Exercise, Sleep Quality, and Physical Health during the COVID-19 Pandemic.

OBJECTIVES: Sufficient exercise and high-quality sleep are important for good health, and they may be particularly crucial during the coronavirus pandemic. Sleeping difficulties and insufficient exercise are prevalent in the United States, however, and data indicate little to no change-or even worsening-of these health behaviors before the pandemic. This study explores how exercise quantity coincides with sleep quality in the United States during the pandemic and how both ultimately relate to physical health. METHODS: We used logistic regression and multinomial logistic regression to analyze data from the 2021 Crime, Health, and Politics Survey sampled from the National Opinion Research Center's AmeriSpeak panel. Survey responses were collected between May and June 2021. RESULTS: Results show that more typical weekly exercise and more exercise during the pandemic are significantly associated with higher odds of better current sleep quality and sleep quality during the pandemic, controlling for a variety of sociodemographic factors. Both exercise activity and sleep quality are also significantly associated with higher odds of good physical health. CONCLUSIONS: These findings support the literature that increases in exercise frequency and improved sleep quality are linked and are also associated with better physical health outcomes, even during a global crisis.

Do Religious Struggles Mediate the Association Between Neighborhood Disorder and Health in the United States?

Over the past two decades, numerous studies have linked the subjective experience of neighborhood disorder (perceptions of crime, dilapidation and ambient strains) with poorer health. We test whether religious struggles (religious doubts and feeling abandoned or punished by God) mediate this association. Our counterfactual mediation analyses of data from the 2021 Crime, Health, and Politics Survey (CHAPS) (n = 1741) revealed consistent indirect effects of neighborhood disorder through religious struggles for anger, psychological distress, sleep disturbance, poorer self-rated health, and shorter subjective life expectancy. This study contributes to previous work by integrating the study of neighborhood context and religion.

Systemic immunosuppression depletes peripheral blood regulatory B cells in patients with immune thrombocytopenia.

Regulatory B (Breg) cells are potentially implicated in the pathogenesis of immune thrombocytopenia (ITP). We analysed a prospective cohort of newly diagnosed steroid naïve ITP patients enrolled in the multicentre FLIGHT trial and found that the numbers of Bregs in their peripheral blood were similar to healthy controls. In contrast, Breg numbers were significantly reduced in ITP patients treated with systemic immunosuppression (glucocorticoids or mycophenolate mofetil). We also demonstrate that glucocorticoid treatment impairs Breg interleukin-10 production via an indirect T-cell-mediated mechanism.

SV2B defines a subpopulation of synaptic vesicles.

Synaptic vesicles can undergo several modes of exocytosis, endocytosis, and trafficking within individual synapses, and their fates may be linked to differences in the vesicular protein composition. Here, we mapped the intrasynaptic distribution of the synaptic vesicle proteins SV2B and SV2A in glutamatergic synapses of the hippocampus using three-dimensional electron microscopy. SV2B is almost completely absent from both docked vesicles and a distinct cluster of vesicles found near the active zone. In contrast, SV2A was found in all domains of the synapse and was slightly enriched near the active zone. SV2B and SV2A were found on the membrane in the peri-active zone, suggesting recycling from both clusters of vesicles. SV2B knockout mice displayed an increased seizure induction threshold only in a model employing high-frequency stimulation. Our data show that glutamatergic synapses generate molecularly distinct populations of synaptic vesicles and are able to maintain them at steep spatial gradients. The almost complete absence of SV2B from vesicles at the active zone of wildtype mice may explain why SV2A has been found to be more important for vesicle release.

Medial Prefrontal Cortex Theta Burst Stimulation Improves Treatment Outcomes in Alcohol Use Disorder: A Double-Blind, Sham-Controlled Neuroimaging Study.

Background: Alcohol use disorder (AUD) is associated with elevated brain response to cues. Recent studies have suggested that theta burst stimulation (TBS) to the medial prefrontal cortex (MPFC) can decrease reactivity to cues in a transdiagnostic manner. The goal of this clinical trial was to evaluate the effect of continuous TBS as a tool to decrease drinking behavior and brain reactivity to alcohol cues among individuals with AUD. Methods: A total of 50 individuals with AUD were recruited from an intensive outpatient treatment program. Using a randomized, double-blind, sham-controlled design, participants received 10 sessions of continuous TBS (left frontal pole, 1 session/10 days, 110% resting motor threshold, 3600 pulse/session, cue provocation before and during session). Brain reactivity to alcohol cues was acquired at four time points: at baseline and after all TBS sessions (1 month, 2 months, and 3 months). Results: Overall, 80% of the participants completed all TBS sessions. Individuals who received real TBS were 2.71 times more likely to remain enrolled in the study after 3 months and 3.09 times more likely to remain sober 3 months after treatment initiation. Real TBS also led to a significantly greater reduction in brain reactivity to alcohol cues, specifically a reduction in MPFC-striatum and MPFC-insula connectivity 2 and 3 months after TBS treatment. Conclusions: Ten days of MPFC TBS is well tolerated, reduces drinking, and decreases brain reactivity to alcohol cues for up to 3 months after treatment initiation. These results pave a critical next step in the path toward developing transcranial magnetic stimulation as an intervention for AUD and disorders associated with elevated cue reactivity.

Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.

INFLUENCE OF OBESITY ON VASCULAR DYSFUNCTION AFTER TRAUMATIC HEMORRHAGE.

ABSTRACT: Background: Obesity increases the risk for morbidity and mortality after trauma. These complications are associated with profound vascular damage. Traumatic hemorrhage acutely attenuates vascular responsiveness, but the impact of obesity on this dysfunction is not known. The local inflammatory response in vascular cells is also unknown. We hypothesized that obesity potentiates trauma-induced vascular inflammation and dysfunction. Methods: Male Sprague-Dawley rats (~250 g) were fed normal chow (NC; 13.5% kcal fat, n = 20) or high-fat (HF; 60% kcal fat, n = 20) diets for 6 to 8 weeks. Under anesthesia, hemorrhage was induced by a mesenteric artery laceration, a Grade V splenic injury, and hypotension (MAP = 30-40 mm Hg) for 30 minutes. Vascular responsiveness was assessed ex vivo in isolated mesenteric arteries prehemorrhage and posthemorrhage. Gene expression for IL-1ß, and IL-6, prooxidant nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and α-adrenergic receptor were assessed in carotid artery endothelial cells (ECs) and non-ECs (media + adventitia). Results: In NC rats, hemorrhage attenuated norepinephrine-induced vasoconstriction and endothelium-dependent vasodilation to acetylcholine. In HF rats, baseline norepinephrine-induced vasoconstriction was attenuated compared with NC, but vasoconstriction and endothelium-dependent vasodilation did not change prehemorrhage to posthemorrhage. Hemorrhage led to elevated IL-1ß gene expression in ECs and elevated IL1ß, IL-6, NOX2, and α-adrenergic receptor gene expression in the media + adventitia compared with sham. HF rats had greater EC IL-1 ß and NOX2 gene expression compared with NC rats. The hemorrhage-induced elevation of IL-1ß in the media + adventitia was greatest in HF rats. Conclusion: Traumatic hemorrhage attenuates vascular responsiveness and induces vascular inflammation. The attenuated vascular responsiveness after hemorrhage is absent in obese rats, while the elevated vascular inflammation persists. A HF diet amplifies the arterial inflammation after hemorrhage. Altered vascular responsiveness and vascular inflammation may contribute to worse outcomes in obese trauma patients.

Pyridoxamine treatment ameliorates large artery stiffening and cerebral artery endothelial dysfunction in old mice.

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old control mice, but was maintained in pyridoxamine treated mice. Large artery stiffness decreased in pyridoxamine-treated mice but was unaffected in control mice. Pyridoxamine-treated mice had greater cerebral artery endothelium-dependent dilation compared with old control mice, and not different from young mice. Old control mice had impaired cognitive function; however, pyridoxamine only partially preserved cognitive function in old mice. In summary, pyridoxamine treatment in old mice prevented age-related increases in blood pressure, reduced large artery stiffness, preserved cerebral artery endothelial function, and partially preserved cognitive function. Taken together, these results suggest that pyridoxamine treatment may limit vascular aging.

Religion and sexual identities.

Religion and sexuality have a complex, deep-rooted relationship. Religions often teach how aspects of sexuality should be conducted, typically promoting heterosexuality. Such discourse is at odds with a growing population using sexual minority identities. The tension between one's homonegative faith or religious environment and their sexual minority orientation can lead to poor health outcomes like psychological distress and suicidal ideation. Attempts to change sexual orientation to match religious expectations are futile and frequently harmful. However, sexual minority individuals can find health benefits if they are able to reconcile their religious and sexual identities or find accepting religious/spiritual communities. The COVID-19 pandemic and religious influence on US politics have also shaped the safety of environments for disclosing a sexual minority identity.

Neuronavigation maximizes accuracy and precision in TMS positioning: Evidence from 11,230 distance, angle, and electric field modeling measurements.

BACKGROUND: Researchers and clinicians have traditionally relied on elastic caps with markings to reposition the transcranial magnetic stimulation (TMS) coil between trains and sessions. Newer neuronavigation technology co-registers the patient's head and structural magnetic resonance imaging (MRI) scan, providing the researcher with real-time feedback about how to adjust the coil to be on-target. However, there has been no head to head comparison of accuracy and precision across treatment sessions. OBJECTIVE: /Hypothesis: In this two-part study, we compared elastic cap and neuronavigation targeting methodologies on distance, angle, and electric field (E-field) magnitude values. METHODS: In 42 participants receiving up to 50 total accelerated rTMS sessions in 5 days, we compared cap and neuronavigation targeting approaches in 3408 distance and 6816 angle measurements. In Experiment 1, TMS administrators saved an on-target neuronavigation location at Beam F3, which served as the landmark for all other measurements. Next, the operators placed the TMS coil based on cap markings or neuronavigation software to measure the distance and angle differences from the on-target sample. In Experiment 2, we saved each XYZ coordinate of the TMS coil from cap and neuronavigation targeting in 12 participants to compare the E-field magnitude differences at the cortical prefrontal target in 1106 cap and neuronavigation models. RESULTS: Cap targeting was significantly off-target for distance, placing the coil an average of 10.66 mm off-target (Standard error of the mean; SEM = 0.19 mm) compared to 0.3 mm (SEM = 0.03 mm) for neuronavigation (p < 0.0001). Cap targeting also significantly deviated for angles off-target, averaging 7.79 roll/pitch degrees (SEM = 1.07°) off-target and 5.99 yaw degrees (SEM = 0.12°) off-target; in comparison, neuronavigation targeting positioned the coil 0.34 roll/pitch degrees (SEM = 0.01°) and 0.22 yaw (SEM = 0.004°) off-target (both p < 0.0001). Further analyses revealed that there were significant inter-operator differences on distance and angle positioning for F3 (all p < 0.05), but not neuronavigation. Lastly, cap targeting resulted in significantly lower E-fields at the intended prefrontal cortical target, with equivalent E-fields as 110.7% motor threshold (MT; range = 58.3-127.4%) stimulation vs. 119.9% MT (range = 115-123.3%) from neuronavigated targeting with 120% MT stimulation applied (p < 0.001). CONCLUSIONS: Cap-based targeting is an inherent source of target variability compared to neuronavigation. Additionally, cap-based coil placement is more prone to differences across operators. Off-target coil placement secondary to cap-based measurements results in significantly lower amounts of stimulation reaching the cortical target, with some individuals receiving only 48.6% of the intended on-target E-field. Neuronavigation technology enables more precise and accurate TMS positioning, resulting in the intended stimulation intensities at the targeted cortical level.

In situ probe and inhibitory RNA synthesis using streamlined gene cloning with Gibson assembly.

The synthesis of single-stranded riboprobes or double-stranded RNAs for in situ hybridization and gene knockdowns often use vectors that require time-consuming plasmid restriction digests and inefficient gel purifications. Here, we present a faster protocol for the simultaneous plasmid restriction digestion and Gibson assembly of vectors for the synthesis of both riboprobes and double-stranded RNAs for in situ and RNA interference experiments, respectively. We illustrate the protocol with planaria in situ and RNAi assays, but it is applicable to any organism.

Hyperkalaemia Following Blood Transfusion-a Systematic Review Assessing Evidence and Risks.

Hyperkalaemia following transfusion is widely reported in the literature. Our objective was to critically review recent evidence on hyperkalaemia in association with transfusion and to assess whether specific aspects of transfusion practice can affect the likelihood of developing hyperkalaemia. We searched 9 electronic databases (including MEDLINE, Embase, and Transfusion Evidence Library) using a predefined search strategy, from 2010 to April 8, 2021. Three reviewers performed dual screening, extraction, and risk of bias assessment. We used Cochrane risk of bias (ROB) 2 for assessment of RCTs, ROBINS-I for non-RCTs, and GRADE to assess the certainty of the evidence. We report 7 comparisons of interest in n = 3729 patients from 28 studies (11 RCTs, 4 prospective cohort studies, and 13 retrospective cohort studies): (1) age of blood, (2) washing, (3) filtration, (4) irradiation, (5) fluid type, (6) transfusion vs no transfusion, (7) blood volume/rate. Of the 28 studies included, 25 reported outcomes of potassium (K+) concentration, 17 the number developing hyperkalaemia, 13 mortality, 10 cardiac arrest, and 10 cardiac arrhythmia. Only 16 studies provided analysable data suitable for quantitative analysis. Evidence addressing our outcomes was of very low certainty (downgraded for incomplete outcome data, baseline imbalance, imprecision around the estimate, and small sample size). While 5 studies showed a difference in K+ concentration up to 6 hours posttransfusion for 3 comparisons (age of blood, washing, and transfusion volume/rate), and 3 studies showed a difference in the diagnosis of hyperkalaemia for 2 comparisons (age of blood, and transfusion volume/rate), the evidence was inconsistent across all included studies. There was no difference in any reported outcomes for 4 comparisons (filtration, irradiation, fluid type, or transfusion vs no transfusion). Overall, the reported evidence was too weak to support identification of groups most at risk of hyperkalaemia or to support recommendations on use of short-storage RBC. For other commonly used risk mitigations for hyperkalaemia in transfusion medicine, the (low certainty) evidence was either conflicting or not supportive.

UK national survey of anticoagulation in extra-corporeal photopheresis-Is it time for a UK consensus statement?

BACKGROUND: Extra-corporeal photopheresis (ECP) requires anticoagulation to prevent circuit clotting. Unfractionated heparin (UFH) is currently the only anticoagulant licensed for the ECP system in use in the United Kingdom (UK). Acid citrate dextrose-A (ACD-A) is the preferred anticoagulant for most other apheresis procedures. Anecdotal evidence suggested variability in ECP practice across the UK with some providers using off-label ACD-A. AIMS: We developed a survey together with the UK Photopheresis Society to establish current practice. MATERIALS & METHODS: This was distributed to all 17 ECP providers covering 34 UK sites. RESULTS: Significant variability in practice was demonstrated with only 36% of responding providers (5/14) using UFH exclusively and 29% (4/14) using ACD-A as standard. CONCLUSION: This survey highlights the need for a UK consensus.

Teleology first: Goals before knowledge and belief.

Comparing knowledge with belief can go wrong in two dimensions: If the authors employ a wider notion of knowledge, then they do not compare like with like because they assume a narrow notion of belief. If they employ only a narrow notion of knowledge, then their claim is not supported by the evidence. Finally, we sketch a superior teleological view.

Infection-related morbidity and mortality among older patients with DLBCL treated with full- or attenuated-dose R-CHOP.

Infection-related morbidity and mortality are increased in older patients with diffuse large B-cell lymphoma (DLBCL) compared with population-matched controls. Key predictive factors for infection-related hospitalization during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and deaths as a result of infection in older patients during and after treatment with R-CHOP remain incompletely understood. For this study, 690 consecutively treated patients age 70 years or older who received full-dose or attenuated-dose R-CHOP treatment were analyzed for risk of infection-related hospitalization and infection-related death. Median age was 77 years, and 34.4% were 80 years old or older. Median follow-up was 2.8 years (range, 0.4-8.9 years). Patient and baseline disease characteristics were assessed in addition to intended dose intensity (IDI). Of all patients, 72% were not hospitalized with infection. In 331 patients receiving an IDI ≥80%, 33% were hospitalized with ≥1 infections compared with 23.3% of 355 patients receiving an IDI of <80% (odds ratio, 1.61; 95% confidence interval, 1.15-2.25; P = .006). An increased risk of infection-related admission was independently associated with IDI >80% across the whole cohort. Primary quinolone prophylaxis independently reduced infection-related admission. A total of 51 patients died as a result of infection. The 6-month, 12-month, 2-year, and 5-year cumulative incidences of infection-related death were 3.3%, 5.0%, 7.2%, and 11.1%, respectively. Key independent factors associated with infection-related death were an International Prognostic Index (IPI) score of 3 to 5, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score ≥6, and low albumin, which enabled us to generate a predictive risk score. We defined a smaller group (15%) of patients (IPI score of 0-2, albumin >36 g/L, CIRS-G score <6) in which no cases of infection-related deaths occurred at 5 years of follow-up. Whether patients at higher risk of infection-related death could be targeted with enhanced antimicrobial prophylaxis remains unknown and will require a randomized trial.

Fractures are common within 18 months following first-line R-CHOP in older patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if <18 months; or at progression or death. Of 877 patients identified, 148 were excluded: 121 had progression or died before 6 months; 23 had follow-up <6 months. Across 729 remaining patients, the median age was 77 years, and 68% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Eighty-one fractures occurred within 18 months of follow-up; 42 were symptomatic, including 30 requiring hospital attendance or admission. The cumulative fracture incidence was 6.2% (95% confidence interval [CI], 4.7-8.2) at 6 months; 9.7% (95% CI, 7.8-12.1) at 12 months; and 11.4% (95% CI, 9.3-14.0) at 18 months. Multivariate analysis identified a predisposing history (osteoporosis, osteopenia, prior fracture, and rheumatoid arthritis [RhA]), DLBCL bone involvement at baseline, and receipt of prephase steroids as independent risk factors for fracture. There is a clinically relevant fracture risk and significant associated morbidity in older patients receiving R-CHOP. Careful attention to bone health is warranted in older patients receiving R-CHOP. Randomized studies are required to better define the most effective strategies to reduce fracture risk.