How the T cell signaling network processes information to discriminate between self and agonist ligands.

T cells exhibit remarkable sensitivity and selectivity in detecting and responding to agonist peptides (p) bound to MHC molecules in a sea of self pMHC molecules. Despite much work, understanding of the underlying mechanisms of distinguishing such ligands remains incomplete. Here, we quantify T cell discriminatory capacity using channel capacity, a direct measure of the signaling network's ability to discriminate between antigen-presenting cells (APCs) displaying either self ligands or a mixture of self and agonist ligands. This metric shows how differences in information content between these two types of peptidomes are decoded by the topology and rates of kinetic proofreading signaling steps inside T cells. Using channel capacity, we constructed numerically substantiated hypotheses to explain the discriminatory role of a recently identified slow LAT Y132 phosphorylation step. Our results revealed that in addition to the number and kinetics of sequential signaling steps, a key determinant of discriminatory capability is spatial localization of a minimum number of these steps to the engaged TCR. Biochemical and imaging experiments support these findings. Our results also reveal the discriminatory role of early negative feedback and necessary amplification conferred by late positive feedback.

Hodgkin Lymphoma in Children Under 5 Years: Do They Behave Differently?

The median age of presentation for Hodgkin lymphoma (HL) is lower in developing countries with a higher proportion under 5 years of age possibly attributable to the high prevalence of Epstein-Barr virus-driven disease. It is unclear whether the clinical presentation and outcomes of this cohort are different with concern regarding late effects being most pronounced in this age group. We report the outcome of children under 5 years of age enrolled in the InPOG-HL-15-01, the first multicentric collaborative study for newly diagnosed children and adolescents with HL from India. Thirty-five (9%) of the study population was younger than 5 years with a striking male preponderance of 34:1. They were less likely to have bulky disease, mediastinal or splenic involvement. The outcomes appear to be at least as favorable as in the older patient group. Efforts need to be made to evolve treatment strategies that spare this very young cohort from potential late effects.

Can We Predict Fracture When Using a Short Cementless Femoral Stem in the Anterior Approach?

BACKGROUND: Short cementless femoral stems may allow for easier insertion with less dissection. The use of short stems with the anterior approach (AA) may be associated with a considerable perioperative fracture risk. Our aim was to evaluate whether patient-specific femoral and pelvic morphology and surgical technique, influence the perioperative fracture risk. Furthermore, we sought to describe important anatomical thresholds alerting surgeons. METHODS: A single-center, multi-surgeon retrospective, case-control matched study was performed. Thirty nine periprosthetic fractures (3.4%) in 1,145 primary AA THAs using short cementless stems were identified. These were matched with 78 THA nonfracture controls for factors known to increase the fracture risk. A radiographic analysis using validated software measured femoral (canal flare index [CFI], morphological cortical index [MCI], and calcar-calcar ratio [CCR]) and pelvic (Ilium-ischial ratio [IIR], ilium overhang, and anterior superior iliac spine [ASIS] to greater trochanter distance) morphologies and surgical techniques (% canal fill). A multivariate and Receiver-Operator Curve (ROC) analysis was used to identify fracture predictors. RESULTS: CFI (3.7 ± 0.6 vs 2.9 ± 0.4, P < .001) and CCR (0.5 ± 0.1 vs 0.4 ± 0.1, P = .006) differed. The mean IIR was higher in fracture cases (3.3 ± 0.6 vs 3.0 ± 0.5, P < .001). Percent canal fill was reduced in fracture cases (82.8 ± 7.6 vs 86.7 ± 6.8, P = .007). Multivariate and ROC analyses revealed a threshold CFI of 3.17 which was predictive of fracture (sensitivity: 84.6%/specificity: 75.6%). The fracture risk was 29 times higher when patients had CFI >3.17 and II ratio >3 (OR: 29.2 95% CI: 9.5-89.9, P < .001). CONCLUSION: Patient-specific anatomical parameters are important predictors of a fracture-risk. A careful radiographic analysis would help identify those at a risk of early fracture using short stems, and alternative stem options should be considered.

"Watch Me Grow- Electronic (WMG-E)" surveillance approach to identify and address child development, parental mental health, and psychosocial needs: study protocol.

BACKGROUND: The COVID-19 pandemic and the associated economic recession has increased parental psychosocial stress and mental health challenges. This has adversely impacted child development and wellbeing, particularly for children from priority populations (culturally and linguistically diverse (CALD) and rural/regional communities) who are at an already increased risk of health inequality. The increased mental health and psychosocial needs were compounded by the closure of in-person preventive and health promotion programs resulting in health organisations embracing technology and online services. Watch Me Grow- Electronic (WMG-E) - developmental surveillance platform- exemplifies one such service. WMG-E was developed to monitor child development and guide parents towards more detailed assessments when risk is identified. This Randomised Controlled Trial (RCT) aims to expand WMG-E as a digital navigation tool by also incorporating parents' mental health and psychosocial needs. Children and families needing additional assessments and supports will be electronically directed to relevant resources in the 'care-as-usual' group. In contrast, the intervention group will receive continuity of care, with additional in-person assessment and 'warm hand over' by a 'service navigator' to ensure their needs are met. METHODS: Using an RCT we will determine: (1) parental engagement with developmental surveillance; (2) access to services for those with mental health and social care needs; and (3) uptake of service recommendations. Three hundred parents/carers of children aged 6 months to 3 years (recruited from a culturally diverse, or rural/regional site) will be randomly allocated to the 'care-as-usual' or 'intervention' group. A mixed methods implementation evaluation will be completed, with semi-structured interviews to ascertain the acceptability, feasibility and impact of the WMG-E platform and service navigator. CONCLUSIONS: Using WMG-E is expected to: normalise and de-stigmatise mental health and psychosocial screening; increase parental engagement and service use; and result in the early identification and management of child developmental needs, parental mental health, and family psychosocial needs. If effective, digital solutions such as WMG-E to engage and empower parents alongside a service navigator for vulnerable families needing additional support, will have significant practice and policy implications in the pandemic/post pandemic period. TRIAL REGISTRATION: The trial (Protocol No. 1.0, Version 3.1) was registered with ANZCTR (registration number: ACTRN12621000766819 ) on July 21st, 2021 and reporting of the trial results will be according to recommendations in the CONSORT Statement.

Severe Thrombocytopenia in COVID-19: A Conundrum in Dengue-endemic Areas.

Thrombocytopenia in coronavirus disease-2019 (COVID-19) can be attributed to multiple factors. Most often it is disease related. It is usually mild and if severe often associated with severe COVID-19 disease. It can also be due to drugs (Remdesivir, Tocilizumab) or coinfection with other viruses. Here we report two cases of severe thrombocytopenia in COVID-19 due to dengue coinfection. Most often the thrombocytopenia in dengue is self-resolving, and a careful "wait and watch" should suffice unlike COVID-19, where steroids can help if the cytopenia is due to cytokine storm or immune-mediated effects. HOW TO CITE THIS ARTICLE: Adarsh MB, Abraham A, Kavitha P, Nandakumar MM, Vaman RS. Severe Thrombocytopenia in COVID-19: A Conundrum in Dengue-endemic Areas. Indian J Crit Care Med 2021;25(4):465-466.

Is There a Role for Preclosure Dilute Betadine Irrigation in the Prevention of Postoperative Infection Following Total Joint Arthroplasty?

BACKGROUND: Conflicting evidence exists surrounding the use of preclosure irrigation solutions in primary total joint arthroplasty (TJA). We aimed to determine the role of dilute betadine lavage in preventing early infection after primary TJA. METHODS: We retrospectively reviewed primary TJAs between 2010 and 2018. Dilute betadine lavage was introduced to our practice in November 2014. We included 3513 total hip arthroplasties, 3932 total knee arthroplasties, and 1033 hip resurfacings (HRs). In group 1 (n = 5588), surgical wounds were irrigated with saline; group 2 used dilute betadine solution (n = 2890). Subanalyses using propensity matching based on known risk factors of infection-age, body mass index, American Society of Anesthesiologists grade, diabetes, and procedure-were completed. RESULTS: There were 48 acute infections in group 1 (0.9%) and 23 in group 2 (0.8%) (P = .762). HR without betadine had the highest acute infection prevalence (P = .028). When groups in the whole cohort were propensity score-matched, group 1 had more acute infections than group 2 (P = .033). The effect of betadine was isolated to HR patients. After excluding HR cases, betadine continued to reduce the acute infection rate when compared with the no betadine group, but this was not statistically significant (0.4% vs 0.8%; P = .101). Likewise, we did not find a significant difference in total hip arthroplasty and total knee arthroplasty patients (P = .796). CONCLUSION: There was a decreased infection rate in the betadine group overall when groups were propensity-matched. Because the reduction in the acute infection rate was clinically significant, we feel this practice is an effective means to prevent infections.

CFD simulation of convective heat transfer in vessel with mechanical agitation for milk.

Computational fluid dynamics (CFD) analysis using ANSYS Fluent software has been carried out to investigate velocity profiles and thermal characteristics of milk during heating under mechanically agitated condition. In earlier article experimental data on forced convection heat transfer coefficient h - and correlations of the form N u = a · R e b · P r 0.33 for cow milk, standardised milk and full cream milk in Baffled vessel and Unbaffled vessel with scraping, using Propeller, Flat Six Blade Turbine (FBT), Inclined Six Blade Turbine (IBT) and Paddle impellers were reported. It was noted milk in Baffled vessel with Paddle impeller provided highest h - even at lower rotational speeds followed by Propeller, FBT and IBT impellers. In Unbaffled vessel with scraping, Propeller provided the highest h - followed by FBT and IBT impellers. Hence, the present investigation has been carried out to validate and understand how different velocity of flow currents and their magnitude influence the heat transfer coefficient values in CFD simulation. It also justifies the relative performance of the impellers delineated in the earlier paper. In addition, theoretical values of heat transfer coefficients computed using CFD shows close agreement with experimental values.

Retrospective Study of Nephrotoxicity Rate among Adult Patients Receiving Colistin Compared to ß-lactam Antibiotics.

PURPOSE: Patients receiving colistin for carbapenem-resistant gram-negative bacteria (CR-GNB) infections generally have multiple risk factors for nephrotoxicity, so it might be possible that colistin may be erroneously blamed for the nephrotoxicity. MATERIALS AND METHODS: We retrospectively analyzed case records of patients who received colistin and those who received antibiotics other than colistin [carbapenem or ß-lactam-ß-lactamases inhibitors (ßL-ßLI)] for gram-negative bacteremia. Those patients with preexisting renal failure and those who received antibiotics for <72 hours were excluded from the study. Nephrotoxicity was assessed using the risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, end-stage kidney disease (RIFLE) criteria. RESULTS: Out of the 222 patients, the colistin arm had 118 and the noncolistin arm had 104 patients. Even though the colistin arm had significantly higher number of sicker patients with neutropenia (40.7% vs 14.4%, p = 0.0001), mechanical ventilation (0.0001), having lines (0.0001), on inotropes (0.003), receiving other nephrotoxic drugs (0.0001), and higher Pitt score (p = 0.0001), there was no significant difference in the nephrotoxicity between the two arms (10.2% vs 9.6%, p = 0.89). Logistical regression showed a higher Pitt bacteremia score (p = 0.03) and a higher Charlson comorbidity index (p = 0.02), but not colistin administration (p = 0.32), were independently associated with nephrotoxicity. CONCLUSION: Administration of colistin was not associated with higher rates of nephrotoxicity than carbapenems or ßL-ßLI agents. HOW TO CITE THIS ARTICLE: Ghafur A, Bansal N, Devarajan V, Raja T, Easow J, Raja MA, et al. Retrospective Study of Nephrotoxicity Rate among Adult Patients Receiving Colistin Compared to ß-lactam Antibiotics. IJCCM 2019;23(11):518-522.

Determination of forced convection heat transfer coefficients and development of empirical correlations for milk in vessel with mechanical agitators.

Heating of milk is an important unit operation to produce many milk based products. This process is done either in heat exchangers or in agitated vessels, where the mode and type of heat transfer plays a significant role. Use of mechanical agitator with suitable impeller would result in uniform agitation of the liquid. Data for forced convection heat transfer coefficients for milk in agitated vessel have not been documented. In the present investigation, forced convection heat transfer coefficients for milk, using mechanical agitators in vessels have been determined. Experiments have been conducted in vessels (Baffled as well as Unbaffled vessel) that were designed and fabricated under standard procedure employing: (1) Flat Six Blade Turbine impeller, (2) Inclined Six Blade Turbine impeller, (3) Three Blade Propeller impeller and (4) Two Bladed Paddle. Heat transfer coefficients were determined for h¯ for cow milk (3.5% fat), standardised milk (4.5% fat) and full cream milk (6.0% fat). The Two Bladed Paddle was found to as yield the highest heat transfer coefficient h¯ for all three types of milk. In addition, empirical correlations for the forced convection heat transfer using Nu=a·Reb·Pr0.33 have been developed for each case. These heat transfer correlations derived will find application in large scale design and the experimental setup would be useful for future investigation with different liquids and impellers.

Computational neuroimaging strategies for single patient predictions.

Neuroimaging increasingly exploits machine learning techniques in an attempt to achieve clinically relevant single-subject predictions. An alternative to machine learning, which tries to establish predictive links between features of the observed data and clinical variables, is the deployment of computational models for inferring on the (patho)physiological and cognitive mechanisms that generate behavioural and neuroimaging responses. This paper discusses the rationale behind a computational approach to neuroimaging-based single-subject inference, focusing on its potential for characterising disease mechanisms in individual subjects and mapping these characterisations to clinical predictions. Following an overview of two main approaches - Bayesian model selection and generative embedding - which can link computational models to individual predictions, we review how these methods accommodate heterogeneity in psychiatric and neurological spectrum disorders, help avoid erroneous interpretations of neuroimaging data, and establish a link between a mechanistic, model-based approach and the statistical perspectives afforded by machine learning.

Enhancing antibiotic stewardship by tackling "spurious" penicillin allergy.

Approximately 90-99% of patients with a label of penicillin allergy (PenA) are not allergic when comprehensively investigated. An inaccurate label of PenA has major public health implications-longer hospital stay, more frequent hospital admissions, greater use of fluoroquinolones, glycopeptides, cephalosporins and other expensive antibiotics resulting in significantly higher costs to the health service and predisposing to Clostridium difficile, methicillin-resistant Staphylococcus aureus infections and vancomycin-resistant enterococcus. We describe lessons learnt from recent studies regarding possible reasons contributing to an inaccurate label of PenA as well as propose a concerted multidisciplinary approach to address this important public health problem. Given the unmet need for allergy services in the UK and several other countries and knowledge gaps regarding PenA amongst healthcare professionals, we describe the potential role for a computerized clinical decision support system to enable non-specialists rapidly identify and de-label "low-risk" hospitalized patients with a label of PenA thereby obviating the need for allergy tests. This approach however needs rigorous evaluation for feasibility, safety, patient and physician acceptability, cost-effectiveness and its compatibility with information technology systems currently employed in the health service.

Taking culture seriously: Can we improve the developmental health and well-being of Australian Aboriginal children in out-of-home care?

BACKGROUND: Children in out-of-home care have well-documented health and developmental needs. Research suggests that Aboriginal children in care have unmet health and intervention needs. In metropolitan Sydney, Kari Aboriginal Resources Inc. (KARI), an Aboriginal organization, provides support to indigenous children in care, including clinical assessment and intervention. We wanted to determine the health and developmental needs of a subset of children in out-of-home care with KARI, who had been in stable care for at least a year. We wanted to identify child, carer, and intervention characteristics that contributed to children doing well. We also wanted to identify enablers and barriers to providing culturally competent intervention. METHODS: We used mixed methods. From the KARI clinic database over the past 3 years, we identified children who had been in stable care with KARI for >12 months. We compared clinical measures and outcomes for these children with results from previous audits. We carried out a group discussion and key informant interviews with therapists and caseworkers to identify risk and resilience factors for each child, as well as enablers and barriers to culturally competent intervention. RESULTS: The health and developmental profile of the 26 children identified as being in stable care was similar to that of previous audits. Most (88%) were getting speech pathology intervention; one third were getting occupational therapy and psychological intervention; most children and their carers attended cultural programmes. The majority of children (25/26) improved in their developmental health. Caseworkers and therapists identified risk and resilience factors related to child, carer, and home characteristics. They also identified elements of good practice; systemic issues prevented some interventions from being carried out. CONCLUSIONS: There are challenges delivering a trauma-informed, culturally respectful service to Aboriginal children in out-of-home care in an urban setting, but it can be done if attention is paid to culture and the enablers and barriers are identified.

Monotherapy versus Combination Therapy against Nonbacteremic Carbapenem-resistant Gram-negative Infections: A Retrospective Observational Study.

BACKGROUND: Superiority of colistin-carbapenem combination therapy (CCCT) over colistin monotherapy (CMT) against carbapenem-resistant Gram-negative bacterial (CRGNB) infections is not conclusively proven. AIM: The aim of the current study was to analyze the effectiveness of both strategies against CRGNB nonbacteremic infections. DESIGN: This was a retrospective observational cohort study. SUBJECTS AND METHODS: Case record analysis of patients who had CRGNB nonbacteremic infections identified over a period of 4 years (January 2012-December 2015) was done by medical record review at a tertiary care center in India. STATISTICAL ANALYSIS: P < 0.05 was considered as significant. Multivariate analysis was performed using Cox regression. RESULTS: Out of 153 patients (pneumonia 115, urinary tract infection 17, complicated skin and soft-tissue infection 18, intra-abdominal infection 1, and meningitis 2), 92 patients received CCCT and 61 received CMT. Univariate analysis revealed higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, pneumonia as the diagnosis, and Klebsiella as the causative organism to be the risk factors for higher 28-day mortality (P = 0.036, 0.006, 0.016, respectively). Combination therapy had no significant impact on mortality (odds ratio [OR] = 0.91, 95% confidence interval [CI] = 0.327-2.535, P = 0.857). Multivariate analysis revealed that higher APACHE II score and infection due to Klebsiella were found to be independent risk factors for higher mortality (OR = 3.16 and 4.9, 95% CI = 1.34-7.4 and 2.19-11.2, P = 0.008 and 0.0001, respectively). CONCLUSIONS: In our retrospective single-center series of CRGNB nonbacteremic infections, CCCT was not superior to CMT. Multicenter large observational studies or prospective randomized clinical trials are the need of the hour.

Colistin Nephrotoxicity in Adults: Single Centre Large Series from India.

CONTEXT: Limited Indian data are available on the rate of colistin nephrotoxicity and other risk factors contributing to the development of this important side effect. AIM: This study aims to generate data on colistin nephrotoxicity from a large cohort of Indian patients. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: Case record analysis of patients who received colistin, in an oncology center in India, between January 2011 and December 2015. Nephrotoxicity was assessed using risk, injury, failure, loss, and end-stage (RIFLE) criteria. STATISTICAL ANALYSIS: P < 0.05 was considered as statistically significant. RESULTS: Out of the 229 patients, 13.1% (30/229) developed abnormal RIFLE. Abnormal RIFLE group (n = 30), in comparison to the normal renal function group (n = 199), had higher number of patients in intensive care unit (ICU) (96% vs. 79%, P = 0.02), higher Acute Physiology and Chronic Health Evaluation (APACHE II) score (23 vs. 19 P = 0.0001), Charlson score (5.9 vs. 4.3, P = 0.001), mechanical ventilation (90% vs. 67%, P = 0.016), 28 days mortality (63% vs. 25%, P = 0.0001), and abnormal baseline creatinine (36% vs. 8%, P = 0.001). Coadministration of vancomycin had higher rates of nephrotoxicity (P = 0.039). There was no significant difference in nephrotoxicity between 6 and 9 MU/day dosing pattern (8.8% vs. 13.8%, P = 0.058). CONCLUSION: Nephrotoxicity rate in our retrospective single center large series of patients receiving colistin was 13.1%. Patients with abnormal baseline creatinine, ICU stay, and higher disease severity are at higher risk of nephrotoxicity while on colistin. A daily dose of 9 million does not significantly increase nephrotoxicity compared to the 6 million. Concomitant administration of vancomycin with colistin increases the risk of nephrotoxicity.

Comparative accuracy of supine-only and combined supine-prone myocardial perfusion imaging in men.

BACKGROUND: Combined supine-prone myocardial perfusion imaging (CSP MPI) has been shown to reduce attenuation artifact in comparison to supine-only (SU) MPI in mixed-gender populations with varying risk for coronary artery disease (CAD), often where patients served as their own controls. However, there is limited direct comparison of these imaging strategies in men. METHODS: 934 male patients underwent CSP or SU MPI. Diagnostic certainty of interpretation was compared. Within the cohort, 116 were referred for left heart catheterization (LHC) to assess for CAD. Sensitivity, specificity, and area under the curve (AUC) were compared with additional analysis based on body mass index (BMI). RESULTS: 597 patients completed the SU protocol and 337 patients completed the CSP protocol. Equivocal studies were seen more frequently in the SU group (13%) than in the CSP group (4%, P < .001). At catheterization, the specificity for CSP MPI of 70% was higher than 40% for SU MPI (P = .032). The CSP AUC (0.80 ± 0.06) was significantly larger than SU AUC (0.57 ± 0.05, P = .004). CSP specificity was significantly higher in obese patients. CONCLUSIONS: CSP MPI increases diagnostic certainty and improves test accuracy for CAD detection in men with CAD risk factors, especially obese patients, compared to SU MPI.

Pulmonary hypertension in hypertensive patients: association with diastolic dysfunction and increased pulmonary vascular resistance.

BACKGROUND: Pulmonary hypertension (PH) in patients with systemic hypertension and preserved ejection fraction (PEF) has been described. However, the pathophysiology and consequences are not entirely clear. We sought to distinguish the clinical and anatomic features among hypertensive patients with or without coexistent PH. METHODS: Echocardiograms and records of hypertensive patients with left ventricular (LV) hypertrophy and PEF from January 2009 to January 2011 were reviewed. We identified 174 patients, including 36 with PH (calculated pulmonary artery systolic pressure [PASP] ≥ 35 mmHg), and 138 with normal pulmonary pressures. RESULTS: Hypertensive patients with PH were older (76 ± 13 vs. 65 ± 13 years, P < 0.0001), more often female (91, 70%), had lower estimated glomerular filtration rate (eGFR) (63 ± 44 vs. 88 ± 48 mL/min, P = 0.002), and higher pro-BNP levels (3141 ± 4253 vs. 1219 ± 1900 pg/mL, P = 0.003). PH patients also had larger left atrial areas (23.7 ± 3.8 vs. 20.8 ± 4.6 cm(2) , P = 0.002), evidence of diastolic dysfunction (i.e., septal E/e' 17.6 ± 8.6 vs. 12.7 ± 4.4, P = 0.0005), and higher calculated peripheral vascular resistance (PVR) (2.3 ± 1.1 vs. 1.6 ± 0.4, P < 0.0001). Both PVR and septal E/e' showed strong linear correlation with PASP (P < 0.0001 and P < 0.0001, respectively). CONCLUSIONS: Hypertension in elderly patients is frequently complicated by LV diastolic dysfunction and secondary PH. These hypertensive patients tended to have reduced renal function and higher pro-BNP. Because of the known morbidity and mortality associated with PH, these observations have potentially important implications for target medical therapy.

Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation.

A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases. Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassaemia. This circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes. Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.

Higher Temperatures in Socially Vulnerable US Communities Increasingly Limit Safe Use of Electric Fans for Cooling.

As the globe warms, people will increasingly need affordable, safe methods to stay cool and minimize the worst health impacts of heat exposure. One of the cheapest cooling methods is electric fans. Recent research has recommended ambient air temperature thresholds for safe fan use in adults. Here we use hourly weather reanalysis data (1950-2021) to examine the temporal and spatial evolution of ambient climate conditions in the continental United States (CONUS) considered safe for fan use, focusing on high social vulnerability index (SVI) regions. We find that although most hours in the day are safe for fan use, there are regions that experience hundreds to thousands of hours per year that are too hot for safe fan use. Over the last several decades, the number of hours considered unsafe for fan use has increased across most of the CONUS (on average by ∼70%), with hotspots across the US West and South, suggesting that many individuals will increasingly need alternative cooling strategies. People living in high-SVI locations are 1.5-2 times more likely to experience hotter climate conditions than the overall US population. High-SVI locations also experience higher rates of warming that are approaching and exceeding important safety thresholds that relate to climate adaptation. These results highlight the need to direct additional resources to these communities for heat adaptive strategies.

Long-Term Biochemical Control of a Prospective Cohort of Prostate Cancer Patients Treated With Interstitial Brachytherapy Versus Radical Prostatectomy.

AIMS: To report long-term oncological outcomes of men treated prospectively as part of the American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT) at our institution. MATERIALS AND METHODS: In 2003-2004, patients eligible for SPRIT attended a multidisciplinary educational session, following which they could choose radical prostatectomy, low dose rate brachytherapy (LDR-BT) or randomisation to SPIRIT. Biochemical failure was determined by the accepted definitions of a prostate-specific antigen (PSA) level ≥0.2 ng/ml after radical prostatectomy and the Phoenix definition of PSA ≥2 ng/ml above the nadir after LDR-BT. A sensitivity analysis, using a PSA >0.5 ng/ml to define biochemical failure after LDR-BT and a threshold PSA ≥0.2 ng/ml, was carried out to test the robustness of the results. To account for the competing risk of death, Gray's test was used to test the equality of the cumulative incidence function of biochemical failure between treatment groups. The Kaplan-Meier method was used to estimate overall survival and prostate cancer-specific survival. A P-value ≤0.05 was considered statistically significant. RESULTS: Of 156 patients, 100 received LDR-BT (15 after randomisation) and 56 underwent radical prostatectomy (15 after randomisation). The median follow-up was 12.6 and 14.7 years for LDR-BT and radical prostatectomy, respectively. The median age was 60 years; the median pre-treatment PSA was 5.5 (interquartile range 4.3-7.1). No significant differences in patient characteristics were found between groups. Two patients received adjuvant radiotherapy after radical prostatectomy. The cumulative incidence function of biochemical failure was 0%, 1.1% and 2.4% at 5, 10 and 15 years, respectively, in the LDR-BT arm versus 8.5%, 15.8% and 15.8% in the radical prostatectomy arm (P < 0.001). These results were consistent when varying the definition of biochemical failure defined as PSA ≥0.5 ng/ml (P = 0.01). At 15 years, overall survival was higher in patients treated with radical prostatectomy compared with those treated with LDR-BT; however, no statistical difference was found in prostate cancer-specific survival. CONCLUSION: In low-risk prostate cancer patients, LDR-BT offers excellent long-term oncological outcomes comparable with radical prostatectomy, in addition to the previously reported advantage for LDR-BT in urinary and sexual quality of life domains and patient satisfaction.