Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

Would You Rather: Quantifying TBI Survivor Perceptions of Functional Status via Their Surrogates.

OBJECTIVE: To quantify health utilities of the Glasgow Outcome Scale-Extended (GOSE) states after actual Traumatic Brain Injury (TBI). BACKGROUND: Recovery after TBI is measured using the GOSE, a validated clinical trial endpoint. A recent public survey quantified the health utilities of some GOSE states after hypothetical TBI as worse than death. However, no health utilities exist for disability after actual TBI. METHODS: This national computer-adaptive survey followed EQUATOR-CHERRIES guidelines and recruited adult TBI survivors (injury>1 y prior) via their available surrogates. Using a standard gamble approach in randomized order, participants gave preferences for post-TBI categorical health states ranging from GOSE 2-8. We calculated median [interquartile range, IQR] health utilities for each GOSE state, from -1 (worse than death) to 1 (full health), with 0 as reference (death, GOSE 1). RESULTS: Of 515 eligible, 298 surrogates (58%) consented and completed the scenarios on TBI survivors' behalf. TBI survivors had a current median GOSE 5 [3-7]. GOSE 2, GOSE 3, and GOSE 4 were rated worse than death by 89%, 64%, and 38%, respectively. The relationship was nonlinear, and intervals were unequal between states, with a bimodal distribution for GOSE 4. CONCLUSIONS: In this index study of actual post-TBI disability, poor neurologic outcomes represented by GOSE 2-4 were perceived as worse than death by at least one in three survivors. Similar to previously reported public perceptions after a hypothetical TBI, these long-term perceptions may inform earlier post-TBI shared decision making, as well as help shape value-based research and quality of care. LEVEL OF EVIDENCE: II, Economic & Value-based Evaluations.

Surrogate Perception of Disability after Hospitalization for Traumatic Brain Injury.

BACKGROUND: The Glasgow Outcome Scale Extended (GOSE) is a measure of recovery after traumatic brain injury (TBI). Public surveys rate some GOSE states as worse than death. Direct family experience caring for patients with TBI may impact views of post-TBI disability. STUDY DESIGN: We conducted a national cross-sectional computer-adaptive survey of surrogates of TBI dependents incurring injury more than 1 year earlier. Using a standard gamble approach in randomized order, surrogates evaluated preferences for post-TBI GOSE states from GOSE 2 (bedridden, unaware) to GOSE 8 (good recovery). We calculated median (interquartile range [IQR]) health utilities for each post-TBI state, ranging from -1 to 1, with 0 as reference (death = GOSE 1), and assessed sociodemographic associations using proportional odds logistic regression modeling. RESULTS: Of 515 eligible surrogates, 298 (58%) completed scenarios. Surrogates were median aged 46 (IQR 35 to 60), 54% married, with Santa Clara strength of faith 14 (10 to 18). TBI dependents had a median GOSE5 (3 to 7). Median (IQR) health utility ratings for GOSE 2, GOSE 3, and GOSE 4 were -0.06 (-0.50 to -0.01), -0.01 (-0.30 to 0.45), and 0.30 (-0.01 to 0.80), rated worse than death by 91%, 65%, and 40%, respectively. Surrogates rated GOSE 4 (daily partial help) worse than the general population. Married surrogates rated GOSE 4 higher (p < 0.01). Higher strength of faith was associated with higher utility scores across GOSE states (p = 0.034). CONCLUSIONS: In this index study of surrogate perceptions about disability after TBI, poor neurologic outcomes-vegetative, needing all-day or partial daily assistance-were perceived as worse than death by at least 1 in 3 surrogates. Surrogate perceptions differed from the unexposed public. Long-term perceptions about post-TBI disability may inform earlier, tailored shared decision-making after neurotrauma.

Insights into synaptic functionality and resistive switching in lead iodide flexible memristor devices.

Neuromorphic platforms are gaining popularity due to their superior efficiency, low power consumption, and adaptable parallel signal processing capabilities, overcoming the limitations of traditional von Neumann architecture. We conduct an in-depth investigation into the factors influencing the resistive switching mechanism in memristor devices utilizing lead iodide (PbI2). We establish correlations between device performance and morphological features, unveiling synaptic like behaviour of device making it suitable for range of flexible neuromorphic applications. Notably, a highly reliable unipolar switching mechanism is identified, exhibiting stability even under mechanical strain (with a bending radius of approximately 4 mm) and in high humidity environment (at 75% relative humidity) without the need for encapsulation. The investigation delves into the complex interplay of charge transport, ion migration and the active interface, elucidating the factors contributing to the remarkable resistive switching observed in PbI2-based memristors. The detailed findings highlight synaptic behaviors akin to the modulation of synaptic strengths, with an impressive potentiation and depression of 2 × 104 cycles, emphasizing the role of spike time-dependent plasticity (STDP). The flexible platform demonstrates exceptional performance, achieving a simulated accuracy rate of 95.06% in recognizing modified patterns from the National Institute of Standards and Technology (MNIST) dataset with just 30 training epochs. Ultimately, this research underscores the potential of PbI2-based flexible memristor devices as versatile component for neuromorphic computing. Moreover, it demonstrate the robustness of PbI2 memristors in terms of their resistive switching capabilities, showcasing resilience both mechanically and electrically. This underscores their potential in replicating synaptic functions for advanced information processing systems.

Early administration of canine parvovirus monoclonal antibody prevented mortality after experimental challenge.

OBJECTIVE: To evaluate the effectiveness of canine parvovirus monoclonal antibody (CPMA) as a treatment against canine parvovirus (CPV-2)-induced mortality and to support USDA product licensure. ANIMALS: 28 purpose-bred Beagle dogs aged 8 weeks were randomized to the treated (n = 21) or control (7) group. METHODS: Dogs were challenged intranasally with 104.2 TCID50 virulent CPV-2b on Day 0 and monitored for 14 days for fecal viral shed and clinical disease. All dogs began shedding CPV-2 on Day 4 and were treated intravenously with a single dose of either CPMA (0.2 mL/kg) or saline (equal volume). No additional treatments were given to either group. Feces and sera were collected for quantitative analysis of fecal viral shed (hemagglutination) and antibody responses (hemagglutination inhibition and dot-blot ELISA), respectively. Dogs were monitored twice daily for parameters including lymphopenia, fever, vomiting, abnormal feces, inappetence, and lethargy. Humane endpoints triggered euthanasia by a veterinarian masked to treatment groups. The primary outcome variable was prevention of mortality as compared to controls. RESULTS: Mortality was prevented in all CPMA-treated dogs compared to 57% mortality in the control group (P = .0017, Fisher exact test). Canine parvovirus monoclonal antibody-treated dogs also experienced less severe and/or shorter durations of diarrhea, fever, vomiting, CPV-2 shedding in feces, and lymphopenia. Both groups showed similar immunoglobulin M responses as measured by semiquantitative analysis. CLINICAL RELEVANCE: Intravenous administration of CPMA can effectively improve clinical outcome when administered early in CPV-2 disease. Canine parvovirus monoclonal antibody treatment after proven infection does not interfere with adaptive immunity.

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

In-hospital catatonia, delirium, and coma and mortality: Results from the delirium and catatonia prospective cohort investigation.

BACKGROUND: Catatonia, a form of acute brain dysfunction typically linked with severe affective and psychotic disorders, occurs in critical illness with delirium and coma. Delirium and coma are associated with mortality, though catatonia's relationship with mortality is unclear. We aim to describe whether catatonia, delirium, and coma are associated with mortality. METHODS: We enrolled a convenience cohort of critically ill adults (N = 378) at an academic medical center. We assessed catatonia, delirium, and coma using the Bush-Francis Catatonia Rating Scale, the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale, respectively. We tested the associations between previous day brain dysfunction state occurrence with in-hospital and one-year mortality using multivariable time-dependent risk models. Additionally, we tested the association between brain dysfunction duration and one-year mortality. RESULTS: Catatonia was not associated with death on the day after diagnosis during hospitalization, and neither previous catatonia occurrence nor duration was associated with one-year mortality. Delirium was not associated with death on any day following diagnosis during hospitalization, and neither previous delirium occurrence nor duration was associated with one-year mortality. The occurrence of coma was associated with death on any day after diagnosis during hospitalization (HR 2.30,CI 1.19-4.44,p = 0.014), as well as through one year following hospital discharge (HR 1.68,CI 1.09-2.59,p = 0.02). CONCLUSIONS: Coma, but neither catatonia nor delirium, was associated with future day in-hospital and one-year mortality. More research is needed to understand catatonia's clinical impact. Delirium results differ from existing literature likely due to cohort demographics and size. Coma results highlight the prognostic significance of suppressed arousal while critically ill.

Association Between Emergency Medical Service Agency Volume and Mortality in Trauma Patients.

OBJECTIVE: The aim of this study was to evaluate the association of annual trauma patient volume on outcomes for emergency medical services (EMS) agencies. BACKGROUND: Regionalization of trauma care saves lives. The underlying concept driving this is a volume-outcome relationship. EMS are the entry point to the trauma system, yet it is unknown if a volume-outcome relationship exists for EMS. METHODS: A retrospective analysis of prospective cohort including 8 trauma centers and 20 EMS air medical and metropolitan ground transport agencies. Patients 18 to 90 years old with injury severity scores ≥9 transported from the scene were included. Patient and agency-level risk-adjusted regression determined the association between EMS agency trauma patient volume and early mortality. RESULTS: A total of 33,511 were included with a median EMS agency volume of 374 patients annually (interquartile range: 90-580). Each 50-patient increase in EMS agency volume was associated with 5% decreased odds of 6-hour mortality (adjusted odds ratio=0.95; 95% CI: 0.92-0.99, P =0.03) and 3% decreased odds of 24-hour mortality (adjusted odds ratio=0.97; 95% CI: 0.95-0.99, P =0.04). Prespecified subgroup analysis showed EMS agency volume was associated with reduced odds of mortality for patients with prehospital shock, requiring prehospital airway placement, undergoing air medical transport, and those with traumatic brain injury. Agency-level analysis demonstrated that high-volume (>374 patients/year) EMS agencies had a significantly lower risk-standardized 6-hour mortality rate than low-volume (<374 patients/year) EMS agencies (1.9% vs 4.8%, P <0.01). CONCLUSIONS: A higher volume of trauma patients transported at the EMS agency level is associated with improved early mortality. Further investigation of this volume-outcome relationship is necessary to leverage quality improvement, benchmarking, and educational initiatives.

Prehospital Time Following Traumatic Injury Is Independently Associated With the Need for In-Hospital Blood and Early Mortality for Specific Injury Types.

OBJECTIVE: Treating traumatic hemorrhage is time sensitive. Prehospital care and transport modes (eg, helicopter and ground) may influence in-hospital events. We hypothesized that prehospital time (on-scene time [OST] and total prehospital time [TPT]) and transport mode are associated with same-day transfusion and mortality. Furthermore, we sought to identify regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. METHODS: We obtained prehospital, in-hospital, and trauma registry data from an 8-center cohort of adult nonburn trauma patients from 2017 to 2022 directly transported from the scene to the hospital and having an Injury Severity Score (ISS) > 9 for the Task Order 1 project of the Linking Investigators in Trauma and Emergency Services research network. We excluded patients missing prehospital times, patients < 18 years of age, patients from interfacility transfers, and recipients of prehospital blood. Our same-day outcomes were in-hospital transfusions within 4 hours and 24-hour mortality. Each outcome was adjusted using multivariable logistic regression for covariates of prehospital phases (OST and TPT), mode of transport (helicopter and ground), age, sex, ISS, Glasgow Coma Scale motor subscale score < 6, and field hypotension (systolic blood pressure < 90 mm Hg). We evaluated the association of prehospital time on outcomes for scene missions by transport mode across severe injury patterns defined by Abbreviated Injury Scale > 2 body regions. RESULTS: Of 78,198 subjects, 34,504 were eligible for the study with a mean age of 47.6 ± 20.3 years, ISS of 18 ± 11, OST of 15.9 ± 9.5 minutes, and TPT of 48.7 ± 20.3 minutes. Adjusted for injury severity and demographic factors, transport type significantly modified the relationship between prehospital time and outcomes. The association of OST and TPT with the odds of 4-hour transfusion was absent for the ground emergency medical services (GEMS) cohort and present for the helicopter emergency medical services (HEMS) ambulance cohort, whereas these times were associated with decreased 24-hour mortality for both transport types. When stratifying by injury to most anatomic regions, OST and TPT were associated with a decreased need for 4-hour transfusions in the GEMS cohort. However, OST was associated with increased early transfusion only among patients with severe injuries of the thorax, and this association persisted after adjusting additionally for injury type (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.00-1.05; P = .02). The presence of polytrauma supported an association between prehospital time and decreased 24-hour mortality for the GEMS cohort (OST: OR = 0.97; 95% CI, 0.95-0.99; P < .01; TPT: OR = 0.99; 95% CI, 0.98-0.99; P = .02), whereas no injuries showed significant association of helicopter prehospital time on mortality after adjustment. CONCLUSION: We determined that transport type affects the relationship between prehospital time and hospital outcomes (4-hour transfusion: positive relationship for HEMS and negative for GEMS, 24-hour mortality: negative for both transport types). Furthermore, we identified regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. Of these regions, most notable were severe isolated injuries to the thorax that supported a positive relationship between HEMS OST and 4-hour transfusions and polytrauma that showed a negative relationship between GEMS OST or TPT and 24-hour mortality after adjustment.

Traumatic pneumocephalus as a possible early sign of acute spinal cord injury: Case report.

Background: Traumatic pneumocephalus (TPC) following craniofacial injuries is common, but isolated TPC secondary to pneumorrhachis (PR) is the rare result of upward gas migration from the spinal canal. In the absence of craniofacial and grossly unstable spinal fractures, the etiology of TPC in polytrauma can be elusive and an underlying diagnosis of acute spinal cord injury (SCI) can be easily missed. We report the first polytrauma case where TPC was the most reliable early sign of SCI. Case Description: A 34-year-old polytrauma female with imaging findings of TPC, which was later found to be secondary to an underlying SCI. As a focused exam could not be performed at admission, the TPC was first attributed to undiagnosed craniofacial injuries. Tertiary survey revealed the patient being paraplegic and MRI workup demonstrated an acute SCI at the T3-T4 level. PR was the most likely cause of TPC in the absence of other craniofacial injuries. Outcome: The patient did not have a meaningful recovery given the extensive hemispheric infarcts, spinal cord injury, and respiratory failure. Conclusions: Although uncommon, TPC may be an important radiographic sign suggesting the possibility of an underlying SCI in polytrauma patients. especially when focused neurologic assessment is limited at admission. Polytrauma patients with TPC and PR in the absence of coexisting craniofacial fractures require an urgent spine consultation by the ER physician, with possible early spine MRI workup. We suggest a diagnostic algorithm for the early identification of SCI in polytrauma patients presenting with TPC and propose considering 3 groups which may have different risks for SCI based on their clinical presentation and the presence of PR.

Differences in Health Professionals' Engagement With Electronic Health Records Based on Inpatient Race and Ethnicity.

Importance: US health professionals devote a large amount of effort to engaging with patients' electronic health records (EHRs) to deliver care. It is unknown whether patients with different racial and ethnic backgrounds receive equal EHR engagement. Objective: To investigate whether there are differences in the level of health professionals' EHR engagement for hospitalized patients according to race or ethnicity during inpatient care. Design, Setting, and Participants: This cross-sectional study analyzed EHR access log data from 2 major medical institutions, Vanderbilt University Medical Center (VUMC) and Northwestern Medicine (NW Medicine), over a 3-year period from January 1, 2018, to December 31, 2020. The study included all adult patients (aged ≥18 years) who were discharged alive after hospitalization for at least 24 hours. The data were analyzed between August 15, 2022, and March 15, 2023. Exposures: The actions of health professionals in each patient's EHR were based on EHR access log data. Covariates included patients' demographic information, socioeconomic characteristics, and comorbidities. Main Outcomes and Measures: The primary outcome was the quantity of EHR engagement, as defined by the average number of EHR actions performed by health professionals within a patient's EHR per hour during the patient's hospital stay. Proportional odds logistic regression was applied based on outcome quartiles. Results: A total of 243 416 adult patients were included from VUMC (mean [SD] age, 51.7 [19.2] years; 54.9% female and 45.1% male; 14.8% Black, 4.9% Hispanic, 77.7% White, and 2.6% other races and ethnicities) and NW Medicine (mean [SD] age, 52.8 [20.6] years; 65.2% female and 34.8% male; 11.7% Black, 12.1% Hispanic, 69.2% White, and 7.0% other races and ethnicities). When combining Black, Hispanic, or other race and ethnicity patients into 1 group, these patients were significantly less likely to receive a higher amount of EHR engagement compared with White patients (adjusted odds ratios, 0.86 [95% CI, 0.83-0.88; P < .001] for VUMC and 0.90 [95% CI, 0.88-0.92; P < .001] for NW Medicine). However, a reduction in this difference was observed from 2018 to 2020. Conclusions and Relevance: In this cross-sectional study of inpatient EHR engagement, the findings highlight differences in how health professionals distribute their efforts to patients' EHRs, as well as a method to measure these differences. Further investigations are needed to determine whether and how EHR engagement differences are correlated with health care outcomes.

Modifiable in-hospital factors for 12-month global cognition, post-traumatic stress disorder symptoms, and depression symptoms in adults hospitalized with COVID-19.

BACKGROUND: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months. METHODS: This was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively. FINDINGS: Two hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85). CONCLUSION: Potentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms).

Prognostics of Systemic Malignancy ICD-O Topography and Morphology Types on Brain Metastases: An NCDB Time-to-event Cohort.

BACKGROUND: The primary site and histology of systemic malignancy are known predictors of progression to brain metastases (BM). We investigated the combinational interactions of International Classification of Diseases for Oncology (ICD-O) primary topography and morphology types on the survival of BM after adjusting for relevant clinical and demographic prognostic factors. METHODS: The cohort included all adult patients with BM at diagnosis of an invasive malignancy in the National Cancer Database (2010 to 2018). The sample consisted of 180,150 entries out of 14,279,749 cancer patients screened. A survival analysis of the topography-specific and histology-specific time to death was performed. Multivariate Cox regression revealed violations of the proportional hazard assumption for multiple covariates. Parametric models using a log-logistic distribution best described the population survival pattern. RESULTS: The primary topography "prostate" and morphology "choriocarcinoma" provided the strongest survival benefit among ICD-O types, whereas BM from prostate demonstrated a 14-month median overall increase in survival probability. Favorable prognostics were BM from breast, bone/joints, and testis; also, the morphologies of carcinoid tumor, mature B-cell lymphoma, and papillary adenocarcinoma. Poor prognostics were BM from gastrointestinal (liver, biliary tree, pancreas, and gallbladder) and gynecologic malignancies. All morphologies of spindle cell carcinoma, hemangiosarcoma, undifferentiated carcinoma, Ewing sarcoma, pseudosarcomatous carcinoma, renal cell carcinoma/sarcomatoid, signet ring cell carcinoma, spindle cell sarcoma, and squamous cell carcinoma/spindle cell were associated with poor survival. CONCLUSIONS: This is the largest cohort providing an unbiased estimate of the adjusted ICD-O topography and morphology effect sizes. The results can be summarized as a booklet for prognostic classification of disease in patients with BM secondary to systemic malignancy.

Standardising the biochemical confirmation of adult male hypogonadism; a joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine.

Background: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilis eassay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain.Design: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. Results: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. Conclusions: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.

Standardising the biochemical confirmation of adult male hypogonadism: A joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine.

BACKGROUND: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. DESIGN: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. RESULTS: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. CONCLUSIONS: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.

A Technique of Deep Brain Stimulation of the Globus Pallidus Interna for Dystonia Under General Anesthesia With Sevoflurane.

Background Globus pallidus interna (GPi) deep brain stimulation (DBS) is an established surgical procedure that confers a benefit in medication refractory dystonia. Patients with generalized dystonia require general anesthesia (GA) for the surgery as their movements may hinder the surgical procedure. General anesthetics tend to dampen the microelectrode recordings (MERs) from the GPi. Methods We describe our experience with a series of consecutive patients with dystonia who underwent bilateral GPi DBS using standard DBS and MER under GA using sevoflurane as the maintenance general anesthetic drug. All patients had Medtronic 3,387 leads implanted and connected to an RC battery. Patients underwent sequential programming of the DBS after the surgery. Results The mean age of the 13 patients who underwent DBS of the GPi for dystonia was 46.5 years with a range from 29 to 71 years. Every patient in our case series received various doses of (1.37% to 2.11%) inhaled sevoflurane for anesthesia maintenance. Sevoflurane provided adequate anesthesia and allowed accurate MERs from the GPi. No adverse effects were encountered. On follow-up and sequential DBS programming, patients had significant improvements in dystonia attesting to the accuracy of the electrode placements. Conclusions We report our experience using sevoflurane for maintenance of GA for bilateral GPi DBS for dystonia. The main benefits identified have been adequate anesthesia and reduction of dystonia-related movements to allow the performance of the DBS surgery. The MER signals from the GPi were not suppressed by sevoflurane. This allowed accurate mapping and placement of the DBS implants in the GPi.

Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). BACKGROUND: Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. METHODS: This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16-64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. RESULTS: Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (- 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes. CONCLUSION: Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

Risk Factors associated with COVID-19 Patients in India: A Single Center Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: The coronavirus disease 2019 (COVID-19) outbreak has caused a worldwide pandemic, resulting in >3.8 million deaths. Our aim is to identify the risk factors associated with in-hospital mortality using survival analysis considering the characteristics and outcomes of COVID-19 patients admitted to a dedicated tertiary-care hospital in Mumbai, India. MATERIALS AND METHODS: In a retrospective cohort study, 565 patients admitted from 28th March 2020 to 30th June 2020 were enrolled, and a follow-up was conducted till August 2020. To investigate the impact of COVID-19, survival analysis was performed using the Kaplan-Meier method. Potential risk factors associated with mortality were analyzed using logistic regression models for multivariate analysis and the Cox proportional hazards model for estimating hazard ratios (HRs). RESULTS: From the 565 positive COVID-19 cases, 49 patients died (8.7%) and 516 (91.3%) were discharged. Overall, 119 patients (20%) required intensive care unit (ICU) admission, of which 70 (58%) patients survived. The Kaplan-Meier survival curve showed a significant association of COVID-19 infection with age (≥60; p = 0.008), hypertension (p = 0.03), dialysis (p = 0.0001), lung commodities (p = 0.01), breathlessness (p = 0.0001), severe disease upon high-resolution computed tomography (HRCT) analysis (p = 0.0001), ICU admission (p = 0.0001), and low lymphocyte count at admission (p = 0.0001). Additionally, patients receiving tocilizumab (p = 0.0001) and deprived of hydroxychloroquine (HCQ) + azithromycin (azee) (p = 0.0001) were estimated at a high risk of mortality. INTERPRETATION AND CONCLUSION: Coronavirus disease 2019 (COVID-19) increased the risk of mortality in patients with increased age, comorbidities, and severe symptoms upon treatment with an immunosuppressant (tocilizumab). However, patients treated with HCQ + azee showed favorable results due to their antiviral effects in vitro.