Neuromodulation and Neurophysiology on the Timescale of Learning and Decision-Making.

Nervous systems evolved to effectively navigate the dynamics of the environment to achieve their goals. One framework used to study this fundamental problem arose in the study of learning and decision-making. In this framework, the demands of effective behavior require slow dynamics-on the scale of seconds to minutes-of networks of neurons. Here, we review the phenomena and mechanisms involved. Using vignettes from a few species and areas of the nervous system, we view neuromodulators as key substrates for temporal scaling of neuronal dynamics.

Targeted DNA Sequencing in Diagnosis of Malignant Phyllodes Tumors With Emphasis on Tumors With Keratin and p63 Expression.

The differential diagnosis of malignant spindle cell neoplasms in the breast most frequently rests between malignant phyllodes tumor (MPT) and metaplastic carcinoma (MBC). Diagnosis of MPT can be challenging due to diffuse stromal overgrowth, keratin (CK) and/or p63 immunopositivity, and absent CD34 expression, which can mimic MBC, especially in core biopsies. Distinction of MPT from MBC has clinical implications, with differences in surgical approach, chemotherapy, and radiation. In this study, we evaluated MPTs (78 tumors, 64 patients) for stromal CK, p63, and CD34 expression and profiled a subset (n = 31) by targeted next-generation DNA sequencing, with comparison to MBC (n = 44). Most MPTs (71%) were CK+ and/or p63+, including 32% CK+ (25/77 focal) and 65% p63+ (32/66 focal, 10/66 patchy, and 1/66 diffuse). Thirty percent of MPTs expressed both CK and p63 (20/66), compared with 95% of MBCs (40/42, P < .001). CK and/or p63 were positive in CD34+ and CD34- MPTs. Recurrent genetic aberrations in MPTs involved TERT, TP53, MED12, CDKN2A, chromatin modifiers, growth factor receptors/ligands, and phosphoinositide-3 kinase (PI-3K) and MAPK pathway genes. Only MED12 (39%, 12/31) and SETD2 (13%, 4/31) were exclusively mutated in MPTs and not MBCs (P < .001 and P = .044, respectively), whereas PIK3R1 mutations were only found in MBCs (37%, 13/35, P < .001). Comparative literature review additionally identified ARID1B, EGFR, FLNA, NRAS, PDGFRB, RAD50, and RARA alterations enriched or exclusively in MPTs vs MBCs. MED12 was mutated in MPTs with diffuse stromal overgrowth (53%, 9/17), CD34- MPTs (41%, 7/17), and CK+ and/or p63+ MPTs (39%, 9/23), including 36% of CD34- MPTs with CK and/or p63 expression. Overall, MED12 mutation and/or CD34 expression were observed in 68% (21/31) MPTs, including 61% (14/23) of CK+ and/or p63+ tumors. Our results emphasize the prevalence of CK and p63 expression in MPTs and demonstrate the diagnostic utility of next-generation DNA sequencing, especially in MPTs with confounding factors that can mimic MBC.

Development of a Quality Indicator Set for the Optimal Acute Management of Moderate to Severe Traumatic Brain Injury in the Australian Context.

BACKGROUND: The aim of this study was to develop a consensus-based set of indicators of high-quality acute moderate to severe traumatic brain injury (msTBI) clinical management that can be used to measure structure, process, and outcome factors that are likely to influence patient outcomes. This is the first stage of the PRECISION-TBI program, which is a prospective cohort study that aims to identify and promote optimal clinical management of msTBI in Australia. METHODS: A preliminary set of 45 quality indicators was developed based on available evidence. An advisory committee of established experts in the field refined the initial indicator set in terms of content coverage, proportional representation, contamination, and supporting evidence. The refined indicator set was then distributed to a wider Delphi panel for assessment of each indicator in terms of validity, measurement feasibility, variability, and action feasibility. Inclusion in the final indicator set was contingent on prespecified inclusion scoring. RESULTS: The indicator set was structured according to the care pathway of msTBI and included prehospital, emergency department, neurosurgical, intensive care, and rehabilitation indicators. Measurement domains included structure indicators, logistic indicators, and clinical management indicators. The Delphi panel consisted of 44 participants (84% physician, 12% nursing, and 4% primary research) with a median of 15 years of practice. Of the 47 indicators included in the second round of the Delphi, 32 indicators were approved by the Delphi group. CONCLUSIONS: This study identified a set of 32 quality indicators that can be used to structure data collection to drive quality improvement in the clinical management of msTBI. They will also be used to guide feedback to PRECISION-TBI's participating sites.

Combined Infection Control Interventions Protect Essential Food Workers from Occupational Exposures to SARS-CoV-2 in the Agricultural Environment.

Essential food workers experience elevated risks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to prolonged occupational exposures in food production and processing areas, shared transportation (car or bus), and employer-provided shared housing. Our goal was to quantify the daily cumulative risk of SARS-CoV-2 infection for healthy susceptible produce workers and to evaluate the relative reduction in risk attributable to food industry interventions and vaccination. We simulated daily SARS-CoV-2 exposures of indoor and outdoor produce workers through six linked quantitative microbial risk assessment (QMRA) model scenarios. For each scenario, the infectious viral dose emitted by a symptomatic worker was calculated across aerosol, droplet, and fomite-mediated transmission pathways. Standard industry interventions (2-m physical distancing, handwashing, surface disinfection, universal masking, ventilation) were simulated to assess relative risk reductions from baseline risk (no interventions, 1-m distance). Implementation of industry interventions reduced an indoor worker's relative infection risk by 98.0% (0.020; 95% uncertainty interval [UI], 0.005 to 0.104) from baseline risk (1.00; 95% UI, 0.995 to 1.00) and an outdoor worker's relative infection risk by 94.5% (0.027; 95% UI, 0.013 to 0.055) from baseline risk (0.487; 95% UI, 0.257 to 0.825). Integrating these interventions with two-dose mRNA vaccinations (86 to 99% efficacy), representing a worker's protective immunity to infection, reduced the relative infection risk from baseline for indoor workers by 99.9% (0.001; 95% UI, 0.0002 to 0.005) and outdoor workers by 99.6% (0.002; 95% UI, 0.0003 to 0.005). Consistent implementation of combined industry interventions, paired with vaccination, effectively mitigates the elevated risks from occupationally acquired SARS-CoV-2 infection faced by produce workers. IMPORTANCE This is the first study to estimate the daily risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across a variety of indoor and outdoor environmental settings relevant to food workers (e.g., shared transportation [car or bus], enclosed produce processing facility and accompanying breakroom, outdoor produce harvesting field, shared housing facility) through a linked quantitative microbial risk assessment framework. Our model has demonstrated that the elevated daily SARS-CoV-2 infection risk experienced by indoor and outdoor produce workers can be reduced below 1% when vaccinations (optimal vaccine efficacy, 86 to 99%) are implemented with recommended infection control strategies (e.g., handwashing, surface disinfection, universal masking, physical distancing, and increased ventilation). Our novel findings provide scenario-specific infection risk estimates that can be utilized by food industry managers to target high-risk scenarios with effective infection mitigation strategies, which was informed through more realistic and context-driven modeling estimates of the infection risk faced by essential food workers daily. Bundled interventions, particularly if they include vaccination, yield significant reductions (>99%) in daily SARS-CoV-2 infection risk for essential food workers in enclosed and open-air environments.

Diagnostic utility of FOXO1 immunohistochemistry for rhabdomyosarcoma classification.

AIMS: Rhabdomyosarcomas currently are classified into one of four subtypes (alveolar, embryonal, spindle cell/sclerosing, or pleomorphic) according to their morphological, immunohistochemical, and molecular genetic features. The alveolar subtype is characterised by a recurrent translocation involving PAX3 or PAX7 and FOXO1; identification of this translocation is important for appropriate classification and prognostication. In this study, we aimed to explore the diagnostic utility of FOXO1 immunohistochemistry for rhabdomyosarcoma classification. METHODS/RESULTS: A monoclonal antibody targeting a FOXO1 epitope retained in the fusion oncoprotein was used to study 105 rhabdomyosarcomas. FOXO1 was positive for expression by immunohistochemistry in all 25 alveolar rhabdomyosarcomas, with 84% showing diffuse expression in greater than 90% of neoplastic cells; the remainder of alveolar rhabdomyosarcomas displayed at least moderate staining in a minimum of 60% of lesional cells. Apart from three spindle cell rhabdomyosarcomas showing heterogeneous nuclear immunoreactivity in 40-80% of tumour cells, the 80 cases of embryonal, pleomorphic, and spindle cell/sclerosing rhabdomyosarcoma were negative for FOXO1 expression (96.3% specific) when using a threshold of nuclear staining in 20% of neoplastic cells to determine positivity. Variable cytoplasmic staining was present in a fraction of all rhabdomyosarcoma subtypes. Nonneoplastic lymphocytes, endothelial cells, and Schwann cells also showed variably intense nuclear anti-FOXO1 immunoreactivity. CONCLUSION: Taken together, our findings suggest that FOXO1 immunohistochemistry is a highly sensitive and relatively specific surrogate marker of the PAX3/7::FOXO1 fusion oncoprotein in rhabdomyosarcoma. Cytoplasmic immunoreactivity, expression in nonneoplastic tissues, and limited nuclear staining of nonalveolar rhabdomyosarcomas represent potential pitfalls in interpretation.

Systematic reviews and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: mortality, morbidity, and organ failure.

BACKGROUND: Mortality, morbidity, and organ failure are important and common serious harms after surgery. However, there are many candidate measures to describe these outcome domains. Definitions of these measures are highly variable, and validity is often unclear. As part of the International Standardised Endpoints in Perioperative Medicine (StEP) initiative, this study aimed to derive a set of standardised and valid measures of mortality, morbidity, and organ failure for use in perioperative clinical trials. METHODS: Three domains of endpoints (mortality, morbidity, and organ failure) were explored through systematic literature review and a three-stage Delphi consensus process using methods consistently applied across the StEP initiative. Reliability, feasibility, and patient-centredness were assessed in round 3 of the consensus process. RESULTS: A high level of consensus was achieved for two mortality time points, 30-day and 1-yr mortality, and these two measures are recommended. No organ failure endpoints achieved threshold criteria for consensus recommendation. The Clavien-Dindo classification of complications achieved threshold criteria for consensus in round 2 of the Delphi process but did not achieve the threshold criteria in round 3 where it scored equivalently to the Post Operative Morbidity Survey. Clavien-Dindo therefore received conditional endorsement as the most widely used measure. No composite measures of organ failure achieved an acceptable level of consensus. CONCLUSIONS: Both 30-day and 1-yr mortality measures are recommended. No measure is recommended for organ failure. One measure (Clavien-Dindo) is conditionally endorsed for postoperative morbidity, but our findings suggest that no single endpoint offers a reliable and valid measure to describe perioperative morbidity that is not dependent on the quality of deli-vered care. Further refinement of current measures, or development of novel measures, of postoperative morbidity might improve consensus in this area.

Comparison of 6-Month Outcomes of Survivors of COVID-19 versus Non-COVID-19 Critical Illness.

Rationale: The outcomes of survivors of critical illness due to coronavirus disease (COVID-19) compared with non-COVID-19 are yet to be established. Objectives: We aimed to investigate new disability at 6 months in mechanically ventilated patients admitted to Australian ICUs with COVID-19 compared with non-COVID-19. Methods: We included critically ill patients with COVID-19 and non-COVID-19 from two prospective observational studies. Patients were eligible if they were adult (age ⩾ 8 yr) and received ⩾24 hours of mechanical ventilation. In addition, patients with COVID-19 were eligible with a positive laboratory PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Measurements and Main Results: Demographic, intervention, and hospital outcome data were obtained from electronic medical records. Survivors were contacted by telephone for functional outcomes with trained outcome assessors using the World Health Organization Disability Assessment Schedule 2.0. Between March 6, 2020, and April 21, 2021, 120 critically ill patients with COVID-19, and between August 2017 and January 2019, 199 critically ill patients without COVID-19, fulfilled the inclusion criteria. Patients with COVID-19 were older (median [interquartile range], 62 [55-71] vs. 58 [44-69] yr; P = 0.019) with a lower Acute Physiology and Chronic Health Evaluation II score (17 [13-20] vs. 19 [15-23]; P = 0.011). Although duration of ventilation was longer in patients with COVID-19 than in those without COVID-19 (12 [5-19] vs. 4.8 [2.3-8.8] d; P < 0.001), 180-day mortality was similar between the groups (39/120 [32.5%] vs. 70/199 [35.2%]; P = 0.715). The incidence of death or new disability at 180 days was similar (58/93 [62.4%] vs. 99/150 [66/0%]; P = 0.583). Conclusions: At 6 months, there was no difference in new disability for patients requiring mechanical ventilation for acute respiratory failure due to COVID-19 compared with non-COVID-19. Clinical trial registered with www.clinicaltrials.gov (NCT04401254).

Contemporary diagnostic approach to atypical vascular lesion and angiosarcoma.

Vascular neoplasms account for a substantial fraction of cutaneous mesenchymal tumors, spanning from clinically indolent benign lesions to highly aggressive malignancies. These neoplasms present a distinctive challenge in terms of their diagnostic histopathology, both because of the breadth of their morphological manifestations and because of the significant histological overlap between different entities, even benign and malignant ones. The post-radiotherapy setting is particularly problematic diagnostically, insofar as radiation exposure predisposes not only to secondary angiosarcoma, but also to atypical vascular lesion, a largely benign proliferation of cutaneous blood vessels typically affecting the breast. To address these challenges, we explore the clinical, histological, and molecular features of malignant vascular neoplasia, including primary and secondary subtypes, through the comparative lens of atypical vascular lesion. In addition to highlighting the key morphological indicators of malignancy in superficial vasoformative tumors, we offer an approach that integrates clinical characteristics and molecular genetic profiling to facilitate accurate classification. With this current knowledge as our foundation, we also look ahead in an effort to frame some of the key unanswered questions regarding superficial vascular malignancies and their natural history, clinical management, and molecular underpinnings.

Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800 m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea-level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ), end-tidal partial pressures of oxygen ( P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V ̇ E ${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (-11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min-1 vs. +13 beats min-1 , P = 0.019). Between B1 and B4, adults increased V ̇ E ${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V ̇ E ${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2  = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V ̇ E ${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800 m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Towards novel measurements of remodeling activity in cortical bone: implications for osteoporosis and related pharmaceutical treatments.

Bone remodelling is performed by basic multicellular units (BMUs) that resorb and subsequently form discrete packets of bone tissue. Normally, the resorption and formation phases of BMU activity are tightly coupled spatially and temporally to promote relatively stable bone mass and bone quality. However, dysfunctional remodelling can lead to bone loss and is the underlying cause of osteoporosis. This review surveys how BMU activity is altered in postmenopausal, disuse and glucocorticoid-induced osteoporosis as well as the impact of anabolic and anti-resorptive pharmaceutical treatments. The dysfunctional remodelling observed during disease and following medical intervention bares many testable hypotheses regarding the regulation of BMU activity and may provide novel insights that challenge existing paradigms of remodelling dynamics, particularly the poorly understood BMU coupling mechanisms. Most bone remodelling research has focused on trabecular bone and 2D analyses, as technical challenges limit the direct assessment of BMU activity in cortical bone. Recent advances in imaging technology present an opportunity to investigate cortical bone remodelling in vivo. This review discusses innovative experimental methods, such as 3D and 4D (i.e. time- lapsed) evaluation of BMU morphology and trajectory, that may be leveraged to improve the understanding of the spatio-temporal coordination of BMUs in cortical bone.

Comparison of 6-month outcomes of sepsis versus non-sepsis critically ill patients receiving mechanical ventilation.

BACKGROUND: Data on long-term outcomes after sepsis-associated critical illness have mostly come from small cohort studies, with no information about the incidence of new disability. We investigated whether sepsis-associated critical illness was independently associated with new disability at 6 months after ICU admission compared with other types of critical illness. METHODS: We conducted a secondary analysis of a multicenter, prospective cohort study in six metropolitan intensive care units in Australia. Adult patients were eligible if they had been admitted to the ICU and received more than 24 h of mechanical ventilation. There was no intervention. RESULTS: The primary outcome was new disability measured with the WHO Disability Assessment Schedule 2.0 (WHODAS) 12 level score compared between baseline and 6 months. Between enrollment and follow-up at 6 months, 222/888 (25%) patients died, 100 (35.5%) with sepsis and 122 (20.1%) without sepsis (P < 0.001). Among survivors, there was no difference for the incidence of new disability at 6 months with or without sepsis, 42/106 (39.6%) and 106/300 (35.3%) (RD, 0.00 (- 10.29 to 10.40), P = 0.995), respectively. In addition, there was no difference in the severity of disability, health-related quality of life, anxiety and depression, post-traumatic stress, return to work, financial distress or cognitive function. CONCLUSIONS: Compared to mechanically ventilated patients of similar acuity and length of stay without sepsis, patients with sepsis admitted to ICU have an increased risk of death, but survivors have a similar risk of new disability at 6 months. Trial registration NCT03226912, registered July 24, 2017.

People in intensive care with COVID-19: demographic and clinical features during the first, second, and third pandemic waves in Australia.

OBJECTIVE: To compare the demographic and clinical features, management, and outcomes for patients admitted with COVID-19 to intensive care units (ICUs) during the first, second, and third waves of the pandemic in Australia. DESIGN, SETTING, AND PARTICIPANTS: People aged 16 years or more admitted with polymerase chain reaction-confirmed COVID-19 to the 78 Australian ICUs participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project during the first (27 February - 30 June 2020), second (1 July 2020 - 25 June 2021), and third COVID-19 waves (26 June - 1 November 2021). MAIN OUTCOME MEASURES: Primary outcome: in-hospital mortality. SECONDARY OUTCOMES: ICU mortality; ICU and hospital lengths of stay; supportive and disease-specific therapies. RESULTS: 2493 people (1535 men, 62%) were admitted to 59 ICUs: 214 during the first (9%), 296 during the second (12%), and 1983 during the third wave (80%). The median age was 64 (IQR, 54-72) years during the first wave, 58 (IQR, 49-68) years during the second, and 54 (IQR, 41-65) years during the third. The proportion without co-existing illnesses was largest during the third wave (41%; first wave, 32%; second wave, 29%). The proportion of ICU beds occupied by patients with COVID-19 was 2.8% (95% CI, 2.7-2.9%) during the first, 4.6% (95% CI, 4.3-5.1%) during the second, and 19.1% (95% CI, 17.9-20.2%) during the third wave. Non-invasive (42% v 15%) and prone ventilation strategies (63% v 15%) were used more frequently during the third wave than during the first two waves. Thirty patients (14%) died in hospital during the first wave, 35 (12%) during the second, and 281 (17%) during the third. After adjusting for age, illness severity, and other covariates, the risk of in-hospital mortality was similar for the first and second waves, but 9.60 (95% CI, 3.52-16.7) percentage points higher during the third than the first wave. CONCLUSION: The demographic characteristics of patients in intensive care with COVID-19 and the treatments they received during the third pandemic wave differed from those of the first two waves. Adjusted in-hospital mortality was highest during the third wave.

Determinants of Adherence to Best Practice in Severe Traumatic Brain Injury: A Qualitative Study.

BACKGROUND: Management of patients with severe traumatic brain injury (sTBI) is highly variable and inconsistently aligned with evidence derived from high-quality trials, including those examining intravenous fluid resuscitation and use of decompressive craniectomy surgery. This study explored the barriers and facilitators of general and specific evidence-based practices in sTBI from the perspectives of stakeholder clinicians. METHODS: This was a qualitative study of semistructured interviews conducted with specialist clinicians responsible for acute care of patients with sTBI. Interview analysis was guided by the Theoretical domains framework (TDF), and key themes were mapped to relevant TDF behavioral domains. RESULTS: Ten neurosurgeons, 12 intensive care specialists, and three trauma physicians from six high-income countries participated between May 2020 and May 2021. Key TDF domains were environmental context and resources, social influences, and beliefs about consequences. Evidence-aligned management of patients with sTBI is perceived to be facilitated by admission to academic research-oriented hospitals, development of local practice protocols, and interdisciplinary collaboration. Determinants of specific practices varied and included health policy change for fluid resuscitation and development of patient-centered goals for surgical decision-making. CONCLUSIONS: In choosing interventions for patients with sTBI, clinicians integrate local environmental, social, professional, and emotional influences with evidence and associated clinical practice guideline recommendations. This study highlights determinants of evidence-based practice that may inform implementation efforts and thereby improve outcomes for patients with sTBI.

Decontamination of SARS-CoV-2 from cold-chain food packaging provides no marginal benefit in risk reduction to food workers.

Countries continue to debate the need for decontamination of cold-chain food packaging to reduce possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) fomite transmission among frontline workers. While laboratory-based studies demonstrate persistence of SARS-CoV-2 on surfaces, the likelihood of fomite-mediated transmission under real-life conditions is uncertain. Using a quantitative microbial risk assessment model of a frozen food packaging facility, we simulated 1) SARS-CoV-2 fomite-mediated infection risks following worker exposure to contaminated plastic packaging; and 2) reductions in these risks from masking, handwashing, and vaccination. In a frozen food facility without interventions, SARS-CoV-2 infection risk to a susceptible worker from contact with contaminated packaging was 1.5 × 10-3 per 1h-period (5th - 95th percentile: 9.2 × 10-6, 1.2 × 10-2). Standard food industry infection control interventions, handwashing and masking, reduced risk (99.4%) to 8.5 × 10-6 risk per 1h-period (5th - 95th percentile: 2.8 × 10-8, 6.6 × 10-5). Vaccination of the susceptible worker (two doses Pfizer/Moderna, vaccine effectiveness: 86-99%) with handwashing and masking reduced risk to 5.2 × 10-7 risk per 1h-period (5th - 95th percentile: 1.8 × 10-9, 5.4 × 10-6). Simulating increased transmissibility of current and future variants (Delta, Omicron), (2-, 10-fold viral shedding) among a fully vaccinated workforce, handwashing and masking continued to mitigate risk (1.4 × 10-6 - 8.8 × 10-6 risk per 1h-period). Additional decontamination of frozen food plastic packaging reduced infection risks to 1.2 × 10-8 risk per 1h-period (5th - 95th percentile: 1.9 × 10-11, 9.5 × 10-8). Given that standard infection control interventions reduced risks well below 1 × 10-4 (World Health Organization water quality risk thresholds), additional packaging decontamination suggest no marginal benefit in risk reduction. Consequences of this decontamination may include increased chemical exposures to workers, food quality and hazard risks to consumers, and unnecessary added costs to governments and the global food industry.

Controlling risk of SARS-CoV-2 infection in essential workers of enclosed food manufacturing facilities.

The SARS-CoV-2 global pandemic poses significant health risks to workers who are essential to maintaining the food supply chain. Using a quantitative risk assessment model, this study characterized the impact of risk reduction strategies for controlling SARS-CoV-2 transmission (droplet, aerosol, fomite-mediated) among front-line workers in a representative indoor fresh fruit and vegetable manufacturing facility. We simulated: 1) individual and cumulative SARS-CoV-2 infection risks from close contact (droplet and aerosols at 1-3 m), aerosol, and fomite-mediated exposures to a susceptible worker following exposure to an infected worker during an 8 h-shift; and 2) the relative reduction in SARS-CoV-2 infection risk attributed to infection control interventions (physical distancing, mask use, ventilation, surface disinfection, hand hygiene, vaccination). Without mitigation measures, the SARS-CoV-2 infection risk was largest for close contact (droplet and aerosol) at 1 m (0.96, 5th - 95th percentile: 0.67-1.0). In comparison, risk associated with fomite (0.26, 5th - 95th percentile: 0.10-0.56) or aerosol exposure alone (0.05, 5th - 95th percentile: 0.01-0.13) at 1 m distance was substantially lower (73-95%). At 1 m, droplet transmission predominated over aerosol and fomite-mediated transmission, however, this changed by 3 m, with aerosols comprising the majority of the exposure dose. Increasing physical distancing reduced risk by 84% (1-2 m) and 91% (1-3 m). Universal mask use reduced infection risk by 52-88%, depending on mask type. Increasing ventilation (from 0.1 to 2-8 air changes/hour) resulted in risk reductions of 14-54% (1 m) and 55-85% (2 m). Combining these strategies, together with handwashing and surface disinfection, resulted in <1% infection risk. Partial or full vaccination of the susceptible worker resulted in risk reductions of 73-92% (1 m risk range: 0.08-0.26). However, vaccination paired with other interventions (ACH 2, mask use, or distancing) was necessary to achieve infection risks <1%. Current industry SARS-CoV-2 risk reduction strategies, particularly when bundled, provide significant protection to essential food workers.

African American Cancer Survivors' Perspectives on Cancer Clinical Trial Participation in a Safety-Net Hospital: Considering the Role of the Social Determinants of Health.

Although there has been an increase focus on recruitment of minority populations at safety-net hospitals into cancer clinical trials, there is still a paucity of research exploring minority participation in cancer clinical trials at safety-net settings. The study utilized a multi-level, qualitative approach to assess the clinical and non-clinical facilitators and barriers to African American participation in cancer clinical trials at a safety-net hospital. From June 2018 to July 2019, cancer survivors (n = 25) were recruited from a cancer center at a safety-net hospital in the southeastern USA and participated in a 60-min focus group. Data was coded and analyzed to identify the most prominent themes. Most participants were female (78%), with a mean age of 56 years. The majority were diagnosed with breast cancer (68%) and disabled or unemployed (55%). Major themes identified were (1) lack of understanding of cancer clinical trials, (2) perceptions and fears of cancer clinical trials, and (3) preferred role and characteristics of patient navigator. The barriers and facilitators to enrollment in cancer clinical trials were more pronounced in the safety-net setting, given the overdue burden of social determinants of health. Study findings yield important insights and essential practices for recruiting and engaging underrepresented Black cancer patients into cancer clinical trials, specifically for safety-net settings. Including patient navigators may help traverse potential barriers to cancer clinical trial participation and will allow for the attention to social determinants of health, and ultimately increase the number of African Americans participating in cancer clinical trials.

Evaluation of medical emergency team medication management practices in acute hospitals: A multicentre study.

BACKGROUND: Medical emergency teams use medications to rescue deteriorating patients. Medication management is the system of steps and processes, including prescribing, distribution, administration, and monitoring, to achieve the best outcomes from medication use. Systems or standards for medication management by medical emergency teams have not been defined. OBJECTIVES: The aim of the study was to propose potential solutions to improve medical emergency team medication management by evaluating medication supply and related medication management practices during medical emergency team activations and understanding clinicians' perceptions about medical emergency team medication management in acute hospitals. METHODS: A prospective multicentre audit of intensive care unit-equipped hospitals in Victoria, Australia, was conducted. After advertisement and invitation via scheduled email newsletters to hospitals, a representative of the medical emergency team from each hospital self-administered an online audit tool during December 2019 and January 2020. Audit data were analysed descriptively, and perceptions were analysed using content analysis. RESULTS: Responses were received from 32 of the 44 (72.7%) eligible hospitals. At 17 of the 32 (53.1%) hospitals, arrest trolleys provided medications for medical emergency team activations, in addition to arrest calls. At 15 of the 32 (46.9%) hospitals, separate, dedicated medical emergency team medication supplies were used to care for deteriorating patients. Dedicated medical emergency team supplies contained a median of 20 (range = 8-37) medications, predominantly cardiovascular (median = 8, mode = 7, range = 4-16) and neurological medications (median and mode = 6, range = 0-11). Variation was observed in all storage and other supply-related medication management practices studied. The four most frequent categories of clinicians' perceptions described systematic challenges with availability of the right medication in the right place at the right time. CONCLUSIONS: Current supply and related medication management practices and clinicians' perceptions demonstrated further development is necessary for medication management to meet the needs of medical emergency team clinicians and their patients.

Pipette Olympics: An Engaging Exercise for Undergraduate Laboratory Training.

Pipetting is an important technique used in almost every molecular neuroscience method including but not limited to, PCR, reverse transcription, immunohistochemistry, chromatin immunoprecipitation, and cell culture. The COVID-19 pandemic has robbed the undergraduate population of time to practice in person laboratory techniques. In response, we have devised a standardized, quick, and fun way to instruct students on the fundamentals of pipetting, serial dilutions, and basic statistical analysis. Here, we offer a standardized protocol for instructors to use to teach undergraduates valuable skills while providing friendly competition. We also offer an example of an undergraduate performing the steps of this protocol with example results and the results from three separate undergrads' first two attempts. This exercise provides laboratories with a method to reintroduce undergraduates to lab basics while standardizing the training thereby saving time lost to the pandemic.

The impact of distance on post-ICU disability.

BACKGROUND: Nonurban residential living is associated with adverse outcomes for a number of chronic health conditions. However, it is unclear what effect it has amongst survivors of critical illness. OBJECTIVES: The purpose of this study is to determine whether patients living greater than 50 km from the treating intensive care unit (ICU) have disability outcomes at 6 months that differ from people living within 50 km. METHODS: This was a multicentre, prospective cohort study conducted in five metropolitan ICUs. Participants were adults admitted to the ICU, who received >24 h of mechanical ventilation and survived to hospital discharge. In a secondary analysis of these data, the cohort was dichotomised based on residential distance from the treating ICU: <50 km and ≥50 km. The primary outcome was patient-reported disability using the 12-item World Health Organization's Disability Assessment Schedule (WHODAS 2.0). This was recorded at 6 months after ICU admission by telephone interview. Secondary outcomes included health status as measured by EQ-5D-5L return to work and psychological function as measured by the Hospital Anxiety and Depression Scale (HADS). Multivariable logistic regression was used to assess the association between distance from the ICU and moderate to severe disability, adjusted for potential confounders. Variables included in the multivariable model were deemed to be clinically relevant and had baseline imbalance between groups (p < 0.10). These included marital status and hours of mechanical ventilation. Sensitivity analysis was also conducted using distance in kilometres as a continuous variable. RESULTS: A total of 262 patients were enrolled, and 169 (65%) lived within 50 km of the treating ICU and 93 (35%) lived ≥50 km from the treating ICU (interquartile range [IQR] 10-664 km). There was no difference in patient-reported disability at 6 months between patients living <50 km and those living ≥50 km (WHODAS total disability % [IQR] 10.4 [2.08-25] v 14.6 [2.08-20.8], P = 0.74). There was also no difference between groups for the six major life domains of the WHODAS. There was no difference in rates of anxiety or depression as measured by HADS score (HADS anxiety median [IQR] 4 [1-7] v 3 [1-7], P = 0.60) (HADS depression median [IQR] 3 [1-6] v 3 [1-6], P = 0.62); health status as measured by EQ-5D (mean [SD] 66.7 [20] v 69.8 [22.2], P = 0.24); or health-related unemployment (% (N) 39 [26] v 25 [29.1], P = 0.61). After adjusting for confounders, living ≥50 km from the treating ICU was not associated with increased disability (odds ratio 0.61, 95% confidence interval: 0.33-1.16; P = 0.13) CONCLUSIONS: Survivors of intensive care in Victoria, Australia, who live at least 50 km from the treating ICU did not have greater disability than people living less than 50 km at 6 months after discharge. Living 50 km or more from the treating ICU was not associated with disability, nor was it associated with anxiety or depression, health status, or unemployment due to health.

Cost-effectiveness of bariatric surgery and non-surgical weight management programmes for adults with severe obesity: a decision analysis model.

OBJECTIVES: To determine the most cost-effective weight management programmes (WMPs) for adults, in England with severe obesity (BMI ≥ 35 kg/m2), who are more at risk of obesity related diseases. METHODS: An economic evaluation of five different WMPs: 1) low intensity (WMP1); 2) very low calorie diets (VLCD) added to WMP1; 3) moderate intensity (WMP2); 4) high intensity (Look AHEAD); and 5) Roux-en-Y gastric bypass (RYGB) surgery, all compared to a baseline scenario representing no WMP. We also compare a VLCD added to WMP1 vs. WMP1 alone. A microsimulation decision analysis model was used to extrapolate the impact of changes in BMI, obtained from a systematic review and meta-analysis of randomised controlled trials (RCTs) of WMPs and bariatric surgery, on long-term risks of obesity related disease, costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) measured as incremental cost per QALY gained over a 30-year time horizon from a UK National Health Service (NHS) perspective. Sensitivity analyses explored the impact of long-term weight regain assumptions on results. RESULTS: RYGB was the most costly intervention but also generated the lowest incidence of obesity related disease and hence the highest QALY gains. Base case ICERs for WMP1, a VLCD added to WMP1, WMP2, Look AHEAD, and RYGB compared to no WMP were £557, £6628, £1540, £23,725 and £10,126 per QALY gained respectively. Adding a VLCD to WMP1 generated an ICER of over £121,000 per QALY compared to WMP1 alone. Sensitivity analysis found that all ICERs were sensitive to the modelled base case, five year post intervention cessation, weight regain assumption. CONCLUSIONS: RYGB surgery was the most effective and cost-effective use of scarce NHS funding resources. However, where fixed healthcare budgets or patient preferences exclude surgery as an option, a standard 12 week behavioural WMP (WMP1) was the next most cost-effective intervention.