A Proteome-wide Fission Yeast Interactome Reveals Network Evolution Principles from Yeasts to Human.

Here, we present FissionNet, a proteome-wide binary protein interactome for S. pombe, comprising 2,278 high-quality interactions, of which ∼ 50% were previously not reported in any species. FissionNet unravels previously unreported interactions implicated in processes such as gene silencing and pre-mRNA splicing. We developed a rigorous network comparison framework that accounts for assay sensitivity and specificity, revealing extensive species-specific network rewiring between fission yeast, budding yeast, and human. Surprisingly, although genes are better conserved between the yeasts, S. pombe interactions are significantly better conserved in human than in S. cerevisiae. Our framework also reveals that different modes of gene duplication influence the extent to which paralogous proteins are functionally repurposed. Finally, cross-species interactome mapping demonstrates that coevolution of interacting proteins is remarkably prevalent, a result with important implications for studying human disease in model organisms. Overall, FissionNet is a valuable resource for understanding protein functions and their evolution.

Reassuring pregnancy outcomes in women with mild COL4A3-5-related disease (Alport syndrome) and genetic type of disease can aid personalized counseling.

Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.

User-Centered Design of a Preference-Driven Patient Activation Tool for Optimizing Depression Treatment in Integrated Primary Care Settings (The Transform DepCare Study).

BACKGROUND: Few patient engagement tools incorporate the complex patient experiences, contexts, and workflows that limit depression treatment implementation. OBJECTIVE: Describe a user-centered design (UCD) process for operationalizing a preference-driven patient activation tool. DESIGN: Informed by UCD and behavior change/implementation science principles, we designed a preference-driven patient activation prototype for engaging patients in depression treatment. We conducted three usability cycles using different recruitment/implementation approaches: near live/live testing in primary care waiting rooms (V1-2) and lab-based think aloud testing (V3) oversampling older, low-literacy, and Spanish-speaking patients in the community and via EHR algorithms. We elicited clinician and "heuristic" expert input. MAIN MEASURES: We administered the system usability scale (SUS) all three cycles and pre-post V3, the patient activation measure, decisional conflict scale, and depression treatment barriers. We employed descriptive statistics and thematically analyzed observer notes and transcripts for usability constructs. RESULTS: Overall, 43 patients, 3 clinicians, and 5 heuristic (a usability engineering method for identifying usability problems) experts participated. Among patients, 41.9% were ≥ 65 years old, 79.1% female, 23.3% Black, 62.8% Hispanic, and 55.8% Spanish-speaking and 46.5% had ≤ high school education. We described V1-3 usability (67.2, 77.3, 81.8), treatment seeking (92.3%, 87.5%, 92.9%), likelihood/comfort discussing with clinician (76.9%, 87.5%, 100.0%), and pre vs. post decisional conflict (23.7 vs. 15.2), treatment awareness (71.4% vs. 92.9%), interest in antidepressants (7.1% vs. 14.3%), and patient activation (66.8 vs. 70.9), with fewer barriers pertaining to cost/insurance, access/coordination, and self-efficacy/stigma/treatment efficacy. Key themes included digital literacy, understandability, high acceptability for aesthetics, high usefulness of patient/clinician videos, and workflow limitations. We adapted manual entry/visibility/content; added patient activation and a personalized algorithm; and proposed flexible, care manager delivery leveraging clinic screening protocols. DISCUSSION: We provide an example of leveraging UCD to design/adapt a real-world, patient experience and workflow-aligned patient activation tool in diverse populations.

Characterizing the impact of thermoregulation in patients after cardiac arrest: a retrospective cohort study.

PURPOSE: Core body temperature has been extensively investigated as a thereuptic target in care after cardiac arrest. Nevertheless, the integrity of thermoregulation in patients after cardiac arrest has not been well studied. We sought to evaluate whether low spontaneous body temperature after cardiac arrest is associated with increased death and a worse neurologic outcome, and whether patients with low spontaneous body temperature exhibit features suggestive of impaired thermoregulation. METHODS: We conducted a single-centre retrospective cohort study. We included all adult patients who underwent temperature control with hypothermia after cardiac arrest between 1 January 2014 and 30 June 2020. The primary exposure was low spontaneous core body temperature (< 35 °C) at initiation of hypothermia therapy. The primary outcome was in-hospital death and the secondary outcome was poor neurologic outcomes at discharge. RESULTS: Five hundred and ninety-seven adult patients, comprising both in- and out-of-hospital cardiac arrests, were included. Patients with low spontaneous body temperature also had slightly lower average temperature, and more frequent transient but controlled breakthrough fever episodes in the first 24 hr. In the multivariable logistic regression analysis, low spontaneous body temperature was associated with higher odds of in-hospital death (odds ratio, 2.9; 95% confidence interval, 1.9 to 4.2; P < 0.001). CONCLUSION: In this single-centre retrospective cohort study, low spontaneous core body temperature was associated with poor outcomes in patients after cardiac arrest. Patients with low spontaneous body temperature also exhibited features suggestive of impaired thermoregulation. Further research is needed to determine whether body temperature upon presentation reflects the robustness of the patient's underlying physiology and severity of brain insult after a cardiac arrest.

RéSUMé: OBJECTIF: La température corporelle centrale a fait l'objet d'études approfondies en tant que cible thérapeutique dans les soins après un arrêt cardiaque. Néanmoins, l'intégrité de la thermorégulation après un arrêt cardiaque n'a pas été bien étudiée. Nous avons cherché à évaluer si une température corporelle spontanément basse après un arrêt cardiaque était associée à une augmentation de la mortalité et à une issue neurologique plus grave, et si les individus ayant une température corporelle spontanément basse présentaient des caractéristiques suggérant une altération de la thermorégulation. MéTHODE: Nous avons mené une étude de cohorte rétrospective monocentrique. Nous avons inclus tou·tes les patient·es adultes ayant bénéficié d'un contrôle de température lors d'une hypothermie après un arrêt cardiaque entre le 1er janvier 2014 et le 30 juin 2020. L'exposition principale était une température corporelle centrale spontanément basse (< 35 °C) au début du traitement de l'hypothermie. Le critère d'évaluation principal était le décès à l'hôpital, et le critère d'évaluation secondaire était de mauvaises issues neurologiques à la sortie de l'hôpital. RéSULTATS: Cinq cent quatre-vingt-dix-sept patient·es adultes, ayant subi des arrêts cardiaques à l'hôpital ou hors de l'hôpital, ont été inclus·es. Les patient·es ayant une température corporelle spontanément basse avaient également une température moyenne légèrement plus basse et des épisodes de fièvre paroxystique transitoires mais contrôlés plus fréquents au cours des premières 24 heures. Dans l'analyse de régression logistique multivariée, une température corporelle spontanément basse était associée à une probabilité plus élevée de décès à l'hôpital (rapport de cotes, 2,9; intervalle de confiance à 95 %, 1,9 à 4,2; P < 0,001). CONCLUSION: Dans cette étude de cohorte rétrospective monocentrique, une température corporelle centrale spontanément basse a été associée à de mauvais devenirs après un arrêt cardiaque. Les patient·es présentant une température corporelle spontanément basse présentaient également des caractéristiques suggérant une altération de la thermorégulation. D'autres recherches sont nécessaires pour déterminer si la température corporelle lors de la présentation reflète la robustesse de la physiologie sous-jacente des patient·es et la gravité de la lésion cérébrale après un arrêt cardiaque.

A systematic review of psychosocial interventions for people with intellectual disabilities and dementia.

OBJECTIVES: As the life expectancy of individuals with intellectual disabilities (ID) continues to increase, there is an increased risk of developing dementia. While psychosocial interventions are gaining prominence, evidence is limited for people with both dementia and ID. This review discusses the effectiveness of direct psychosocial interventions and adaptations to facilitate delivery within this population. METHODS: The review followed the PRISMA guidelines. Five electronic databases, grey literature, and reference lists of included articles were searched for relevant studies. 10 eligible studies were appraised and analysed by narrative synthesis. RESULTS: Ten distinct interventions were identified and categorised based on their purpose and delivery. All interventions were beneficial in improving a range of outcomes, though some studies were of low quality and most had small samples. Common adaptations included simplification of tasks and material, higher staff-to-client ratio, and alternative communication methods. CONCLUSION: There is emerging evidence for several psychosocial interventions for people with ID and dementia, though further research is required on effectiveness and generalisability. The adaptations discussed may guide implementation into routine care and contribute to current policies and guidelines on improving ID and dementia care.

Structural stigma within inpatient care for people who inject drugs: implications for harm reduction.

BACKGROUND:  Individuals suffering with addiction have historically experienced disproportionally high levels of stigma. The process of inpatient care for those with substance abuse disorder (SUD) is multifaceted, shaped by the interplay of human interactions within the healthcare team and overarching structural factors like policy. While existing literature predominantly addresses personal and interpersonal stigma, the influence of structural stigma on care delivery practices remains understudied. Our research aims to investigate the impact of structural stigma on care processes for individuals with SUD admitted to acute medicine units. METHODS:  We conducted a secondary analysis of observation notes and interview transcripts utilizing an analytic framework related to structural stigma adapted from previous research. Data was collected from June 2019 to January 2020 in 2 hospitals. 81 participants consented to observation and 25 to interviews. Interviews were conducted with patients (n = 8), healthcare staff (n = 16), and caregivers (n = 1). RESULTS:  Each aspect of care for people with SUD is adversely influenced by structural forms of stigma. There was evidence of a gap in accessing care and time pressures which deteriorated care processes. Structural stigma also manifested in the physical spaces designed for care and the lack of adequate resources available for mental health and addictions care. We found that structural stigma perpetuated other forms of implicit and explicit stigma. CONCLUSIONS:  Structural stigma and other forms of stigma are interconnected. Improving care for people with SUD in hospital settings may require addressing structural forms of stigma such as how physical spaces are designed and how mental healthcare is integrated with physical healthcare within inpatient settings.

Factors associated with obtaining prescribed safer supply among people accessing harm reduction services: findings from a cross-sectional survey.

BACKGROUND: With growing rates of unregulated drug toxicity death and concerns regarding COVID-19 transmission among people who use drugs, in March 2020, prescribed safer supply guidance was released in British Columbia. This study describes demographic and substance use characteristics associated with obtaining prescribed safer supply and examines the association between last 6-month harm reduction service access and obtaining prescribed safer supply. METHODS: Data come from the 2021 Harm Reduction Client Survey administered at 17 harm reduction sites across British Columbia. The sample included all who self-reported use of opioids, stimulants, or benzodiazepines in the prior 3 days (N = 491), given active use of these drugs was a requirement for eligibility for prescribed safer supply. The dependent variable was obtaining a prescribed safer supply prescription (Yes vs. No). The primary independent variables were access to drug checking services and access to overdose prevention services in the last 6 months (Yes vs. No). Descriptive statistics (Chi-square tests) were used to compare the characteristics of people who did and did not obtain a prescribed safer supply prescription. Multivariable logistic regression models were run to examine the association of drug checking services and overdose prevention services access with obtaining prescribed safer supply. RESULTS: A small proportion (n = 81(16.5%)) of the sample obtained prescribed safer supply. After adjusting for gender, age, and urbanicity, people who reported drug checking services access in the last 6 months had 1.67 (95% CI 1.00-2.79) times the odds of obtaining prescribed safer supply compared to people who had not contacted these services, and people who reported last 6 months of overdose prevention services access had more than twice the odds (OR 2.08 (95% CI 1.20-3.60)) of prescribed safer supply access, compared to people who did not access these services. CONCLUSIONS: Overall, the proportion of respondents who received prescribed safer supply was low, suggesting that this intervention is not reaching all those in need. Harm reduction services may serve as a point of contact for referral to prescribed safer supply. Additional outreach strategies and service models are needed to improve the accessibility of harm reduction services and of prescribed safer supply in British Columbia.

Preliminary safety and efficacy of laser stricturotomy for treatment of refractory biliary anastomotic strictures following liver transplantation.

Biliary anastomotic stricture (BAS) is a frequent complication of liver transplantation and is associated with reduced graft survival and patient morbidity. Existing treatments for BAS involve dilation of the stricture though placement of 1 or more catheters for 6 to 24 months yielding limited effectiveness in transplant patients. In this case series, we present preliminary safety and efficacy of a novel percutaneous laser stricturotomy treatment in a cohort of 5 posttransplant patients with BAS refractory to long-term large bore catheterization. In all patients, holmium or thulium laser was used to excise the stricture and promote biliary re-epithelization. There were no periprocedural complications. Technical success was 100% and at mean follow-up time of 22 months, there have been no recurrences. In conclusion, percutaneous laser stricturotomy demonstrates preliminary safety and efficacy in treatment of refractory BAS following liver transplantation.

Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies.

BACKGROUNDS: Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. METHODS: Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. RESULTS: We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. CONCLUSIONS: These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.

Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+ /CD54+ NK cells.

Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES). In vitro, IL-15, in contrast to IL-2, enriches for CD25+ /CD54+ NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors in vitro and in vivo. Thus, strategies to enrich CD25+ /CD54+ NK cells for adoptive cell therapy should be considered.

To Use or Not to Use? Quantifying the Benefit of Microcatheter Use in Adrenal Vein Sampling.

Adrenal vein sampling is a technically difficult procedure with reported sampling success rates as low as 41%. Routine microcatheter use has been suggested by some to improve sampling adequacy. This study is a single-institution retrospective review of adrenal vein sampling procedures performed from 2014 to 2021 to quantify sample selectivity and adequacy with and without the use of a microcatheter. Microcatheter sampling was performed in 43 (47%) of 92 cases on the right adrenal gland and 44 (48%) of 92 cases on the left adrenal gland. Mean selectivity index was significantly higher bilaterally with microcatheters (right, 36.8 vs 27.7; P = .05; left, 33.9 vs 19.9 left; P < .001). However, sampling adequacy rates did not significantly differ between microcatheter and 5-F sampling bilaterally (right, 91% vs 90%; P = .88; left, 96% vs 98%; P = .51). Adrenal hemorrhage occurred exclusively with right-sided microcatheter sampling (n = 6, 13%). In conclusion, although microcatheter sampling increases mean selectivity index, it does not change sampling adequacy rate and may increase the risk of right adrenal hemorrhage.

Amphetamine-Related Emergency Department Visits in Ontario, Canada, 2003-2020.

OBJECTIVES: Despite unregulated amphetamine use increasing, there are limited data on related emergency department (ED) visits in Canada. Our primary objective was to examine trends in amphetamine-related ED visits over time in Ontario, including by age and sex. Secondary objectives were to examine whether patient characteristics were associated with ED revisit within 6 months. METHODS: Using administrative claims and census data, we calculated annual patient- and encounter-based rates of amphetamine-related ED visits from 2003 to 2020 among individuals 18+ years of age. We also performed a retrospective cohort study of individuals with amphetamine-related ED visits between 2019 and 2020 to determine whether select factors were associated with ED revisit within 6 months. Multivariable logistic regression modelling was used to measure associations. RESULTS: The population-based rate of amphetamine-related ED visits increased nearly 15-fold between 2003 (1.9/100,000 Ontarians) and 2020 (27.9/100,000 Ontarians). Seventy-five percent of individuals returned to the ED for any reason within 6 months. Psychosis and use of other substances were both independently associated with ED revisit for any reason within 6 months (psychosis: AOR = 1.54, 95% CI = 1.30-1.83; other substances: AOR = 1.84, 95% CI = 1.57-2.15), whereas having a primary care physician was negatively associated with ED revisit (AOR = 0.77, 95% CI = 0.60-0.98). CONCLUSIONS: Increasing rates of amphetamine-related ED visits in Ontario are cause for concern. Diagnoses of psychosis and the use of other substances may serve to identify individuals who are most likely to benefit from both primary and substance-specific care.

Associations with experience of non-fatal opioid overdose in British Columbia, Canada: a repeated cross sectional survey study.

INTRODUCTION: Lives lost in North America due to the unregulated drug poisoning emergency are preventable and those who survive an opioid overdose may suffer long-term disability. Rates of opioid overdose more than doubled following the onset of the COVID-19 pandemic in British Columbia, Canada. MATERIALS AND METHODS: Our analytical sample was comprised of 1447 participants from the 2018, 2019, and 2021 Harm Reduction Client Survey who responded yes or no to having experienced an opioid overdose in the past 6 months. Participants were recruited from harm reduction sites from across British Columbia. We used logistic regression to explore associations of experiencing an opioid overdose. RESULTS: Overall, 21.8% of participants reported experiencing an opioid overdose in the last six months (18.2% in 2019 and 26.6% in 2021). The following factors were positively associated with increased adjusted odds of experiencing a non-fatal opioid overdose: cis men relative to cis women (AOR 1.49, 95% CI 1.10-2.02), unstably housed compared to people with stable housing (AOR 1.87, 95% CI 1.40-2.50), and participants from 2021 compared to those from 2019 (AOR 3.06, 95% CI 1.57-5.97). The effects of both previous experience of a stimulant overdose and having witnessed an opioid overdose depended on the year of study, with both effects decreasing over subsequent years. CONCLUSIONS: Overdoses have increased over time; in 2021 more than one in four participants experienced an overdose. There is an urgent need for policy and program development to meaningfully address the unregulated drug poisoning emergency through acceptable life-saving interventions and services to prevent overdoses and support overdose survivors.

Comparative chemical genomic profiling across plant-based hydrolysate toxins reveals widespread antagonism in fitness contributions.

The budding yeast Saccharomyces cerevisiae has been used extensively in fermentative industrial processes, including biofuel production from sustainable plant-based hydrolysates. Myriad toxins and stressors found in hydrolysates inhibit microbial metabolism and product formation. Overcoming these stresses requires mitigation strategies that include strain engineering. To identify shared and divergent mechanisms of toxicity and to implicate gene targets for genetic engineering, we used a chemical genomic approach to study fitness effects across a library of S. cerevisiae deletion mutants cultured anaerobically in dozens of individual compounds found in different types of hydrolysates. Relationships in chemical genomic profiles identified classes of toxins that provoked similar cellular responses, spanning inhibitor relationships that were not expected from chemical classification. Our results also revealed widespread antagonistic effects across inhibitors, such that the same gene deletions were beneficial for surviving some toxins but detrimental for others. This work presents a rich dataset relating gene function to chemical compounds, which both expands our understanding of plant-based hydrolysates and provides a useful resource to identify engineering targets.

Differences in mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine immunogenicity among patients undergoing dialysis.

BACKGROUND: Differences in immunogenicity between mRNA SARS-CoV-2 vaccines have not been well characterized in patients undergoing dialysis. We compared the serologic response in patients undergoing maintenance hemodialysis after vaccination against SARS-CoV-2 with BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). METHODS: We conducted a prospective observational cohort study at 2 academic centres in Toronto, Canada, from Feb. 2, 2021, to July 20, 2021, which included 129 and 95 patients who received the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines, respectively. We measured SARS-CoV-2 immunoglobulin G antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD) and nucleocapsid protein (anti-NP) at 6-7 and 12 weeks after the second dose of vaccine and compared those levels with the median convalescent serum antibody levels from 211 controls who were previously infected with SARS-CoV-2. RESULTS: At 6-7 weeks after 2-dose vaccination, we found that 51 of 70 patients (73%) who received BNT162b2 and 83 of 87 (95%) who received mRNA-1273 attained convalescent levels of anti-spike antibody (p < 0.001). In those who received BNT162b2, 35 of 70 (50%) reached the convalescent level for anti-RBD compared with 69 of 87 (79%) who received mRNA-1273 (p < 0.001). At 12 weeks after the second dose, anti-spike and anti-RBD levels were significantly lower in patients who received BNT162b2 than in those who received mRNA-1273. For anti-spike, 70 of 122 patients (57.4%) who received BNT162b2 maintained the convalescent level versus 68 of 71 (96%) of those who received mRNA-1273 (p < 0.001). For anti-RBD, 47 of 122 patients (38.5%) who received BNT162b2 maintained the anti-RBD convalescent level versus 45 of 71 (63%) of those who received mRNA-1273 (p = 0.002). INTERPRETATION: In patients undergoing hemodialysis, mRNA-1273 elicited a stronger humoral response than BNT162b2. Given the rapid decline in immunogenicity at 12 weeks in patients who received BNT162b2, a third dose is recommended in patients undergoing dialysis as a primary series, similar to recommendations for other vulnerable populations.

From distress to detachment: exploring how providing care for stigmatized patients influences the moral development of medical trainees.

In acute hospital settings, medical trainees are often confronted with moral challenges and negative emotions when caring for complex and structurally vulnerable patients. These challenges may influence the long term moral development of medical trainees and have significant implications for future clinical practice. Despite the importance of moral development to medical education, the topic is still relatively under-explored. To gain a deeper understanding of moral development in trainees, we conducted a qualitative exploration of how caring for a stigmatized population influences their moral development. Data were collected from 48 medical trainees, including observational field notes, supplemental interviews, and medical documentation from inpatient units of two urban teaching hospitals in a Canadian context. Utilizing a practice-based approach which draws on constructivist grounded theory, we conducted constant comparative coding and analysis. We found that caring for stigmatized populations appeared to trigger frustration in medical trainees, which often perpetuated feelings of futility as well as avoidance behaviours. Additionally, hospital policies, the physical learning environment, variability in supervisory practices, and perceptions of judgment and mistrust all negatively influenced moral development and contributed to apathy and moral detachment which has implications for the future. Recognizing the dynamic and uncertain nature of care for stigmatized patients, and addressing the influence of structural and material factors provide an opportunity to support moral experiences within clinical training, and to improve inequities.

Readmission Following Hospitalization for Traumatic Brain Injury: A Nationwide Study.

OBJECTIVE: To determine whether sociodemographic and clinical factors were associated with nonelective readmission within 30 days of hospitalization for traumatic brain injury (TBI). Secondary objectives were to examine the effects of TBI severity on readmission and characterize primary reasons for readmission. SETTING: Hospitalized patients in the United States, using the 2014 Nationwide Readmission Database. PARTICIPANTS: All patients hospitalized with a primary diagnosis of TBI between January 1, 2014, and November 30, 2014. We excluded patients (1) with a missing or invalid length of stay or admission date, (2) who were nonresidents, and 3) who died during their index hospitalization. DESIGN: Observational study; cohort study. MAIN MEASURES: Survey weighting was used to compute national estimates of TBI hospitalization and nonelective 30-day readmission. Associations between sociodemographic and clinical factors with readmission were assessed using unconditional logistic regression with and without adjustment for suspected confounders. RESULTS: There were 135 542 individuals who were hospitalized for TBI; 8.9% of patients were readmitted within 30 days of discharge. Age (strongest association for 65-74 years vs 18-24 years: adjusted odds ratio [AOR], 2.57; 95% CI: 2.02-3.27), documentation of a fall (AOR, 1.24; 95% CI: 1.13-1.35), and intentional self-injury (AOR, 3.13; 95% CI: 1.88-5.21) at the index admission were positively associated with readmission. Conversely, history of a motor vehicle (AOR, 0.69; 95% CI: 0.62-0.78) or cycling (AOR, 0.56; 95% CI: 0.40-0.77) accident was negatively associated with readmission. Females were also less likely to be readmitted following hospitalization for a TBI (AOR, 0.87; 95% CI: 0.82-0.92). CONCLUSIONS: Many sociodemographic and clinical factors were found to be associated with acute readmission following hospitalizations for TBI. Future studies are needed to determine the extent to which readmissions following TBI hospitalizations are preventable.

Patient-derived organoid (PDO) platforms to facilitate clinical decision making.

Based on recent advances in organoid research as well as the need to find more accurate models for drug screening in cancer research, patient-derived organoids have emerged as an effective in vitro model system to study cancer. Showing numerous advantages over 2D cell lines, 3D cell lines, and primary cell culture, organoids have been applied in drug screening to demonstrate the correlation between genetic mutations and sensitivity to targeted therapy. Organoids have also been used in co-clinical trials to compare drug responses in organoids to clinical responses in the corresponding patients. Numerous studies have reported the successful use of organoids to predict therapy response in cancer patients. Recently, organoids have been adopted to predict treatment response to radiotherapy and immunotherapy. The development of high throughput drug screening and organoids-on-a-chip technology can advance the use of patient-derived organoids in clinical practice and facilitate therapeutic decision-making.

Crabtree/Warburg-like aerobic xylose fermentation by engineered Saccharomyces cerevisiae.

Bottlenecks in the efficient conversion of xylose into cost-effective biofuels have limited the widespread use of plant lignocellulose as a renewable feedstock. The yeast Saccharomyces cerevisiae ferments glucose into ethanol with such high metabolic flux that it ferments high concentrations of glucose aerobically, a trait called the Crabtree/Warburg Effect. In contrast to glucose, most engineered S. cerevisiae strains do not ferment xylose at economically viable rates and yields, and they require respiration to achieve sufficient xylose metabolic flux and energy return for growth aerobically. Here, we evolved respiration-deficient S. cerevisiae strains that can grow on and ferment xylose to ethanol aerobically, a trait analogous to the Crabtree/Warburg Effect for glucose. Through genome sequence comparisons and directed engineering, we determined that duplications of genes encoding engineered xylose metabolism enzymes, as well as TKL1, a gene encoding a transketolase in the pentose phosphate pathway, were the causative genetic changes for the evolved phenotype. Reengineered duplications of these enzymes, in combination with deletion mutations in HOG1, ISU1, GRE3, and IRA2, increased the rates of aerobic and anaerobic xylose fermentation. Importantly, we found that these genetic modifications function in another genetic background and increase the rate and yield of xylose-to-ethanol conversion in industrially relevant switchgrass hydrolysate, indicating that these specific genetic modifications may enable the sustainable production of industrial biofuels from yeast. We propose a model for how key regulatory mutations prime yeast for aerobic xylose fermentation by lowering the threshold for overflow metabolism, allowing mutations to increase xylose flux and to redirect it into fermentation products.

Imprecision and Preferences in Interpretation of Verbal Probabilities in Health: a Systematic Review.

INTRODUCTION: Many health providers and communicators who are concerned that patients will not understand numbers instead use verbal probabilities (e.g., terms such as "rare" or "common") to convey the gist of a health message. OBJECTIVE: To assess patient interpretation of and preferences for verbal probability information in health contexts. METHODS: We conducted a systematic review of literature published through September 2020. Original studies conducted in English with samples representative of lay populations were included if they assessed health-related information and elicited either (a) numerical estimates of verbal probability terms or (b) preferences for verbal vs. quantitative risk information. RESULTS: We identified 33 original studies that referenced 145 verbal probability terms, 45 of which were included in at least two studies and 19 in three or more. Numerical interpretations of each verbal term were extremely variable. For example, average interpretations of the term "rare" ranged from 7 to 21%, and for "common," the range was 34 to 71%. In a subset of 9 studies, lay estimates of verbal probability terms were far higher than the standard interpretations established by the European Commission for drug labels. In 10 of 12 samples where preferences were elicited, most participants preferred numerical information, alone or in combination with verbal labels. CONCLUSION: Numerical interpretation of verbal probabilities is extremely variable and does not correspond well to the numerical probabilities established by expert panels. Most patients appear to prefer quantitative risk information, alone or in combination with verbal labels. Health professionals should be aware that avoiding numeric information to describe risks may not match patient preferences, and that patients interpret verbal risk terms in a highly variable way.