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We estimated the probability of undetected emergence of the SARS-CoV-2 Omicron variant in 25 low and middle-income countries (LMICs) prior to December 5, 2021. In nine countries, the risk exceeds 50%; in Turkey, Pakistan and the Philippines, it exceeds 99%. Risks are generally lower in the Americas than Europe or Asia.

The small biomolecule methionine (Met) is a fundamental amino acid required for a vast range of biological processes such as protein synthesis, cancer metabolism, and epigenetics. However, it is still difficult to visualize the subcellular distribution of small biomolecules including Met in a minimally invasive manner. Here, we demonstrate stimulated Raman scattering (SRS) imaging of cellular uptake of deuterated methionine (d

Although testing, contact tracing, and case isolation programs can mitigate COVID-19 transmission and allow the relaxation of social distancing measures, few countries worldwide have succeeded in scaling such efforts to levels that suppress spread. The efficacy of test-trace-isolate likely depends on the speed and extent of follow-up and the prevalence of SARS-CoV-2 in the community. Here, we use a granular model of COVID-19 transmission to estimate the public health impacts of test-trace-isolate programs across a range of programmatic and epidemiological scenarios, based on testing and contact tracing data collected on a university campus and surrounding community in Austin, TX, between October 1, 2020, and January 1, 2021. The median time between specimen collection from a symptomatic case and quarantine of a traced contact was 2 days (interquartile range [IQR]: 2 to 3) on campus and 5 days (IQR: 3 to 8) in the community. Assuming a reproduction number of 1.2, we found that detection of 40% of all symptomatic cases followed by isolation is expected to avert 39% (IQR: 30% to 45%) of COVID-19 cases. Contact tracing is expected to increase the cases averted to 53% (IQR: 42% to 58%) or 40% (32% to 47%), assuming the 2- and 5-day delays estimated on campus and in the community, respectively. In a tracing-accelerated scenario, in which 75% of contacts are notified the day after specimen collection, cases averted increase to 68% (IQR: 55% to 72%). An accelerated contact tracing program leveraging rapid testing and electronic reporting of test results can significantly curtail local COVID-19 transmission.

Despite advances in cancer genomics and the increased use of genomic medicine, metastatic cancer is still mostly an incurable and fatal disease. With diminishing returns from traditional drug discovery strategies, and high clinical failure rates, more emphasis is being placed on alternative drug discovery platforms, such as ex vivo approaches. Ex vivo approaches aim to embed biological relevance and inter-patient variability at an earlier stage of drug discovery, and to offer more precise treatment stratification for patients. However, these techniques also have a high potential to offer personalised therapies to patients, complementing and enhancing genomic medicine. Although an array of approaches are available to researchers, only a minority of techniques have made it through to direct patient treatment within robust clinical trials. Within this review, we discuss the current challenges to ex vivo approaches within clinical practice and summarise the contemporary literature which has directed patient treatment. Finally, we map out how ex vivo approaches could transition from a small-scale, predominantly research based technology to a robust and validated predictive tool. In future, these pre-clinical approaches may be integrated into clinical cancer pathways to assist in the personalisation of therapy choices and to hopefully improve patient experiences and outcomes.

Community mitigation strategies to combat COVID-19, ranging from healthy hygiene to shelter-in-place orders, exact substantial socioeconomic costs. Judicious implementation and relaxation of restrictions amplify their public health benefits while reducing costs. We derive optimal strategies for toggling between mitigation stages using daily COVID-19 hospital admissions. With public compliance, the policy triggers ensure adequate intensive care unit capacity with high probability while minimizing the duration of strict mitigation measures. In comparison, we show that other sensible COVID-19 staging policies, including France’s ICU-based thresholds and a widely adopted indicator for reopening schools and businesses, require overly restrictive measures or trigger strict stages too late to avert catastrophic surges. As proof-of-concept, we describe the optimization and maintenance of the staged alert system that has guided COVID-19 policy in a large US city (Austin, Texas) since May 2020. As cities worldwide face future pandemic waves, our findings provide a robust strategy for tracking COVID-19 hospital admissions as an early indicator of hospital surges and enacting staged measures to ensure integrity of the health system, safety of the health workforce, and public confidence., Selection of COVID-19 mitigation measures requires balancing health outcomes with economic impacts. Here, the authors derive a system to set triggers for increasing mitigation measures to preserve healthcare capacity, and describe how it has been used to support public health decision making in Austin, Texas.

We used the incidence of spike gene target failures identified during PCR testing to provide an early projection of the prevalence of severe acute respiratory syndrome coronavirus 2 variant B.1.1.7 in a university setting in Texas, USA, before sequencing results were available. Findings from a more recent evaluation validated those early projections.

DNA helicases are involved in nearly all facets of genome integrity, and in humans, mutations in helicase-encoding genes are often linked to diseases of genomic instability. Two highly studied and evolutionarily conserved helicase families are the PIF1 and RecQ helicases. Enzymes in these families have known roles in DNA replication, recombination, and repair, as well as telomere maintenance, DNA recombination, and transcription. Although genetics, structural biology, and a variety of other techniques have been used to study these helicases, ensemble analyses of their basic biochemical activities such as DNA binding, ATP hydrolysis, and DNA unwinding have made significant contributions to our understanding of their physiological roles. Here, we present general methods to generate recombinant proteins from both helicase families, as well as standard biochemical assays to investigate their activities on DNA.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge. Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT. We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T. In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm. In mice, the magnetic device guided intravenously administered MNP (50nm) from the circulation into the brain where they localised within mouse BT. Furthermore, MDT of magnetised Temozolomide (TMZ

With the need to quickly advance knowledge dissemination in rapid-paced fields, and more recently in response to the urgency of the COVID-19 pandemic, prepublishing has been brought to the forefront. SPI-Hub™, a publicly available journal selection decision support tool, is being strategically enhanced to address prospective authors' critical needs in navigating and selecting the most appropriate preprint or traditional publication venue.

The integration of advanced analytics and artificial intelligence (AI) technologies into the practice of medicine holds much promise. Yet, the opportunity to leverage these tools carries with it an equal responsibility to ensure that principles of equity are incorporated into their implementation and use. Without such efforts, tools will potentially reflect the myriad of ways in which data, algorithmic, and analytic biases can be produced, with the potential to widen inequities by race, ethnicity, gender, and other sociodemographic factors implicated in disparate health outcomes. We propose a set of strategic assertions to examine before, during, and after adoption of these technologies in order to facilitate healthcare equity across all patient population groups. The purpose is to enable generalists to promote engagement with technology companies and co-create, promote, or support innovation and insights that can potentially inform decision-making and health care equity.

Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery, and is associated with increased morbidity and mortality. Inflammation has been implicated as an etiology of POAF. Mitochondrial DNA (mtDNA) has been shown to initiate inflammation. This study analyzed inflammatory mechanisms of POAF by evaluating mtDNA, neutrophils, and cytokines/chemokines in the pericardial fluid and blood after cardiac surgery.Blood and pericardial fluid from patients who underwent coronary artery bypass or heart valve surgery, or both, were collected intraoperatively and at 4, 12, 24, and 48 hours postoperatively. Real-time polymerase chain reaction was used to quantify mtDNA in the pericardial fluid and blood. A Luminex (Luminex Corp, Austin, TX) assay was used to study cytokine and chemokine levels. Flow cytometry was used to analyze neutrophil infiltration and activation in the pericardial fluid.Samples from 100 patients were available for analysis. Postoperatively, mtDNA and multiple cytokine levels were higher in the pericardial fluid versus blood. Patients who had POAF had significantly higher levels of mtDNA in the pericardial fluid compared with patients who did not (P.001, area under the curve 0.74). There was no difference in the mtDNA concentration in the blood between the POAF group and non-POAF group (P = .897). Neutrophil concentration increased in the pericardial fluid over time from a baseline of 0.8% to 56% at 48 hours (P.01).The pericardial space has a high concentration of inflammatory mediators postoperatively. Mitochondrial DNA in the pericardial fluid was strongly associated with the development of POAF. This finding provides insight into a possible mechanism of inflammation that may contribute to POAF, and may offer novel therapeutic targets.

Clostridioides difficile is the single most deadly bacterial pathogen in the United States, and its global prevalence and outsized health impacts underscore the need for more effective therapeutic options. Towards this goal, a novel group of modified peptidoglycan hydrolases with significant in vitro bactericidal activity have emerged as potential candidates for treating C. difficile infections (CDI). To date, discovery and development efforts directed at these CDI-specific lysins have been limited, and in particular there has been no systematic comparison of known or newly discovered lysin candidates. Here, we detail bioinformatics-driven discovery of six new anti-C. difficile lysins belonging to the amidase-3 family of enzymes, and we describe experimental comparison of their respective catalytic domains (CATs) with highly active CATs from the literature. Our quantitative analyses include metrics for expression level, inherent antibacterial activity, breadth of strain selectivity, killing of germinating spores, and structural and functional measures of thermal stability. Importantly, prior studies have not examined stability as a performance metric, and our results show that the panel of eight enzymes possess widely variable thermal denaturation temperatures and resistance to heat inactivation, including some enzymes that exhibit marginal stability at body temperature. Ultimately, no single enzyme dominated with respect to all performance measures, suggesting the need for a balanced assessment of lysin properties during efforts to find, engineer, and develop candidates with true clinical potential.

Background Previous research from our center has shown that 27% of the pediatric trauma transfers from referring facilities are potentially preventable. Our hospital is the only level 1 pediatric trauma center (PTC) in our state, and we are developing a pediatric trauma telehealth network to help keep certain injured children closer to home. We instituted a pediatric trauma telehealth program with a partnering community-based hospital in our state and aim to report our experience over the first year. Methods All pediatric trauma patients that presented to our partnering hospital from January 2019 to February 2020 were reviewed. Disposition was: a) telehealth consultation, b) admission to the children's unit without a telehealth consultation per our head trauma protocol, or c) transfer without telehealth consultation. Data on demographics, hospital course, and disposition were collected via chart review. Results Eight patients underwent telehealth consults and another 8 patients were admitted to the partnering hospital's children's unit based on the head trauma protocol without a telehealth consult. Patient's ages ranged from 7 months to 15 years. Of the patients that underwent telehealth consult, 7 presented with a head injury and 1 presented with a rib fracture/small pneumothorax. The patient with a pneumothorax was observed for 6 h and discharged home after a repeat chest x-ray was stable. All 15 patients with head injuries were observed and discharged from either the emergency department or children's unit after passing concussion testing. No patients required transfer to our PTC after observation, and none were readmitted. Fifty-six patients were transferred without telehealth consultation, and 3 of these patients could potentially have avoided transfer with a telehealth consultation. Conclusions Telehealth in pediatric trauma can be a safe mechanism for preventing the transfer of patients that can be safely observed at a partnering hospital. From a facility that transfers an average of 30 trauma patients per year to our hospital, this program prevented 16 such transfers. Development of a head trauma protocol in collaboration with a pediatric neurosurgeon leads to an unexpected number of patients being admitted to the partnering hospital for observation without utilization of a telehealth consultation. Type of study Retrospective study. Level of evidence III

During rollout of coronavirus disease vaccination, policymakers have faced critical trade-offs. Using a mathematical model of transmission, we found that timing of vaccination rollout would be expected to have a substantially greater effect on mortality rate than risk-based prioritization and uptake and that prioritizing first doses over second doses may be lifesaving.

We develop theoretical foundations of resonator networks, a new type of recurrent neural network introduced in Frady, Kent, Olshausen, and Sommer ( 2020 ), a companion article in this issue, to solve a high-dimensional vector factorization problem arising in Vector Symbolic Architectures. Given a composite vector formed by the Hadamard product between a discrete set of high-dimensional vectors, a resonator network can efficiently decompose the composite into these factors. We compare the performance of resonator networks against optimization-based methods, including Alternating Least Squares and several gradient-based algorithms, showing that resonator networks are superior in several important ways. This advantage is achieved by leveraging a combination of nonlinear dynamics and searching in superposition, by which estimates of the correct solution are formed from a weighted superposition of all possible solutions. While the alternative methods also search in superposition, the dynamics of resonator networks allow them to strike a more effective balance between exploring the solution space and exploiting local information to drive the network toward probable solutions. Resonator networks are not guaranteed to converge, but within a particular regime they almost always do. In exchange for relaxing the guarantee of global convergence, resonator networks are dramatically more effective at finding factorizations than all alternative approaches considered.

Background Learning curves and skill attrition with aging have been reported to impair outcomes in select surgical subspecialties, but their role in complex cardiac surgery remains unknown. Methods From 1986 to 2019, 2314 patients underwent reoperative cardiac surgery: coronary artery bypass grafting (n = 543), valve (n = 1527), or combined coronary artery bypass grafting and valve (n = 244). Thirty-four different surgeons in practice between 1 and 39 years were included. Standardized mortality ratio (observed-to-expected) was determined for all surgeons in each post-training year of experience. Results Risk-adjusted cumulative sum change-point analysis was used to define five distinct career phases: 0 to 4 years, 5 to 8 years, 9 to 17 years, 18 to 28 years, and 29 to 39 years. With 5 to 8 years and 18 to 28 years of experience, standardized mortality ratio was near unity (0.95 and 1.05, respectively) and lowest with 9 to 17 years of experience (0.78, P = .03). In the youngest experience group (0 to 4 years), observed and expected mortality were both highest, and standardized mortality ratio was elevated at 1.29, which approached statistical significance (P = .059). In the oldest experience group (29 to 39 years), expected mortality was low compared with most other groups but observed mortality increased, yielding a significantly elevated standardized mortality ratio at 1.53 (P = .032). Conclusions Standardized mortality ratios with reoperative cardiac surgery were highest early and late in a surgeon’s career and lowest in mid career. As surgeons gain experience, outcomes improve through the first two career decades, then stabilize in the third decade before declining in the fourth decade.

Significance The glycosylation of proteins is a major protein modification that occurs extensively in eukaryotes. Glycosidases in the secretory pathway that trim N-linked glycans play key roles in protein quality control and in the specific modifications leading to mature glycoproteins. Inhibition of glucosidases in the secretory pathway is a proven therapeutic strategy, that holds great promise in the treatment of viral disease. The enzyme endo-α-1,2-mannosidase (MANEA) provides an alternative processing pathway to evade glucosidase inhibitors. We report the three-dimensional structure of human MANEA and complexes with enzyme inhibitors that we show act as antivirals for bovine viral diarrhea and human dengue viruses. The structure of MANEA will support inhibitor optimization and the development of more potent antivirals., Mammalian protein N-linked glycosylation is critical for glycoprotein folding, quality control, trafficking, recognition, and function. N-linked glycans are synthesized from Glc3Man9GlcNAc2 precursors that are trimmed and modified in the endoplasmic reticulum (ER) and Golgi apparatus by glycoside hydrolases and glycosyltransferases. Endo-α-1,2-mannosidase (MANEA) is the sole endo-acting glycoside hydrolase involved in N-glycan trimming and is located within the Golgi, where it allows ER-escaped glycoproteins to bypass the classical N-glycosylation trimming pathway involving ER glucosidases I and II. There is considerable interest in the use of small molecules that disrupt N-linked glycosylation as therapeutic agents for diseases such as cancer and viral infection. Here we report the structure of the catalytic domain of human MANEA and complexes with substrate-derived inhibitors, which provide insight into dynamic loop movements that occur on substrate binding. We reveal structural features of the human enzyme that explain its substrate preference and the mechanistic basis for catalysis. These structures have inspired the development of new inhibitors that disrupt host protein N-glycan processing of viral glycans and reduce the infectivity of bovine viral diarrhea and dengue viruses in cellular models. These results may contribute to efforts aimed at developing broad-spectrum antiviral agents and help provide a more in-depth understanding of the biology of mammalian glycosylation.

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and continues to portend poor survival, despite multimodal treatment using surgery and chemoradiotherapy. The addition of tumour-treating fields (TTFields)—an approach in which alternating electrical fields exert biophysical force on charged and polarisable molecules known as dipoles—to standard therapy, has been shown to extend survival for patients with newly diagnosed GBM, recurrent GBM and mesothelioma, leading to the clinical approval of this approach by the FDA. TTFields represent a non-invasive anticancer modality consisting of low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz), alternating electric fields delivered via cutaneous transducer arrays configured to provide optimal tumour-site coverage. Although TTFields were initially demonstrated to inhibit cancer cell proliferation by interfering with mitotic apparatus, it is becoming increasingly clear that TTFields show a broad mechanism of action by disrupting a multitude of biological processes, including DNA repair, cell permeability and immunological responses, to elicit therapeutic effects. This review describes advances in our current understanding of the mechanisms by which TTFields mediate anticancer effects. Additionally, we summarise the landscape of TTFields clinical trials across various cancers and consider how emerging preclinical data might inform future clinical applications for TTFields.

Social distancing orders have been enacted worldwide to slow the coronavirus disease (COVID-19) pandemic, reduce strain on healthcare systems, and prevent deaths. To estimate the impact of the timing and intensity of such measures, we built a mathematical model of COVID-19 transmission that incorporates age-stratified risks and contact patterns and projects numbers of hospitalizations, patients in intensive care units, ventilator needs, and deaths within US cities. Focusing on the Austin metropolitan area of Texas, we found that immediate and extensive social distancing measures were required to ensure that COVID-19 cases did not exceed local hospital capacity by early May 2020. School closures alone hardly changed the epidemic curve. A 2-week delay in implementation was projected to accelerate the timing of peak healthcare needs by 4 weeks and cause a bed shortage in intensive care units. This analysis informed the Stay Home-Work Safe order enacted by Austin on March 24, 2020.

Pressure–velocity-based analysis of arterial wave intensity gives clinically relevant information about the performance of the heart and vessels, but its utility is limited because accurate pressure measurements can only be obtained invasively. Diameter–velocity-based wave intensity can be obtained noninvasively using ultrasound; however, due to the nonlinear relationship between blood pressure and arterial diameter, the two wave intensities might give disparate clinical indications. To test the magnitude of the disagreement, we have generated an age-stratified virtual population to investigate how the two dominant nonlinearities, viscoelasticity and strain-stiffening, cause the two formulations to differ. We found strong agreement between the pressure–velocity and diameter–velocity methods, particularly for the systolic wave energy, the ratio between systolic and diastolic wave heights, and older subjects. The results are promising regarding the introduction of noninvasive wave intensities in the clinic.

The reduced efficacy of voluntary imitation in autism is suggested to be underpinned by differences in sensorimotor processing. We examined whether the imitation of novel atypical biological kinematics by autistic adults is enhanced by imitating a model in a predictable blocked practice trial order. This practice structure is expected to facilitate trial-to-trial sensorimotor processing, integration and encoding of biological kinematics. The results showed that neurotypical participants were generally more effective at imitating the biological kinematics across all experimental phases. Importantly, and compared to a pre-test where imitation was performed in a randomised (unpredictable) trial order, the autistic participants learned to imitate the atypical kinematics more effectively following an acquisition phase of repeatedly imitating the same model during blocked practice. Data from the post-test showed that autistic participants remained effective at imitating the atypical biological kinematics when the models were subsequently presented in a randomised trial order. These findings show that the reduced efficacy of voluntary imitation in autism can be enhanced during learning by facilitating trial-to-trial processing and integration of sensorimotor information using blocked practice. Lay Abstract Autistic people sometimes find it difficult to copy another person’s movement accurately, especially if the movement is unfamiliar or novel (e.g. to use chop sticks). In this study, we found that autistic people were generally less accurate at copying a novel movement than non-autistic people. However, by making a small adjustment and asking people to copy this movement for a set number of attempts in a predictable manner, we showed that autistic people did successfully learn to copy a new movement. This is a very important finding for autistic people because rather than thinking they cannot copy new movements, all that needs to be considered is for parents/guardians, teachers and/or support workers to make a small adjustment so that learning occurs in a predictable manner for new skills to be successfully acquired through copying. The implications from this study are wide-ranging as copying (imitation) and motor learning are important developmental processes for autistic infants and children to acquire in order to interact within the world. Therefore, practising these behaviours in the most effective way can certainly help the developmental pathway.

Forecasting the burden of COVID-19 has been impeded by limitations in data, with case reporting biased by testing practices, death counts lagging far behind infections, and hospital census reflecting time-varying patient access, admission criteria, and demographics. Here, we show that hospital admissions coupled with mobility data can reliably predict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission rates and healthcare demand. Using a forecasting model that has guided mitigation policies in Austin, TX, we estimate that the local reproduction number had an initial 7-d average of 5.8 (95% credible interval [CrI]: 3.6 to 7.9) and reached a low of 0.65 (95% CrI: 0.52 to 0.77) after the summer 2020 surge. Estimated case detection rates ranged from 17.2% (95% CrI: 11.8 to 22.1%) at the outset to a high of 70% (95% CrI: 64 to 80%) in January 2021, and infection prevalence remained above 0.1% between April 2020 and March 1, 2021, peaking at 0.8% (0.7-0.9%) in early January 2021. As precautionary behaviors increased safety in public spaces, the relationship between mobility and transmission weakened. We estimate that mobility-associated transmission was 62% (95% CrI: 52 to 68%) lower in February 2021 compared to March 2020. In a retrospective comparison, the 95% CrIs of our 1, 2, and 3 wk ahead forecasts contained 93.6%, 89.9%, and 87.7% of reported data, respectively. Developed by a task force including scientists, public health officials, policy makers, and hospital executives, this model can reliably project COVID-19 healthcare needs in US cities.

Older adults are underrepresented in cancer clinical trials despite accounting for most of the disease burden. Geriatric assessment (GA) could be used in clinical trials of cancer drugs for older adults to improve the clinical evidence for cancer drug use among older adults.To examine patterns of use of GA in cancer clinical trials.We undertook a systematic review of the studies reporting use of GA in a clinical trial setting for all cancer types and published between January 2010 and January 2020. Characteristics of GA use were extracted for each study, along with study phase, cancer type, and participant age (PROSPERO: CRD42020170584).We identified 320 studies and 63 studies met the final inclusion criteria. Among 74 purposes of GA use, the most common was to examine the association between impairments in GA domains and clinical outcomes (28/74, 38%). Among 258 GA domains assessed across 63 studies, physical status (59/258, 23%) and comorbidities (50/258, 19%) were most often evaluated. There was significant heterogeneity in the instruments used to assess physical function (n = 16) and mood disorders (n = 7). Most studies were phase 2 (32/63, 51%).GA is most often used in clinical trial settings to examine associations between GA-identified deficits and clinical outcomes. Significant heterogeneity exists in the GA instruments used across trials. Comprehensive and consistent incorporation of GA into future cancer clinical trial designs could help collect more older adult-specific clinical information and adjust trial eligibility criteria to increase representation by older adults.

Benzodiazepines have proven to be highly effective for treating insomnia and anxiety. Although considered safe when taken for a short period of time, a major risk-benefit dilemma arises in the context of long-term use, relating to addiction, withdrawal symptoms, and potential side effects. For these reasons, benzodiazepines are not recommended for treating chronic sleep disorders, anxiety disorders, nor for people over the age of 65, and withdrawal among long-term users is a public health issue. Indeed, only 5% of patients manage to discontinue using these drugs on their own. Even with the help of a general practitioner, this rate does not exceed 25 to 30% of patients, of which approximately 7% manage to remain drug-free in the long term. Cognitive Behavioral Therapies (CBT) offer a crucial solution to this problem, having been shown to increase abstinence success to 70-80%. This article examines traditional and novel CBT techniques in this regard, such as Acceptance and Commitment Therapy, which address both the underlying condition (insomnia/anxiety) and the substance-related disorder. The theoretical framework and evidence supporting the use of these approaches are reviewed. Finally, current research gaps are discussed, and key research perspectives are proposed.

As coronavirus disease spreads throughout the United States, policymakers are contemplating reinstatement and relaxation of shelter-in-place orders. By using a model capturing high-risk populations and transmission rates estimated from hospitalization data, we found that postponing relaxation will only delay future disease waves. Cocooning vulnerable populations can prevent overwhelming medical surges.

Natural killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αβ T cell receptors (TCR) and recognize α-galactosylceramides. However, CD1d also presents structurally distinct lipids to NKT cells expressing diverse TCRs (type II NKT cells), but our knowledge of the antigens for type II NKT cells is limited. An early study identified a nonlipidic NKT cell agonist, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), which is notable for its similarity to common sulfa drugs, but its mechanism of NKT cell activation remained unknown. Here, we demonstrate that a range of pentamethylbenzofuransulfonates (PBFs), including PPBF, activate polyclonal type II NKT cells from human donors. Whereas these sulfa drug–like molecules might have acted pharmacologically on cells, here we demonstrate direct contact between TCRs and PBF-treated CD1d complexes. Further, PBF-treated CD1d tetramers identified type II NKT cell populations expressing αβTCRs and γδTCRs, including those with variable and joining region gene usage (TRAV12-1–TRAJ6) that was conserved across donors. By trapping a CD1d–type II NKT TCR complex for direct mass-spectrometric analysis, we detected molecules that allow the binding of CD1d to TCRs, finding that both selected PBF family members and short-chain sphingomyelin lipids are present in these complexes. Furthermore, the combination of PPBF and short-chain sphingomyelin enhances CD1d tetramer staining of PPBF-reactive T cell lines over either molecule alone. This study demonstrates that nonlipidic small molecules, which resemble sulfa drugs implicated in systemic hypersensitivity and drug allergy reactions, are targeted by a polyclonal population of type II NKT cells in a CD1d-restricted manner.

Objective Obesity is a strong and independent factor for the development of atrial fibrillation (AF), and adversely impacts the success of catheter ablation procedures for AF. This study evaluated the impact of body mass index (BMI) on the outcomes following surgical ablation of AF. Methods Between 2003 and 2019, 236 patients underwent a stand-alone biatrial Cox maze IV procedure (CMP-IV) for refractory AF. Obesity was defined as BMI ≥30 kg/m2. Patients were divided into two groups: BMI 2 ( n = 100) and BMI ≥30 kg/m2 ( n = 136). Freedom from atrial tachyarrhythmia (ATA) was determined using electrocardiography, Holter, or pacemaker interrogation at 1 year and annually thereafter. Recurrence was defined as any documented ATA lasting ≥30 s. Predictors of recurrence were determined using multivariable logistic regression. Preoperative and procedural outcomes were compared between groups. Results Obese patients had a higher rate of diabetes (16% vs 7%, P = 0.044) and larger left atrial diameter (4.9 ± 1.1 cm vs 4.6 ± 1.0 cm, P = 0.021) when compared to non-obese patients. There was no difference in major complication rate between the groups (4% vs 7%, P = 0.389). There was no operative mortality in either group. During 4.1 ± 2.4 years of follow-up, there was no significant difference in freedom from ATA with or without antiarrhythmic drugs in obese patients when compared to the non-obese group ( P > 0.05). Absence of sinus rhythm at discharge predicted AF recurrence up to 7 years postoperatively. Conclusions As opposed to catheter ablation, obesity did not adversely impact the short and long-term outcomes of stand-alone surgical ablation with CMP-IV, and BMI was not a predictor of AF recurrence. Additionally, there was no significant increase in major complications in obese patients.

The surgical treatment of atrial fibrillation has evolved over the past 2 decades due to the advent of ablation technology, and the introduction of less invasive surgical approaches. Current devices produce ablation lines that aim to replace the incisions of traditional surgical ablation strategies, such as the Cox-Maze procedure. This has helped to simplify and shorten surgical ablation procedures and has allowed for the development of minimally invasive surgical techniques. This review discusses surgical ablation energy sources and devices, providing background on device characteristics, mechanism of tissue injury, and success in creating transmural lesions.

Spencer J Keene,1–3 Rachel E Jordan,1 Frits ME Franssen,3,4 Frank de Vries,2,5 James Martin,1 Alice Sitch,1,6 Alice Margaret Turner,1 Andrew P Dickens,1 David Fitzmaurice,7 Peymane Adab1 1Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; 2Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Center+, Maastricht, the Netherlands; 3Ciro, Horn, the Netherlands; 4Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands; 5Utrecht Institute for Pharmaceutical Sciences Utrecht University, Utrecht, The Netherlands; 6NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK; 7Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UKCorrespondence: Rachel E JordanInstitute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UKTel +44 0121 414 6775Email r.e.jordan@bham.ac.ukBackground: Reviews suggest that the ADO score is the most discriminatory prognostic score for predicting mortality among chronic obstructive pulmonary disease (COPD) patients, but a full evaluation and external validation within primary care settings is critical before implementation.Objectives: To validate the ADO score in prevalent and screen-detected primary care COPD cases at 3 years and at shorter time periods.Patients and methods: One thousand eight hundred and ninety-two COPD cases were recruited between 2012 and 2014 from 71 United Kingdom general practices as part of the Birmingham COPD Cohort study. Cases were either on the practice COPD register or screen-detected. We validated the ADO score for predicting 3-year mortality with 1-year and 2-year mortality as secondary endpoints using discrimination (area-under-the-curve (AUC)) and calibration plots.Results: One hundred and fifty-four deaths occurred within 3 years. The ADO score was discriminatory for predicting 3-year mortality (AUC= 0.74; 95% CI: 0.69–0.79). Similar performance was foundfor 1- (AUC= 0.73; 0.66–0.80) and 2-year mortality (0.72; 0.67–0.76). The ADO score showed reasonable calibration for predicting 3-year mortality (calibration slope 0.95; 0.70–1.19) but over-predicted in cases with higher predicted risks of mortality at 1 (0.79; 0.45–1.13) and 2-year (0.79; 0.57–1.01) mortality.Discussion: The ADO score showed promising discrimination in predicting 3-year mortality in a primary care population including screen-detected cases. It may need to be recalibrated if it is used to provide risk predictions for 1- or 2-year mortality since, in these time-periods, over-prediction was evident, especially in cases with higher predicted mortality risks.Keywords: pulmonary disease, chronic obstructive, mortality, prognosis, validation studies

Background Inappropriate sinus tachycardia (IST) is a rare clinical disorder characterized by an elevated resting heart rate and an exaggerated rate response to exercise or autonomic stress. Pharmacologic therapy and catheter ablation are considered first-line treatments for IST but can yield suboptimal relief of symptoms. The results of surgical ablation at our center were reviewed for patients with refractory IST. Methods Between 1987 and 2018, 18 patients underwent surgical sinoatrial (SA) node isolation for treatment-refractory IST. All 18 patients had previously failed pharmacologic therapy, and 15 patients had failed catheter ablation of the SA node. Results Ten patients underwent a median sternotomy, and 8 patients underwent a minimally invasive right thoracotomy. The SA node was isolated with the use of surgical incisions, cryoablation, or bipolar radiofrequency ablations. Sinus tachycardia was eliminated in 100% of patients in the immediate postoperative period. Long-term follow-up data were available for 17 patients, with a mean follow-up of 11.4 ± 7.9 years. At last follow-up, 100% of patients were free from recurrent symptomatic IST. More than 80% of patients were completely asymptomatic, whereas 3 patients reported occasional palpitations. Four patients were on β-blockers, and 5 patients required subsequent pacemaker implantation. All 8 patients who underwent minimally invasive isolation were in normal sinus rhythm at last follow-up, and only 1 patient complained of palpitations. Conclusions Surgical isolation of the SA node is a feasible treatment for IST refractory to pharmacologic therapy and catheter ablation. A minimally invasive surgical approach offers a less morbid alternative to traditional median sternotomy.

Giardiasis is a common gastrointestinal disease of humans and various animal species worldwide. In this study, 302 stool samples were collected from West African Dwarf and Sokoto Red breeds of goats in Ogun State, Nigeria, and screened for Giardia intestinalis coproantigens using enzyme-linked immunosorbent assay (ELISA). The genotypes of G. intestinalis in faecal samples collected from 152 goats raised on selected farms were identified by polymerase chain reaction (PCR) amplification and sequence analyses of the small subunit ribosomal RNA (ssu rRNA), glutamate dehydrogenase (gdh), triosephosphate isomerase (tpi) and β-giardin (bg) genes. Based on ELISA, an overall prevalence of 45.7% was recorded with the infection rates in pre-weaned (60.2%) and post-weaned goat kids (51.5%) being significantly (p 0.05) higher than in adults (28.2%). Giardia intestinalis DNA was amplified in 31.6% and 29.6% of goat faeces at the ssu rRNA and gdh loci respectively. These were genotyped at the ssu rRNA locus as assemblages B (n = 13) and E (n = 36). Similar results were observed at the gdh locus except that eight isolates contained assemblage E mixed with either assemblage A or B. Additionally, sub-assemblages BI (n = 7) and BIII (n = 2) were identified with up to four single nucleotide polymorphisms (SNPs) occurring in these isolates. Multilocus genotypes (MLG) of all assemblage E isolates were identified using the ssu rRNA and gdh loci while MLG of all isolates containing assemblage B and mixed assemblages were determined after further typing at the tpi and bg loci. Forty-two MLG isolates were identified and these comprised 32, 8 and 2 (sub)-assemblage E, BI and BIII respectively. All isolates with mixed assemblages at the gdh locus were consequently designated as assemblage E by MLG. The assemblage E isolates from goats were genetically related to isolates from cattle, sheep and goats while the assemblage B isolates were related to isolates of human, pig and lemur origin. This suggests that G. intestinalis isolated from goats bred in Ogun State, Nigeria may be capable of cross-species transmission and may be of zoonotic importance.

Significance Accurate prediction of the size and timing of infectious disease outbreaks could help public health officials in planning an appropriate response. This paper compares approaches developed by five different research groups to forecast seasonal influenza outbreaks in real time in the United States. Many of the models show more accurate forecasts than a historical baseline. A major impediment to predictive ability was the real-time accuracy of available data. The field of infectious disease forecasting is in its infancy and we expect that innovation will spur improvements in forecasting in the coming years., Influenza infects an estimated 9–35 million individuals each year in the United States and is a contributing cause for between 12,000 and 56,000 deaths annually. Seasonal outbreaks of influenza are common in temperate regions of the world, with highest incidence typically occurring in colder and drier months of the year. Real-time forecasts of influenza transmission can inform public health response to outbreaks. We present the results of a multiinstitution collaborative effort to standardize the collection and evaluation of forecasting models for influenza in the United States for the 2010/2011 through 2016/2017 influenza seasons. For these seven seasons, we assembled weekly real-time forecasts of seven targets of public health interest from 22 different models. We compared forecast accuracy of each model relative to a historical baseline seasonal average. Across all regions of the United States, over half of the models showed consistently better performance than the historical baseline when forecasting incidence of influenza-like illness 1 wk, 2 wk, and 3 wk ahead of available data and when forecasting the timing and magnitude of the seasonal peak. In some regions, delays in data reporting were strongly and negatively associated with forecast accuracy. More timely reporting and an improved overall accessibility to novel and traditional data sources are needed to improve forecasting accuracy and its integration with real-time public health decision making.

Background Travellers’ diarrhoea (TD) is the most common clinical syndrome affecting travellers. This narrative review summarizes key discoveries reported in the last two years related to TD and suggests areas for future research. Methods A PubMed literature search was conducted for novel data in TD research published between 12 January 2018 and 12 January 2020. Inclusion was based on contribution to epidemiology, aetiology, diagnostics, management and long-term consequences and relevance to public health, discovery and clinical practice. Results The initial literature search yielded 118 articles. We retrieved 72 and reviewed 31 articles for inclusion. The findings support our understanding that TD incidence varies by traveller group and environment with students and military-travel remaining moderately high risk, and control of food and water in mass gathering events remain an important goal. The growth of culture-independent testing has led to a continued detection of previously known pathogens, but also an increased detection frequency of norovirus. Another consequence is the increase in multi-pathogen infections, which require consideration of clinical, epidemiological and diagnostic data. Fluoroquinolone resistant rates continue to rise. New data on non-absorbable antibiotics continue to emerge, offering a potential alternative to current recommendations (azithromycin and fluoroquinolones), but are not recommended for febrile diarrhoea or dysentery or regions/itineraries where invasive pathogens are likely to cause illness. Recent studies investigated the interaction of the microbiome in TD prevention and consequences, and while discriminating features were identified, much uncertainty remains. The prevalence of extended-spectrum beta-lactamase–producing Enterobacteriaceae (ESBL-PE) acquisition and carriage is increasing. Finally, continued research documents the post-infectious consequences, whereas mechanisms of reactive arthritis and post-infectious IBS necessitate further investigation. Conclusions Globally, TD remains an important travel health issue and advances in our understanding continue. More research is needed to mitigate risk factors where possible and develop risk-based management strategies to reduce antibiotic usage and its attendant consequences.

INTRODUCTION: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and results in significant morbidity and mortality. The Cox-Maze IV procedure (CMP-IV) has been shown to have excellent efficacy in returning patients to sinus rhythm, but there have been few reports of late follow-up in sizable cohorts of patients with longstanding persistent AF, the most difficult type of AF to treat. METHODS AND RESULTS: Between May 2003 and March 2020, 174 consecutive patients underwent a stand-alone CMP-IV for longstanding persistent AF. Rhythm outcome was assessed postoperatively for up to 10 years, primarily via prolonged monitoring (Holter monitor, pacemaker interrogation, or implantable loop recorder). Fine-Gray regression was used to investigate factors associated with atrial tachyarrhythmia (ATA) recurrence, with death as a competing risk. Median duration of preoperative AF was 7.8 years (interquartile range: 4.0–12.0 years), with 71% (124/174) having failed at least one prior catheter-based ablation. There were no 30-day mortalities. Freedom from ATAs was 94% (120/128), 83% (53/64), and 88% (35/40) at 1, 5, and 7 years, respectively. On regression analysis, preoperative AF duration and early postoperative ATAs were associated with late ATAs recurrence. CONCLUSION: Despite the majority of patients having a long-duration of preoperative AF and having failed at least one catheter-based ablation, the stand-alone CMP-IV had excellent late efficacy in patients with longstanding persistent AF, with low morbidity and no mortality. We recommend consideration of stand-alone CMP-IV for patients with longstanding persistent AF who have failed or are poor candidates for catheter ablation.

Nearly two months after a near-death car accident, I am in the passenger seat of my younger brother’s car. Two of our friends sit in the back. A crisp December day, we are heading to the local mall...

Food and waterborne protozoan pathogens including Cryptosporidium parvum, Giardia enterica and Toxoplasma gondii are a global concern for human public health. While all three pathogens have been detected in commercial shellfish, there is currently no standard approach for detecting protozoan parasites in shellfish. Common molecular and microscopic methods are limited in the number of pathogens they can simultaneously detect and are often targeted at one or two of these pathogens. Previously, we developed and validated a novel 18S amplicon-based next-generation sequencing assay for simultaneous detection of Cryptosporidium spp., Giardia spp. and T. gondii in shellfish. In this study, we applied the assay for protozoan pathogen detection in wild oysters from Prince Edward Island (PEI). Oysters were harvested from restricted and prohibited areas, classified by the Canadian government according to fecal coliform counts in surrounding waters, and different fractions (whole tissue homogenate and hemolymph) were analyzed. Protozoan DNA was detected using metabarcoding in 28%, of oysters tested (N = 128), and the pathogen read counts in oyster homogenate were considerably higher than those in hemolymph. Protozoan read count thresholds were established for classifying probable oyster contamination with pathogens to account for low levels of background protozoan reads detected in negative controls. Assay results showed protozoan contamination was not associated with harvesting site classifications, suggesting that using fecal indicators for ensuring food safety may be insufficient. Due to the complex matrix, an oyster DNA reduction step may further improve the pathogen detection sensitivity of the assay. Results from this study affirm that novel metabarcoding is a promising screening tool for detection of protozoan pathogens in shellfish.

In patients with hypertrophic obstructive cardiomyopathy, atrial fibrillation is associated with heart failure and increased late mortality. However, the role of surgical ablation in these patients is not well defined. The aim of this study was to evaluate the efficacy of the concomitant Cox-Maze IV procedure in patients undergoing septal myectomy for hypertrophic obstructive cardiomyopathy.Between 2005 and 2019, 347 patients who underwent septal myectomy at a single institution (Washington University School of Medicine, Barnes-Jewish Hospital, St Louis, MO) were retrospectively reviewed. For patients with hypertrophic obstructive cardiomyopathy and atrial fibrillation who underwent a concomitant Cox-Maze IV procedure, freedom from atrial tachyarrhythmias (ATAs) on or off antiarrhythmic drugs (AADs) was evaluated annually. Predictors of ATA recurrence were identified using Fine-Gray regression, with death as a competing risk.A total of 42 patients underwent concomitant septal myectomy and Cox-Maze IV procedures. The majority of patients, 69% (29 of 42), had paroxysmal atrial fibrillation with a 2.5-year median duration. Operative mortality was 7% (3 of 42). New York Heart Association functional class was reduced after surgery (P.01). Rates of freedom from recurrent ATAs at 1- and 5-year intervals were 93% (27 of 29) and 100% (14 of 14), respectively. Rates of freedom from ATAs and AADs were 83% (24 of 29) and 100% (14 of 14) at the same time points, respectively. Increased left atrial diameter predicted first ATA recurrence (P.01). Cerebrovascular accident risk was lower in patients with atrial fibrillation who underwent concomitant Cox-Maze IV and septal myectomy relative to myectomy only (P = .02).Late freedom from ATAs on or off AADs was excellent after Cox-Maze IV and septal myectomy. Although there was a higher than expected rate of perioperative complications, the study results suggest that concomitant surgical ablation should be considered in selected patients with hypertrophic obstructive cardiomyopathy and atrial fibrillation.

We report proof-of-principle experiments regarding a dynamic microarray protocol enabling accurate and semi-quantitative DNA analysis for re-sequencing, fingerprinting and genotyping. Single-stranded target molecules hybridise to surface-bound probes during initial gradual cooling with high-fidelity. Real-time tracking of target denaturation (via fluorescence) during a 'dynamic' gradual heating phase permits 'melt-curve' analysis. The probe most closely matching the target sequence is identified based on the highest melting temperature. We demonstrated a >99% re-sequencing accuracy and a potential detection rate of 1% for SNPs. Experiments employing Hypericum ribosomal ITS regions and HIV genomes illustrated a reliable detection level of 5% plus simultaneous re-sequencing and genotyping. Such performance suggests a range of potential real-world applications involving rapid sequence interrogation, for example, in the Covid-19 pandemic. Guidance is offered towards the development of a commercial platform and dedicated software required to bring this technique into mainstream science.

BackgroundPeriprosthetic infection is a major cause of failure after segmental endoprosthetic reconstruction. The purpose of this study is to determine whether certain aspects of drain output affect infection risk, particularly the 30 mL/day criterion for removal.MethodsTwo hundred and ninety-five patients underwent segmental bone resection and lower limb endoprosthetic reconstruction at one institution. Data on surgical drain management and occurrence of infection were obtained from a retrospective review of patients’ charts and radiographs. Univariate and multivariate Cox regression analyses were performed to identify factors associated with infection.ResultsThirty-one of 295 patients (10.5%) developed infection at a median time of 13 months (range 1–108 months).Staphylococcus aureuswas the most common organism and was responsible for the majority of cases developing within 1 year of surgery. Mean output at the time of drain removal was 72 mL/day. Ten of 88 patients (11.3%) with ≤ 30 mL/day drainage and 21 of 207 patients (10.1%) with > 30 mL/day drainage developed infection (p= 0.84). In multivariate analysis, independent predictive factors for infection included sarcoma diagnosis (HR 4.13, 95% CI 1.4–12.2,p= 0.01) and preoperative chemotherapy (HR 3.29, 95% CI 1.1–9.6,p= 0.03).ConclusionWaiting until drain output is < 30 mL/day before drain removal is not associated with decreased risk of infection for segmental endoprostheses of the lower limb after tumor resection. Sarcoma diagnosis and preoperative chemotherapy were independent predictors of infection.

Alignment of arterial endothelial cells with the mean wall shear stress (WSS) vector is the prototypical example of their responsiveness to flow. However, evidence for this behaviour rests on experiments where many WSS metrics had the same orientation or where they were incompletely characterised. In the present study, we tested the phenomenon more rigorously. Aortic endothelial cells were cultured in cylindrical wells on the platform of an orbital shaker. In this system, orientation would differ depending on the WSS metric to which the cells aligned. Variation in flow features and hence in possible orientations was further enhanced by altering the viscosity of the medium. Orientation of endothelial nuclei was compared to WSS characteristics obtained by computational fluid dynamics. At low mean WSS magnitudes, endothelial cells aligned with the modal WSS vector whilst at high mean WSS magnitudes they aligned so as to minimise the shear acting across their long axis (“transverse WSS”). Their failure to align with the mean WSS vector implies that other aspects of endothelial behaviour attributed to this metric require re-examination. The evolution of a mechanism for minimising transverse WSS is consistent with it having detrimental effects on the cells and with its putative role in atherogenesis.

As COVID-19 spreads across the United States, people experiencing homelessness (PEH) are among the most vulnerable to the virus. To mitigate transmission, municipal governments are procuring isolation facilities for PEH to utilize following possible exposure to the virus. Here we describe the framework for anticipating isolation bed demand in PEH communities that we developed to support public health planning in Austin, Texas during March 2020. Using a mathematical model of COVID-19 transmission, we projected that, under no social distancing orders, a maximum of 299 (95% Confidence Interval: 223, 321) PEH may require isolation rooms in the same week. Based on these analyses, Austin Public Health finalized a lease agreement for 205 isolation rooms on March 27th 2020. As of October 7th 2020, a maximum of 130 rooms have been used on a single day, and a total of 602 PEH have used the facility. As a general rule of thumb, we expect the peak proportion of the PEH population that will require isolation to be roughly triple the projected peak daily incidence in the city. This framework can guide the provisioning of COVID-19 isolation and post-acute care facilities for high risk communities throughout the United States.

IntroductionDelirium is a potentially preventable disorder characterised by acute disturbances in attention and cognition with fluctuating severity. Postoperative delirium is associated with prolonged intensive care unit and hospital stay, cognitive decline and mortality. The development of biomarkers for tracking delirium could potentially aid in the early detection, mitigation and assessment of response to interventions. Because sleep disruption has been posited as a contributor to the development of this syndrome, expression of abnormal electroencephalography (EEG) patterns during sleep and wakefulness may be informative. Here we hypothesise that abnormal EEG patterns of sleep and wakefulness may serve as predictive and diagnostic markers for postoperative delirium. Such abnormal EEG patterns would mechanistically link disrupted thalamocortical connectivity to this important clinical syndrome.Methods and analysisP-DROWS-E (Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography) is a 220-patient prospective observational study. Patient eligibility criteria include those who are English-speaking, age 60 years or older and undergoing elective cardiac surgery requiring cardiopulmonary bypass. EEG acquisition will occur 1–2 nights preoperatively, intraoperatively, and up to 7 days postoperatively. Concurrent with EEG recordings, two times per day postoperative Confusion Assessment Method (CAM) evaluations will quantify the presence and severity of delirium. EEG slow wave activity, sleep spindle density and peak frequency of the posterior dominant rhythm will be quantified. Linear mixed-effects models will be used to evaluate the relationships between delirium severity/duration and EEG measures as a function of time.Ethics and disseminationP-DROWS-E is approved by the ethics board at Washington University in St. Louis. Recruitment began in October 2018. Dissemination plans include presentations at scientific conferences, scientific publications and mass media.Trial registration numberNCT03291626.

Key Points Question Is construction work associated with increased community transmission of coronavirus disease 2019 (COVID-19) and disproportionate morbidity among construction workers in US cities? Findings This decision analytical model of COVID-19 found that resuming construction work during shelter-in-place orders was associated with increased hospitalization risks in the construction workforce and increase transmission in the surrounding community. Based on COVID-19 hospitalization data through August 20, 2020, construction workers had a nearly 5-fold increased risk of hospitalization in central Texas compared with other occupational categories. Meaning The findings of this study suggest that enacting workplace safety policies and providing paid sick leave could protect essential workers in high-contact industries and prevent further widening of disparities in COVID-19 morbidity and mortality., This decision analytical model assesses the association between construction work during the coronavirus disease 2019 (COVID-19) pandemic and hospitalization rates for construction workers and the surrounding community., Importance Policy makers have relaxed restrictions for certain nonessential industries, including construction, jeopardizing the effectiveness of social distancing measures and putting already at-risk populations at greater risk of coronavirus disease 2019 (COVID-19) infection. In Texas, Latinx populations are overly represented among construction workers, and thus have elevated rates of exposure that are compounded by prevalent high-risk comorbidities and lack of access to health care. Objective To assess the association between construction work during the COVID-19 pandemic and hospitalization rates for construction workers and the surrounding community. Design, Setting, and Participants This decision analytical model used a mathematical model of COVID-19 transmission, stratified by age and risk group, with construction workers modeled explicitly. The model was based on residents of the Austin–Round Rock metropolitan statistical area, with a population of 2.17 million. Based on 500 stochastic simulations for each of 15 scenarios that varied the size of the construction workforce and level of worksite transmission risk, the association between continued construction work and hospitalizations was estimated and then compared with anonymized line-list hospitalization data from central Texas through August 20, 2020. Exposures Social distancing interventions, size of construction workforce, and level of disease transmission at construction worksites. Main Outcomes and Measures For each scenario, the total number of COVID-19 hospitalizations and the relative risk of hospitalization among construction workers was projected and then compared with relative risks estimated from reported hospitalization data. Results Allowing unrestricted construction work was associated with an increase of COVID-19 hospitalization rates through mid-August 2020 from 0.38 per 1000 residents to 1.5 per 1000 residents and from 0.22 per 1000 construction workers to 9.3 per 1000 construction workers. This increased risk was estimated to be offset by safety measures (such as thorough cleaning of equipment between uses, wearing of protective equipment, limits on the number of workers at a worksite, and increased health surveillance) that were associated with a 50% decrease in transmission. The observed relative risk of hospitalization among construction workers compared with other occupational categories among adults aged 18 to 64 years was 4.9 (95% CI, 3.8-6.2). Conclusions and Relevance The findings of this study suggest that unrestricted work in high-contact industries, such as construction, is associated with a higher level of community transmission, increased risks to at-risk workers, and larger health disparities among members of racial and ethnic minority groups.

Central blood pressure (cBP) is a highly prognostic cardiovascular (CV) risk factor whose accurate, invasive assessment is costly and carries risks to patients. We developed and assessed novel algorithms for estimating cBP from noninvasive aortic hemodynamic data and a peripheral blood pressure measurement. These algorithms were created using three blood flow models: the two- and three-element Windkessel (0-D) models and a one-dimensional (1-D) model of the thoracic aorta. We tested new and existing methods for estimating CV parameters (left ventricular ejection time, outflow BP, arterial resistance and compliance, pulse wave velocity, and characteristic impedance) required for the cBP algorithms, using virtual (simulated) subjects (n = 19,646) for which reference CV parameters were known exactly. We then tested the cBP algorithms using virtual subjects (n = 4,064), for which reference cBP were available free of measurement error, and clinical datasets containing invasive (n = 10) and noninvasive (n = 171) reference cBP waves across a wide range of CV conditions. The 1-D algorithm outperformed the 0-D algorithms when the aortic vascular geometry was available, achieving central systolic blood pressure (cSBP) errors ≤ 2.1 ± 9.7 mmHg and root-mean-square errors (RMSEs) ≤ 6.4 ± 2.8 mmHg against invasive reference cBP waves (n = 10). When the aortic geometry was unavailable, the three-element 0-D algorithm achieved cSBP errors ≤ 6.0 ± 4.7 mmHg and RMSEs ≤ 5.9 ± 2.4 mmHg against noninvasive reference cBP waves (n = 171), outperforming the two-element 0-D algorithm. All CV parameters were estimated with mean percentage errors ≤ 8.2%, except for the aortic characteristic impedance (≤13.4%), which affected the three-element 0-D algorithm’s performance. The freely available algorithms developed in this work enable fast and accurate calculation of the cBP wave and CV parameters in datasets containing noninvasive ultrasound or magnetic resonance imaging data. NEW & NOTEWORTHY First, our proposed methods for CV parameter estimation and a comprehensive set of methods from the literature were tested using in silico and clinical datasets. Second, optimized algorithms for estimating cBP from aortic flow were developed and tested for a wide range of cBP morphologies, including catheter cBP data. Third, a dataset of simulated cBP waves was created using a three-element Windkessel model. Fourth, the Windkessel model dataset and optimized algorithms are freely available., This work was supported by a PhD Fellowship awarded by the King’s College London and Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging [EP/L015226/1], the British Heart Foundation (BHF) [PG/15/104/31913], and the Wellcome EPSRC Centre for Medical Engineering at King’s College London [WT 203148/Z/16/Z]. The authors acknowledge financial support from the Department of Health through the National Institute for Health Research (NIHR) Cardiovascular MedTech Co-operative at Guy’s and St Thomas’ NHS Foundation Trust (GSTT).