewed about their perspectives on the curriculum's strengths and weaknesses. Compared to 46% of attendings, 80% of RO residents believed that the curriculum should be changed. Twenty percent of residents felt that the traditional didactic lectures were effective in preparing them to manage patients in the clinic, compared to 74% of attendings. Similarly, 10% of residents felt that the journal club sessions were effective vs. 42% of attendings. Finally, 40% of residents felt that the case conferences were effective vs. 67% of attendings. Overall, most respondents (56%) favored change in the curriculum. Our results suggest that the perceptions of the residents did not align with those of the attending physicians with respect to the effectiveness of the curriculum and the need for change. The discrepancies between resident and faculty views highlight the importance of a dedicated change management effort to mitigate this gap. Based on this project, we plan to propose recommended changes in structure to the residency program directors. Main changes would be to increase the interactive nature of the course material, incorporate more ways to increase faculty engagement, and consider self-assessment questions to promote retention. Once we get approval from the residency program leadership, we will follow Kotter's "Eight steps to transforming your organization" to ensure the highest potential for faculty to accept the expectations of a new curriculum.

'Our culture makes us strong': Understanding and working with community strengths among Aboriginal people in western Sydney.

BACKGROUND: Strengths-based approaches to health care are often seen as an alternative to deficit-based approaches and are common in Aboriginal health settings. Despite this, there is little existing research that describes Aboriginal peoples' perspectives about the strengths of their communities. This paper describes cultural strengths and resources as understood by Aboriginal people living in western Sydney. METHODS: In-depth interviews were used to collect qualitative data from two communities on Dharug and Dharrawal Country in western Sydney Australia. Data come from a larger study, which focused on how cultural strengths supported sexual well-being. Fifty-two interviews were conducted with Aboriginal young people (aged 16-24 years) by trained peer interviewers. Additionally, 16 interviews with Aboriginal adults (25 years and older) were conducted by members of the research team. FINDINGS AND DISCUSSION: While opinions varied, four key areas of cultural strength were identified: (1) strong kinship relationships; (2) knowledge sharing; (3) shared experiences, identities, and values; and (4) knowing Country. Throughout these four themes, the sense of connection and belonging is viewed as an important overarching theme. CONCLUSION: Communities are not homogenous with regard to what they view as cultural strengths. Knowing Country and practising culture meant different things to different individuals while providing a similar sense of belonging, connection, and identity. SO WHAT: Health service providers, policies, and programs can use this information to understand the continuing impacts of past policies and events whilst recognising that each community has strengths that can be drawn upon to improve service engagement, knowledge sharing, and health outcomes.

Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART).

PURPOSE: Treatment options for pancreatic ductal adenocarcinoma (PDAC) are commonly limited for patients with advanced age due to medical comorbidities and/or poor performance status. These patients may not be candidates for more aggressive chemotherapy regimens and/or surgical resection leaving few, if any, other effective treatments. Ablative stereotactic MRI-guided adaptive radiation therapy (A-SMART) is both efficacious and safe for PDAC and can achieve excellent long-term local control, however, the appropriateness of A-SMART for elderly patients with inoperable PDAC is not well understood. METHODS: A retrospective analysis was performed of inoperable non-metastatic PDAC patients aged 75 years or older treated on the MRIdian Linac at 2 institutions. Clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional (LRC). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE, v5). RESULTS: A total of 49 patients were evaluated with a median age of 81 years (range, 75-91) and a median follow-up of 14 months from diagnosis. PDAC was classified as locally advanced (46.9%), borderline resectable (36.7%), or medically inoperable (16.3%). Neoadjuvant chemotherapy was delivered to 84% of patients and all received A-SMART to a median 50 Gy (range, 40-50 Gy) in 5 fractions. 1 Year LRC, PFS, and OS were 88.9%, 53.8%, and 78.9%, respectively. Nine patients (18%) had resection after A-SMART and benefited from PFS improvement (26 vs 6 months, P = .01). ECOG PS <2 was the only predictor of improved OS on multivariate analysis. Acute and late grade 3 + toxicity rates were 8.2% and 4.1%, respectively. CONCLUSIONS: A-SMART is associated with encouraging LRC and OS in elderly patients with initially inoperable PDAC. This novel non-invasive treatment strategy appears to be well-tolerated in patients with advanced age and should be considered in this population that has limited treatment options.

Leisure-time physical activity and mortality from influenza and pneumonia: a cohort study of 577 909 US adults.

OBJECTIVE: To examine the association of leisure-time physical activity with mortality from influenza and pneumonia. METHODS: A nationally representative sample of US adults (aged ≥18 years) who participated in the National Health Interview Survey from 1998 to 2018 were followed for mortality through 2019. Participants were classified as meeting both physical activity guidelines if they reported ≥150 min/week of moderate-intensity equivalent aerobic physical activity and ≥2 episodes/week of muscle-strengthening activity. Participants were also classified into five volume-based categories of self-reported aerobic and muscle-strengthening activity. Influenza and pneumonia mortality was defined as having an underlying cause of death with an International Classification of Diseases, 10th Revision code of J09-J18 recorded in the National Death Index. Mortality risk was assessed using Cox proportional hazards, adjusting for sociodemographic and lifestyle factors, health conditions and influenza and pneumococcal vaccination status. Data were analysed in 2022. RESULTS: Among 577 909 participants followed for a median of 9.23 years, 1516 influenza and pneumonia deaths were recorded. Compared with participants meeting neither guideline, those meeting both guidelines had 48% lower adjusted risk of influenza and pneumonia mortality. Relative to no aerobic activity, 10-149, 150-300, 301-600 and >600 min/week were associated with lower risk (by 21%, 41%, 50% and 41%). Relative to <2 episodes/week of muscle-strengthening activity, 2 episodes/week was associated with 47% lower risk and ≥7 episodes/week with 41% higher risk. CONCLUSIONS: Aerobic physical activity, even at quantities below the recommended level, may be associated with lower influenza and pneumonia mortality while muscle-strengthening activity demonstrated a J-shaped relationship.

Physical Activity-Friendly Policies and Community Design Features in the US, 2014 and 2021.

INTRODUCTION: The 2014 Community-Based Survey of Supports for Healthy Eating and Active Living documented the prevalence of US municipal policy and community design supports for physical activity. The survey was repeated in 2021. Our study examined change in the prevalence of supports from 2014 to 2021, overall and by municipality characteristic. METHODS: Municipalities were sampled independently each survey year. We calculated prevalence in 2014 and 2021 and the prevalence ratio (PR) for 15 supports covering zoning codes, park policies and budgets, design standards, Complete Streets policies, and shared use agreements. We used a Bonferroni-corrected Breslow-Day test to test for interaction by municipality characteristic. RESULTS: In 2014 (2,009 municipalities) compared with 2021 (1,882 municipalities), prevalence increased for several zoning codes: block sizes of walkable distances (PR = 1.46), minimum sidewalk width (PR = 1.19), pedestrian amenities along streets (PR = 1.15), continuous sidewalk coverage (PR = 1.14), and building orientation to pedestrian scale (PR = 1.08). Prevalence also increased for design standards requiring dedicated bicycle infrastructure for roadway expansion projects or street retrofits (PR = 1.19). Prevalence declined for shared use agreements (PR = 0.87). The prevalence gap widened between the most and least populous municipalities for Complete Streets policies (from a gap of 33.6 percentage points [PP] in 2014 to 54.0 PP in 2021) and for zoning codes requiring block sizes that were walkable distances (from 11.8 PP to 41.4 PP). CONCLUSION: To continue progress, more communities could consider adopting physical activity-friendly policies and design features.

Myocarditis Attributable to Monkeypox Virus Infection in 2 Patients, United States, 2022.

We report 2 immunocompetent and otherwise healthy adults in the United States who had monkeypox and required hospitalization for viral myocarditis. Both patients were unvaccinated against orthopoxviruses. They had shortness of breath or chest pain and elevated cardiac biomarkers. No immediate complications were observed. They were discharged home after symptoms resolved.

Effects of the 2012 and 2018 US preventive services task force prostate cancer screening guidelines on pathologic outcomes after prostatectomy.

BACKGROUND: In May 2018, the US Preventive Services Task Force (USPSTF) recommended prostate cancer (PCa) screening for ages 55-69 be an individual decision. This changed from the USPSTF's May 2012 recommendation against screening for all ages. The effects of the 2012 and 2018 updates on pathologic outcomes after prostatectomy are unclear. METHODS: This study included 647 patients with PCa who underwent prostatectomy at our institution from 2005 to 2018. Patient groups were those diagnosed before the 2012 update (n = 179), between 2012 and 2018 updates (n = 417), and after the 2018 update (n = 51). We analyzed changes in the age of diagnosis, pathologic Gleason grade group (pGS), pathologic stage, lymphovascular invasion (LVI), and favorable/unfavorable pathology. Multivariable logistic regression adjusting for pre-biopsy covariables (age, prostate-specific antigen [PSA], African American race, family history) assessed impacts of 2012 and 2018 updates on pGS and pathologic stage. A p  < 0.05 was statistically significant. RESULTS: Median age increased from 60 to 63 (p = 0.001) between 2012 and 2018 updates and to 64 after the 2018 update. A significant decrease in pGS1, pGS2, pT2, and favorable pathology (p < 0.001), and a significant increase in pGS3, pGS4, pGS5, pT3a, and unfavorable pathology (p < 0.001) was detected between 2012 and 2018 updates. There was no significant change in pT3b or LVI between 2012 and 2018 updates. On multivariable regression, diagnosis between 2012 and 2018 updates was significantly associated with pGS4 or pGS5 and pT3a (p < 0.001). Diagnosis after the 2018 update was significantly associated with pT3a (p = 0.005). Odds of pGS4 or pGS5 were 3.2× higher (p < 0.001) if diagnosed between 2012 and 2018 updates, and 2.3× higher (p = 0.051) if after the 2018 update. Odds of pT3a were 2.4× higher (p < 0.001) if diagnosed between 2012 and 2018 updates and 2.9× higher (p = 0.005) if after the 2018 update. CONCLUSIONS: The 2012 USPSTF guidelines negatively impacted pathologic outcomes after prostatectomy. Patients diagnosed between 2012 and 2018 updates had increased frequency of higher-risk PCa and lower frequency of favorable disease. In addition, data after the 2018 update demonstrate a continued negative impact on postprostatectomy pathology. Thus, further investigation of the long-term effects of the 2018 USPSTF update is warranted.

Observation of and intention to use new places and changed spaces for physical activity during the COVID-19 pandemic - United States, June 2021.

The COVID-19 pandemic prompted built environment changes throughout the United States. We assessed the prevalence of new places and changed spaces for physical activity as observed by US adults and their intentions to use them. We used data from SummerStyles, a web-based survey of US adults conducted in June 2021 (n = 4073). Respondents were asked if they had discovered new places to be physically active during the past year, and if changes had been made to streets or outdoor areas to allow additional space for recreating. Those responding "yes" were asked if they intended to use the respective space. We estimated the weighted prevalence of adults who observed new places and changed spaces, and their intended use, by sociodemographic and geographic characteristics, physical activity level, and walking status. We compared subgroups with prevalence ratios (PR). Overall, 25.0% of US adults reported discovering new places for physical activity, and 25.3% reported changes to streets and outdoor spaces. Intention to use new places and changed spaces exceeded 50% among all sociodemographic and geographic subgroups. Among those reporting changes, adults who were physically inactive compared to those who were sufficiently active had similar intentions to use new places (PR = 0.83; 95% CI = 0.63, 1.10) and changed spaces (PR = 0.90; 95% CI = 0.69, 1.17). Approximately 1 in 4 adults reported discovering new places or changed spaces to support physical activity during the COVID-19 pandemic, and most intended to use these features. Expanding access to such supportive environments may help promote physical activity participation.

Children, adolescents, and young adults hospitalized with COVID-19 and diabetes in summer 2021.

INTRODUCTION: More information is needed to understand the clinical epidemiology of children and young adults hospitalized with diabetes and COVID-19. We describe the demographic and clinical characteristics of patients <21 years old hospitalized with COVID-19 and either Type 1 or Type 2 Diabetes Mellitus (T1DM or T2DM) during peak incidence of SARS-CoV-2 infection with the B.1.617.2 (Delta) variant. METHODS: This is a descriptive sub-analysis of a retrospective chart review of patients aged <21 years hospitalized with COVID-19 in six US children's hospitals during July-August 2021. Patients with COVID-19 and either newly diagnosed or known T1DM or T2DM were described using originally collected data and diabetes-related data specifically collected on these patients. RESULTS: Of the 58 patients hospitalized with COVID-19 and diabetes, 34 had T1DM and 24 had T2DM. Of those with T1DM and T2DM, 26% (9/34) and 33% (8/24), respectively, were newly diagnosed. Among those >12 years old and eligible for COVID-19 vaccination, 93% were unvaccinated (42/45). Among patients with T1DM, 88% had diabetic ketoacidosis (DKA) and 6% had COVID-19 pneumonia; of those with T2DM, 46% had DKA and 58% had COVID-19 pneumonia. Of those with T1DM or T2DM, 59% and 46%, respectively, required ICU admission. CONCLUSION: Our findings highlight the importance of considering diabetes in the evaluation of children and young adults presenting with COVID-19; the challenges of managing young patients who present with both COVID-19 and diabetes, particularly T2DM; and the importance of preventive actions like COVID-19 vaccination to prevent severe illness among those eligible with both COVID-19 and diabetes.

Characteristics and Clinical Outcomes of Children and Adolescents Aged <18 Years Hospitalized with COVID-19 - Six Hospitals, United States, July-August 2021.

During June 2021, the highly transmissible† B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating strain in the United States. U.S. pediatric COVID-19-related hospitalizations increased during July-August 2021 following emergence of the Delta variant and peaked in September 2021.§ As of May 12, 2021, CDC recommended COVID-19 vaccinations for persons aged ≥12 years,¶ and on November 2, 2021, COVID-19 vaccinations were recommended for persons aged 5-11 years.** To date, clinical signs and symptoms, illness course, and factors contributing to hospitalizations during the period of Delta predominance have not been well described in pediatric patients. CDC partnered with six children's hospitals to review medical record data for patients aged <18 years with COVID-19-related hospitalizations during July-August 2021.†† Among 915 patients identified, 713 (77.9%) were hospitalized for COVID-19 (acute COVID-19 as the primary or contributing reason for hospitalization), 177 (19.3%) had incidental positive SARS-CoV-2 test results (asymptomatic or mild infection unrelated to the reason for hospitalization), and 25 (2.7%) had multisystem inflammatory syndrome in children (MIS-C), a rare but serious inflammatory condition associated with COVID-19.§§ Among the 713 patients hospitalized for COVID-19, 24.7% were aged <1 year, 17.1% were aged 1-4 years, 20.1% were aged 5-11 years, and 38.1% were aged 12-17 years. Approximately two thirds of patients (67.5%) had one or more underlying medical conditions, with obesity being the most common (32.4%); among patients aged 12-17 years, 61.4% had obesity. Among patients hospitalized for COVID-19, 15.8% had a viral coinfection¶¶ (66.4% of whom had respiratory syncytial virus [RSV] infection). Approximately one third (33.9%) of patients aged <5 years hospitalized for COVID-19 had a viral coinfection. Among 272 vaccine-eligible (aged 12-17 years) patients hospitalized for COVID-19, one (0.4%) was fully vaccinated.*** Approximately one half (54.0%) of patients hospitalized for COVID-19 received oxygen support, 29.5% were admitted to the intensive care unit (ICU), and 1.5% died; of those requiring respiratory support, 14.5% required invasive mechanical ventilation (IMV). Among pediatric patients with COVID-19-related hospitalizations, many had severe illness and viral coinfections, and few vaccine-eligible patients hospitalized for COVID-19 were vaccinated, highlighting the importance of vaccination for those aged ≥5 years and other prevention strategies to protect children and adolescents from COVID-19, particularly those with underlying medical conditions.

Heifers with positive genetic merit for fertility traits reach puberty earlier and have a greater pregnancy rate than heifers with negative genetic merit for fertility traits.

This study investigated the hypothesis that dairy heifers divergent in genetic merit for fertility traits differ in the age of puberty and reproductive performance. New Zealand's fertility breeding value (FertBV) is the proportion of a sire's daughters expected to calve in the first 42 d of the seasonal calving period. We used the New Zealand national dairy database to identify and select Holstein-Friesian dams with either positive (POS, +5 FertBV, n = 1,334) or negative FertBV (NEG, -5% FertBV, n = 1,662) for insemination with semen from POS or NEG FertBV sires, respectively. The resulting POS and NEG heifers were predicted to have a difference in average FertBV of 10 percentage points. We enrolled 640 heifer calves (POS, n = 324; NEG, n = 316) at 9 d ± 5.4 d (± standard deviation; SD) for the POS calves and 8 d ± 4.4 d old for the NEG calves. Of these, 275 POS and 248 NEG heifers were DNA parent verified and retained for further study. The average FertBV was +5.0% (SD = 0.74) and -5.1% (SD = 1.36) for POS and NEG groups, respectively. Heifers were reared at 2 successive facilities as follows: (1) calf rearing (enrollment to ∼13 wk of age) and (2) grazier, after 13 wk until 22 mo of age. All heifers wore a collar with an activity sensor to monitor estrus events starting at 8 mo of age, and we collected weekly blood samples when individual heifers reached 190 kg of body weight (BW) to measure plasma progesterone concentrations. Puberty was characterized by plasma progesterone concentrations >1 ng/mL in at least 2 of 3 successive weeks. Date of puberty was defined when the first of these samples was >1 ng/mL. Heifers were seasonally bred for 98 d starting at ∼14 mo of age. Transrectal ultrasound was used to confirm pregnancy and combined with activity data to estimate breeding and pregnancy dates. We measured BW every 2 wk, and body condition and stature at 6, 9, 12, and 15 mo of age. The significant FertBV by day interaction for BW was such that the NEG heifers had increasingly greater BW with age. This difference was mirrored with the significant FertBV by month interaction for average daily gain, with the NEG heifers having a greater average daily gain between 9 and 18 mo of age. There was no difference in heifer stature between the POS and NEG heifers. The POS heifers were younger and lighter at puberty, and were at a lesser mature BW, compared with the NEG heifers. As a result, 94 ± 1.6% of the POS and 82 ± 3.2% of the NEG heifers had reached puberty at the start of breeding. The POS heifers were 20% and 11% more likely to be pregnant after 21 d and 42 d of breeding than NEG heifers (relative risk = 1.20, 95% confidence interval of 1.03-1.34; relative risk = 1.11, 95% confidence interval of 1.01-1.16). Results from this experiment support an association between extremes in genetic merit for fertility base on cow traits and heifer reproduction. Our results indicate that heifer puberty and pregnancy rates are affected by genetic merit for fertility traits, and these may be useful phenotypes for genetic selection.

Health-Related Behaviors and Odds of COVID-19 Hospitalization in a Military Population.

INTRODUCTION: Understanding the impact of behaviors on COVID-19 severity can improve health promotion strategies. We investigated the association between health-related behaviors and odds of hospitalization for COVID-19 in a cohort of military personnel. METHODS: This case-controlled study compared all active-duty US Air Force service members hospitalized for COVID-19 between March 5, 2020, and March 10, 2021 (cases), with their geographically matched peers who had COVID-19 and were treated as outpatients (controls). We used logistic regression to compare cases and controls according to self-reported sleep duration, physical activity, dietary factors, binge alcohol consumption, and tobacco use - with and without adjustment for sociodemographic factors, body mass index, physical fitness level, pertinent disease history, and psychological distress - resulting in crude and adjusted odds ratios (ORs) with 95% CIs. The trend between sugar-sweetened beverage (SSB) consumption and hospitalization odds was assessed by using the Cochran-Armitage test. RESULTS: Ninety-three hospitalized cases were matched to 372 ambulatory controls. Adjusting for baseline characteristics and other health-related behaviors, cases were more likely than controls to report fewer than 7 hours of sleep, compared with 7 to 9 hours (OR = 1.84; 95% CI, 1.07-3.16), and were more likely than controls to consume 3 or more SSBs per week, compared with fewer than 3 SSBs (OR = 1.74; 95% CI, 1.03-2.92). In a dose-response relationship, higher SSB consumption was associated with greater odds of being hospitalized (P value for trend = .02). CONCLUSION: Interventions that address short sleep duration and SSB consumption may reduce morbidity from COVID-19 among military service members and potentially in the broader US population.

Baseline-dependent effect of dopamine's precursor L-tyrosine on working memory gating but not updating.

Adaptive goal-directed behavior requires a dynamic balance between maintenance and updating within working memory (WM). This balance is controlled by an input-gating mechanism implemented by dopamine in the basal ganglia. Given that dopaminergic manipulations can modulate performance on WM-related tasks, it is important to gain mechanistic insight into whether such manipulations differentially affect updating (i.e., encoding and removal) and the closely-related gate opening/closing processes that respectively enable/prevent updating. To clarify this issue, 2.0 g of dopamine's precursor L-tyrosine was administered to healthy young adults (N = 45) in a double-blind, placebo-controlled, within-subjects study. WM processes were empirically distinguished using the reference-back paradigm, which isolates performance related to updating, gate opening, and gate closing. L-tyrosine had a selective, baseline-dependent effect only on gate opening, which was evidenced by markedly reduced variance across subjects in gate opening performance in the L-tyrosine compared with the placebo condition, whereas the whole-sample average performance did not differ between conditions. This indicates a pattern of results whereby low-performing subjects improved, whereas high-performing subjects were impaired on L-tyrosine. Importantly, this inverted U-shaped pattern was not explained by regression to the mean. These results are consistent with an inverted-U relationship between dopamine and WM, and they indicate that updating and gating are differentially affected by a dopaminergic manipulation. This highlights the importance of distinguishing these processes when studying WM, for example, in the context of WM deficits in disorders with a dopaminergic pathophysiology.

High activation and skewed T cell differentiation are associated with low IL-17A levels in a hu-PBL-NSG-SGM3 mouse model of HIV infection.

The humanized NOD/SCID/IL-2 receptor γ-chainnull (NSG) mouse model has been widely used for the study of HIV pathogenesis. Here, NSG mice with transgenic expression of human stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 (NSG-SGM3) were injected with peripheral blood leukocytes (PBL mice) from two HIV-infected (HIV+ ) patients who were under anti-retroviral therapy (ART; referred as HIV+ mice) or one HIV-seronegative healthy volunteer (HIV- ). Such mice are either hu-PBL-NSG-SGM3 HIV+ or HIV- mice, depending on the source of PBL. The kinetics of HIV replication and T cell responses following engraftment were evaluated in peripheral blood and secondary lymphoid tissues. High HIV replication and low CD4 : CD8 ratios were observed in HIV+ mice in the absence of anti-retroviral therapy (ART). Consistent with high activation and skewed differentiation of T cells from the HIV-infected donor, HIV+ mice exhibited a higher T cell co-expression of human leukocyte antigen D-related (HLA-DR) and CD38 than HIV- mice, as well as a shifted differentiation to a CCR7- CD45RA+ terminal effector profile, even in the presence of ART. In addition, HIV replication and the activation/differentiation disturbances of T cells were associated with decreased plasma levels of IL-17A. Thus, this hu-PBL-NSG-SGM3 mouse model recapitulates some immune disturbances occurring in HIV-infected patients, underlying its potential use for studying pathogenic events during this infection.

Impact of Altitude-based Hemoglobin Modification on Pediatric Iron Deficiency Anemia Screening.

OBJECTIVE: To determine if additional children attending primary care clinics in moderate-altitude areas would screen positive for anemia if the hemoglobin cutoff were modified for altitude. STUDY DESIGN: This cross-sectional study evaluated children aged 11-19 months of age who had a screening hemoglobin conducted between January 2011 and December 2017 at 4 moderate-altitude (1726-2212 m) and 8 low-altitude (1-20 m) US military clinics. The primary outcome was anemia prevalence (hemoglobin <11 g/dL) in moderate-altitude and low-altitude groups, before and after applying the current World Health Organization model for altitude-based hemoglobin modification. Groups were compared with prevalence ORs adjusted for age, sex, weight-for-length percentile, and parental military rank, and the false-negative proportion was calculated for children with anemia at moderate altitude. RESULTS: Before altitude modification, anemia prevalence was 4.4% in the moderate-altitude group (n = 1488) and 16.8% in the low-altitude group (n = 7090) (prevalence OR, 0.23; 95% CI, 0.17-0.29). After applying the World Health Organization model, anemia prevalence in the moderate-altitude group increased to 14.7% (prevalence OR, 0.82; 95% CI, 0.70-0.97). Nonapplication of the model at moderate altitude resulted in a false-negative proportion of 0.70 (95% CI, 0.63-0.76). CONCLUSIONS: Nonuse of the World Health Organization altitude-based modification model for hemoglobin may result in a large percentage of US children with anemia at moderate altitude screening falsely negative for anemia. Although ancestry disparities in altitude acclimatization may limit universal application of the current World Health Organization model, the existing standard of care may leave children at moderate altitude at risk for complications from iron deficiency anemia.

Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

The ß2-adrenergic receptor (ß2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known ß-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human ß2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the ß2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the ß2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the ß2AR. In cell-signaling studies, 15 inhibits cAMP production through the ß2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits ß-arrestin recruitment to the activated ß2AR. This study presents an allosteric small-molecule ligand for the ß2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

Distinct conformations of GPCR-ß-arrestin complexes mediate desensitization, signaling, and endocytosis.

ß-Arrestins (ßarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR-ßarr complexes: the "tail" conformation, with ßarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the "core" conformation, where, in addition to the phosphorylated C-terminal tail, ßarr is further engaged with the receptor transmembrane core. However, the relationship of these distinct conformations to the various functions of ßarrs is unknown. Here, we created a mutant form of ßarr lacking the "finger-loop" region, which is unable to form the core conformation but retains the ability to form the tail conformation. We find that the tail conformation preserves the ability to mediate receptor internalization and ßarr signaling but not desensitization of G protein signaling. Thus, the two GPCR-ßarr conformations can carry out distinct functions.