Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial.

PURPOSE: Infections cause considerable care home morbidity and mortality. Nitric oxide (NO) has broad-spectrum anti-viral, bacterial and yeast activity in vitro. We assessed the feasibility of supplementing dietary nitrate (NO substrate) intake in care home residents. METHODS: We performed a cluster-randomised placebo-controlled trial in UK residential and nursing care home residents and compared nitrate containing (400 mg) versus free (0 mg daily) beetroot juice given for 60 days. Outcomes comprised feasibility of recruitment, adherence, salivary and urinary nitrate, and ordinal infection/clinical events. RESULTS: Of 30 targeted care homes in late 2020, 16 expressed interest and only 6 participated. 49 residents were recruited (median 8 [interquartile range 7-12] per home), mean (standard deviation) age 82 (8) years, with proxy consent 41 (84%), advance directive for hospital non-admission 8 (16%) and ≥ 1 doses of COVID-19 vaccine 37 (82%). Background dietary nitrate was < 30% of acceptable daily intake. 34 (76%) residents received > 50% of juice. Residents randomised to nitrate vs placebo had higher urinary nitrate levels, median 50 [18-175] v 18 [10-50] mg/L, difference 25 [0-90]. Data paucity precluded clinical between-group comparisons; the outcome distribution was as follows: no infection 32 (67%), uncomplicated infection 0, infection requiring healthcare support 11 (23%), all-cause hospitalisation 5 (10%), all-cause mortality 0. Urinary tract infections were most common. CONCLUSIONS: Recruiting UK care homes during the COVID-19 pandemic was partially successful. Supplemented dietary nitrate was tolerated and elevated urinary nitrate. Together, infections, hospitalisations and deaths occurred in 33% of residents over 60 days. A larger trial is now required. TRIAL REGISTRATION: ISRCTN51124684. Application date 7/12/2020; assignment date 13/1/2021.

Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death.

Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production of other cytokines via a membrane-bound complex 1 or induces cell death via a cytosolic complex 2. To understand how TNF-induced cell death is regulated, we performed mass spectrometry of complex 2 and identified tankyrase-1 as a native component that, upon a death stimulus, mediates complex 2 poly-ADP-ribosylation (PARylation). PARylation promotes recruitment of the E3 ligase RNF146, resulting in proteasomal degradation of complex 2, thereby limiting cell death. Expression of the ADP-ribose-binding/hydrolyzing severe acute respiratory syndrome coronavirus 2 macrodomain sensitizes cells to TNF-induced death via abolishing complex 2 PARylation. This suggests that disruption of ADP-ribosylation during an infection can prime a cell to retaliate with an inflammatory cell death.

Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients.

AIMS: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. METHODS: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2 ) and FiO2 , and the World Health Organisation modified ordinal clinical scale. RESULTS: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P < .0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P = .17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P < .001). CONCLUSION: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

Lumbar Spine Surgery and What We Lost in the Era of the Coronavirus Pandemic: A Survey of the Lumbar Spine Research Society.

STUDY DESIGN: This was a survey of the surgeon members of the Lumbar Spine Research Society (LSRS). OBJECTIVE: The purpose of this study was to assess trends in surgical practice and patient management involving elective and emergency surgery in the early months of the coronavirus pandemic. SUMMARY OF BACKGROUND DATA: The novel coronavirus has radically disrupted medical care in the first half of 2020. Little data exists regarding the exact nature of its effect on spine care. METHODS: A 53-question survey was sent to the surgeon members of the LSRS. Respondents were contacted via email 3 times over a 2-week period in late April. Questions concentrated on surgical and clinical practice patterns before and after the pandemic. Other data included elective surgical schedules and volumes, as well as which emergency cases were being performed. Surgeons were asked about the status of coronavirus disease 2019 (COVID-19) virus testing. Circumstances for performing surgical intervention on patients with and without testing as well as patients testing positive were explored. RESULTS: A total of 43 completed surveys were returned of 174 sent to active surgeons in the LSRS (25%). Elective lumbar spine procedures decreased by 90% in the first 2 months of the pandemic, but emergency procedures did not change. Patients with "stable" lumbar disease had surgeries deferred indefinitely, even beyond 8 weeks if necessary. In-person outpatient visits became increasingly rare events, as telemedicine consultations accounted for 67% of all outpatient spine appointments. In total, 91% surgeons were under some type of confinement. Only 11% of surgeons tested for the coronavirus on all surgical patients. CONCLUSIONS: Elective lumbar surgery was significantly decreased in the first few months of the coronavirus pandemic, and much of outpatient spine surgery was practiced via telemedicine. Despite these constraints, spine surgeons performed emergency surgery when indicated, even when the COVID-19 status of patients was unknown. LEVEL OF EVIDENCE: Level IV.

Impact of COVID-19 pandemic on training of pharmacy residents and fellows: Results from a national survey of postgraduate pharmacy trainees.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has impacted the activities of healthcare workers, including postgraduate pharmacy trainees. Quality training experiences must be maintained to produce competent pharmacy practitioners and maintain program standards. METHODS: A cross-sectional survey of postgraduate pharmacy trainees in the United States was conducted to evaluate training experience changes and assess perceived impacts on residents and fellows following the COVID-19 pandemic's onset. RESULTS: From June 4 through June 22, 2020, 511 pharmacy trainees in 46 states completed the survey. Participants' median age was 26 (interquartile range [IQR], 25-28) years, with included responses from postgraduate year 1 residents (54% of sample), postgraduate year 2 residents (40%), and postgraduate fellows (6%). Compared to experiences prior to the onset of the COVID-19 pandemic, fewer trainees conducted direct patient care (38.5% vs 91.4%, P < 0.001), more worked from home (31.7% vs 1.6%, P < 0.001), and less time was spent with preceptors per day (2 [IQR, 2-6] hours vs 4 [IQR, 1-4] hours, P < 0.001). Sixty-five percent of respondents reported experiencing changes in their training program, 39% reported being asked to work in areas outside of their routine training experience, and 89% stated their training shifted to focus on COVID-19 to some degree. Most respondents perceived either major (9.6%) or minor (52.0%) worsening in quality of experience, with major and minor improvement in quality of experience reported by 5.5% and 8.4% of respondents, respectively. CONCLUSION: Pharmacy resident/fellow experiences were perceived to have been extensively impacted by the COVID-19 pandemic in varying ways. Our findings describe shifts in postgraduate training and may aid in the development of best practices for optimizing trainee experiences in future crises.

Person-Specific Biomolecular Coronas Modulate Nanoparticle Interactions with Immune Cells in Human Blood.

When nanoparticles interact with human blood, a multitude of plasma components adsorb onto the surface of the nanoparticles, forming a biomolecular corona. Corona composition is known to be influenced by the chemical composition of nanoparticles. In contrast, the possible effects of variations in the human blood proteome between healthy individuals on the formation of the corona and its subsequent interactions with immune cells in blood are unknown. Herein, we prepared and examined a matrix of 11 particles (including organic and inorganic particles of three sizes and five surface chemistries) and plasma samples from 23 healthy donors to form donor-specific biomolecular coronas (personalized coronas) and investigated the impact of the personalized coronas on particle interactions with immune cells in human blood. Among the particles examined, poly(ethylene glycol) (PEG)-coated mesoporous silica (MS) particles, irrespective of particle size (800, 450, or 100 nm in diameter), displayed the widest range (up to 60-fold difference) of donor-dependent variance in immune cell association. In contrast, PEG particles (after MS core removal) of 860, 518, or 133 nm in diameter displayed consistent stealth behavior (negligible cell association), irrespective of plasma donor. For comparison, clinically relevant PEGylated doxorubicin-encapsulated liposomes (Doxil) (74 nm in diameter) showed significant variance in association with monocytes and B cells across all plasma donors studied. An in-depth proteomic analysis of each biomolecular corona studied was performed, and the results were compared against the nanoparticle-blood cell association results, with individual variance in the proteome driving differential association with specific immune cell types. We identified key immunoglobulin and complement proteins that explicitly enriched or depleted within the corona and which strongly correlated with the cell association pattern observed across the 23 donors. This study demonstrates how plasma variance in healthy individuals significantly influences the blood immune cell interactions of nanoparticles.