Trends in End-of-Life Care and Satisfaction Among Veterans Undergoing Surgery.

OBJECTIVE: To examine trends in end-of-life care services and satisfaction among Veterans undergoing any inpatient surgery. SUMMARY BACKGROUND DATA: The Veterans Health Administration has undergone system-wide transformations to improve end-of-life care yet the impacts on end-of-life care services use and family satisfaction are unknown. METHODS: We performed a retrospective, cross-sectional analysis of Veterans who died within 90 days of undergoing inpatient surgery between 01/2010 and 12/2019. Using the Veterans Affairs (VA) Bereaved Family Survey (BFS), we calculated the rates of palliative care and hospice use and examined satisfaction with end-of-life care. After risk and reliability adjustment for each VA hospital, we then performed multivariable linear regression model to identify factors associated with the greatest change. RESULTS: Our cohort consisted of 155,250 patients with a mean age of 73.6 years (standard deviation 11.6). Over the study period, rates of palliative care consultation and hospice use increased more than two-fold (28.1% to 61.1% and 18.9% to 46.9%, respectively) while the rate of BFS excellent overall care score increased from 56.1% to 64.7%. There was wide variation between hospitals in the absolute change in rates of palliative care consultation, hospice use and BFS excellent overall care scores. Rural location and ACGME accreditation were hospital-level factors associated with the greatest changes. CONCLUSIONS: Among Veterans undergoing inpatient surgery, improvements in satisfaction with end-of-life care paralleled increases in end-of-life care service use. Future work is needed to identify actionable hospital-level characteristics that may reduce heterogeneity between VA hospitals and facilitate targeted interventions to improve end-of-life care.

Healthy Days at Home Among Older Medicare Beneficiaries With Traumatic Brain Injury Requiring Inpatient Rehabilitation.

OBJECTIVE: The objectives of this study were to characterize and identify correlates of healthy days at home (HDaH) before and after TBI requiring inpatient rehabilitation. Setting: Inpatient hospital, nursing home, and home health services. PARTICIPANTS: Average of n= 631 community-dwelling fee-for-service age 66+ Medicare beneficiaries across 30 replicate samples who were hospitalized for traumatic brain injury (TBI) between 2012 and 2014 and admitted to an inpatient rehabilitation facility (IRF) within 72 hours of hospital discharge. DESIGN: Retrospective study using data from Medicare claims supplemented with data from the National Trauma Databank. MAIN MEASURES: The primary outcome, HDaH, was calculated as time alive not using inpatient hospital, nursing home, and home health services in the year before TBI hospitalization and after IRF discharge. RESULTS: We found HDaH declined from 93.2% in the year before TBI hospitalization to 65.3% in the year after IRF discharge (73.6% among survivors only). Most variability in HDaH was: (1) in the first 3 months after discharge and (2) by discharge disposition, with persons discharged from IRF to another acute hospital having the worst prognosis for utilization and death. In negative binomial regression models, the strongest predictors of HDaH in the year after discharge were rehabilitation Functional Independence Measure mobility score (ß = 0.03; 95% CI, 0.002-0.06) and inpatient Charlson Comorbidity Index score (ß = - 0.06; 95% CI, -0.13 to 0.001). Dual Medicaid eligible was associated with less HDaH among survivors (ß = - 0.37; 95% CI, -0.66 to -0.07). CONCLUSION: In this study, among community-dwelling older adults with TBI, we found a notable decrease in the proportion of time spent alive at home without higher-level care after IRF discharge compared to before TBI. The finding that physical disability and comorbidities were the biggest drivers of healthy days alive in this population suggests that a chronic disease management model is required for older adults with TBI to manage their complex health care needs.

Predictors of Multidimensional Profiles of Participation After Traumatic Brain Injury: A TBI Model Systems Study.

OBJECTIVES: To identify personal, clinical, and environmental factors associated with 4 previously identified distinct multidimensional participation profiles of individuals following traumatic brain injury (TBI). SETTING: Community. PARTICIPANTS: Participants (n = 408) enrolled in the TBI Model Systems (TBIMS) Participation Module, all 1 year or more postinjury. DESIGN: Secondary data analysis of cross-sectional data from participants in a multicenter TBIMS module study on participation conducted between May 2006 and September 2007. Participants provided responses to questionnaires via a telephone interview at their study follow-up (1, 2, 5, 10, or 15 years postinjury). MAIN MEASURES: Participants provided responses to personal (eg, demographic), clinical (eg, function), environmental (eg, neighborhood type), and participation measures to create multidimensional participation profiles. Data from measures collected at the time of injury (preinjury questionnaire, injury characteristics) were also included. The primary outcome was assignment to one of 4 multidimensional participation profile groups based on participation frequency, importance, satisfaction, and enfranchisement. The measures used to develop the profiles were: Participation Assessment with Recombined Tools-Objective, Importance, and Satisfaction scores, each across 3 domains (Productivity, Social Relationships, Out and About in the Community) and the Enfranchisement Scale (contributing to one's community, feeling valued by the community, choice and control). RESULTS: Results of the multinomial regression analysis, with 4 distinct participation profile groups as the outcome, indicated that education, current employment, current illicit drug use, current driving status, community type, and Functional Independence Measure Cognitive at follow-up significantly distinguished participation profile groups. Findings suggest a trend toward differences in participation profile groups by race/Hispanic ethnicity. CONCLUSIONS: Understanding personal, clinical, and environmental factors associated with distinct participation outcome profiles following TBI may provide more personalized and nuanced guidance to inform rehabilitation intervention planning and/or ongoing clinical monitoring.

Establishing a plan to improve pediatric patient comfort during PIV insertions and blood specimen collection: a quality improvement effort.

HIGHLIGHTS: Patient comfort during peripheral intravenous (PIV) insertion and specimen collection was increased. The authors extended the contingency plan implemented for PICC insertion to include PIV insertion and specimen collection. The authors met their goals by using quality improvement methodology. Prioritizing patient comfort often requires institutional culture change. BACKGROUND: Needle procedures can cause pain and distress, especially in pediatric patients.1 Retrospective data collected at a freestanding pediatric facility revealed that approximately 30% of pediatric patients were not demonstrating sufficient levels of comfort during peripheral intravenous (PIV) catheter insertion and specimen collection (lab draws) even after successful implementation of comfort measures by the vascular access team (VAT) in an adjacent procedure (eg peripherally inserted central catheter placement). The current quality improvement project was implemented to support adaptation and expansion of previous lessons learned to PIVs and lab draws specifically. DESIGN AND METHODS: The VAT used the Pediatric Sedation State Scale,2 a standardized assessment tool integrated into the electronic medical record, to assess procedural comfort during PIVs and lab draws from February 2021 through April 2023. A total of 24 134 patients aged 0 to 18 years were included in the data collection. Interventions were delivered concurrently and included (1) reeducation/ongoing support for implementation of the Comfort Promise3 measures, (2) the creation and implementation of advanced comfort options, and (3) culture change. AIMS AND OBJECTIVES: The goal of the interventions was to improve the percentage of pediatric patients achieving adequate levels of comfort beginning at 68% in year 1 to 90% in year 2. RESULTS: From February 2021 to April 2023, the VAT team was able to improve procedural comfort scores from 68% to 90% of pediatric patients with adequate comfort for lab draws and/or PIV insertions. CONCLUSIONS: While standard comfort measures are a good first step in pain management during needle procedures, they are not sufficient for every pediatric patient. Nitrous, sedation, and the use of anxiolytics and analgesics can play an important role in reducing pain and anxiety during needle procedures and should be considered for patients not achieving adequate levels of comfort with standard comfort measures.

Differential cell motion: A mathematical model of anterior posterior sorting.

Here, we investigate how a subpopulation of cells can move through an aggregate of cells. Using a stochastic force-based model of Dictyostelium discoideum when the population is forming a slug, we simulate different strategies for prestalk cells to reliably move to the front of the slug while omitting interaction with the substrate thus ignoring the overall motion of the slug. Of the mechanisms that we simulated, prestalk cells being more directed is the best strategy followed by increased asymmetric motive forces for prestalk cells. The lifetime of the cell adhesion molecules, while not enough to produce differential motion, did modulate the results of the strategies employed. Finally, understanding and simulating the appropriate boundary conditions are essential to correctly predict the motion.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

BACKGROUND: Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. METHODS: We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. RESULTS: 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/µL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/µL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/µL; IQR: 47-142; WBC: 45 cells/µL; IQR: 8-128). Among those with CSF WBC <5 cells/µL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/µL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. CONCLUSIONS: Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. CLINICAL TRIALS REGISTRATION: NCT01802385.

Using Fluorescence Recovery After Photobleaching data to uncover filament dynamics.

Fluorescence Recovery After Photobleaching (FRAP) has been extensively used to understand molecular dynamics in cells. This technique when applied to soluble, globular molecules driven by diffusion is easily interpreted and well understood. However, the classical methods of analysis cannot be applied to anisotropic structures subjected to directed transport, such as cytoskeletal filaments or elongated organelles transported along microtubule tracks. A new mathematical approach is needed to analyze FRAP data in this context and determine what information can be obtain from such experiments. To address these questions, we analyze fluorescence intensity profile curves after photobleaching of fluorescently labelled intermediate filaments anterogradely transported along microtubules. We apply the analysis to intermediate filament data to determine information about the filament motion. Our analysis consists of deriving equations for fluorescence intensity profiles and developing a mathematical model for the motion of filaments and simulating the model. Two closed forms for profile curves were derived, one for filaments of constant length and one for filaments with constant velocity, and three types of simulation were carried out. In the first type of simulation, the filaments have random velocities which are constant for the duration of the simulation. In the second type, filaments have random velocities which instantaneously change at random times. In the third type, filaments have random velocities and exhibit pausing between velocity changes. Our analysis shows: the most important distribution governing the shape of the intensity profile curves obtained from filaments is the distribution of the filament velocity. Furthermore, filament length which is constant during the experiment, had little impact on intensity profile curves. Finally, gamma distributions for the filament velocity with pauses give the best fit to asymmetric fluorescence intensity profiles of intermediate filaments observed in FRAP experiments performed in polarized migrating astrocytes. Our analysis also shows that the majority of filaments are stationary. Overall, our data give new insight into the regulation of intermediate filament dynamics during cell migration.

What is the relationship between photosensitizing drugs and skin cancer?

ABSTRACT: Many medications are associated with phototoxicity or photoallergy, the two types of photosensitivity. Recently, a warning related to increased skin cancer risk was added to the labeling of the popular diuretic hydrochlorothiazide. This article reviews some photosensitizing medications and describes patient education on preventing and recognizing photosensitivity reactions and skin cancer.

Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. METHODS: In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. RESULTS: A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. CONCLUSIONS: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Research Letter: Characterization of Older Adults Hospitalized With Traumatic Brain Injury Admitted to Long-Term Acute Care Hospitals.

OBJECTIVE: To describe patient, hospital, and geographic characteristics of older adult Medicare beneficiaries hospitalized with traumatic brain injury (TBI) and admitted to long-term acute care hospitals (LTACHs). SETTING: Acute hospital and LTACH facilities. PARTICIPANTS: In total, 15 148 Medicare beneficiaries 65 years and older with an acute TBI hospitalization who were discharged to an LTACH. DESIGN: This retrospective cohort study used data from Centers for Medicare & Medicaid Services' Medicare Enrollment and Provider Analysis and Review data files from 2011 to 2016. MAIN MEASURES: Patient variables (age, sex, premorbid health burden, medical complications and procedures), hospital variables (for-profit status, bed size), and state/regional geographic variation associated with LTACH TBI admission. RESULTS: Older adult Medicare beneficiaries admitted to LTACH facilities following TBI hospitalization were on average 77.1 years old and predominantly White males. In total, 94.6% of the sample had 2+ multimorbidities present during acute hospitalization. Average acute hospital length of stay of the sample was 19.4 days, and rates of acute mechanical ventilation of any duration and tracheostomy procedures were 56.6% and 40%, respectively. Only 4.1% of patients seen in LTACHs were discharged home after LTACH stay; the primary discharge disposition was skilled nursing facilities (41.3%). Geographic analyses indicated that selected Southern and Midwestern states had the greatest number of LTACH facilities and proportion of LTACH admissions. CONCLUSIONS: There has been limited characterization of the hospitalized TBI population admitted to LTACHs. Our findings among older adult Medicare beneficiaries suggest this population is highly medically complex and are seldom discharged home after their LTACH stay. There are also notable geographic variations in LTACH TBI admissions across the United States. More research is warranted to understand long-term functional outcomes among this population.

How Structural Features of a Spring-Based Model of Fibrous Collagen Tissue Govern the Overall Young's Modulus.

While much study has been dedicated to investigating biopolymers' stress-strain response at low strain levels, little research has been done to investigate the almost linear region of biopolymers' stress-strain response and how the microstructure affects it. We propose a mathematical model of fibrous networks, which reproduces qualitative features of collagen gel's stress-strain response and provides insight into the key features which impact the Young's modulus of similar fibrous tissues. This model analyzes the relationship of the Young's modulus of the lattice to internodal fiber length, number of connection points or nodes per unit area, and average number of connections to each node. Our results show that fiber length, nodal density, and level of connectivity each uniquely impact the Young's modulus of the lattice. Furthermore, our model indicates that the Young's modulus of a lattice can be estimated using the effective resistance of the network, a graph theory technique that measures distances across a network. Our model thus provides insight into how the organization of fibers in a biopolymer impact its Young's modulus.

The cardiac effects of hydroxychloroquine in immune-mediated rheumatologic diseases.

ABSTRACT: Hydroxychloroquine, when used to treat patients with rheumatoid arthritis or systemic lupus erythematosus, has been found to reduce cardiovascular disease (CVD). The drug also has been associated with cardiac adverse reactions such as conduction abnormalities. This article reviews the reduction of CVD and the cardiac adverse reactions associated with hydroxychloroquine.

Impact of biological sex on cryptococcal meningitis mortality in Uganda and South Africa.

The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00-1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07-1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94-1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P = .02). Of the 373 participants with CSF biomarkers, men had higher median pro- and anti-inflammatory, monocyte/macrophage differentiation, maturation, and migration, immune exhaustion, and cytotoxicity cytokines than women (P < .05). We identified biological sex as proxy for anemia, a potentially modifiable risk factor for cryptococcal meningitis mortality. Immune response may contribute to the multifaceted underlying mechanisms for the discrepancy in mortality based on sex. LAY SUMMARY: We examined the role of biological sex in cryptococcal meningitis mortality in a large cohort. Our findings reveal significant differences in inflammatory markers by biological sex. Women have significantly higher mortality due to cryptococcal meningitis that is attributable to anemia at baseline.

Positive Beliefs and the Likelihood of Successful Community Discharge From Skilled Nursing Facilities.

OBJECTIVES: To examine the association of patient and direct-care staff beliefs about patients' capability to increase independence with activities of daily living (ADL) and the probability of successful discharge to the community after a skilled nursing facility (SNF) stay. DESIGN: Retrospective cohort study of SNF patients using 100% Medicare inpatient claims and Minimum Data Set resident assessment data. Linear probability models were used to estimate the probability of successful discharge based on patient and staff beliefs about the patient's ability to improve in function, as well as patient and staff beliefs together. Estimates were adjusted for demographics, health status, functional characteristics, and SNF fixed effects. PARTICIPANTS: Fee-for-service Medicare beneficiaries (N=526,432) aged 66 years or older who were discharged to an SNF after hospitalization for stroke, hip fracture, or traumatic brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Successful community discharge (discharged alive within 90d of SNF admission and remaining in the community for ≥30d without dying or health care facility readmission). RESULTS: Patients with positive beliefs about their capability to increase independence with ADLs had a higher adjusted probability of successful discharge than patients with negative beliefs (positive, 63.8%; negative, 57.8%; difference, 6.0%, 95% confidence interval [CI], 5.4-6.6). This remained true regardless of staff beliefs, but the difference in successful discharge probability between patients with positive and negative beliefs was larger when staff had positive beliefs. Conversely, the association between staff beliefs and successful discharge varied based on patient beliefs. If patients had positive beliefs, the difference in the probability of successful discharge between positive and negative staff beliefs was 2.5% (95% CI, 1.0-4.0). If patients had negative beliefs, the difference between positive and negative staff beliefs was -4.6% (95% CI, -6.0 to -3.2). CONCLUSIONS: Patients' beliefs have a significant association with the probability of successful discharge. Understanding patients' beliefs is critical to appropriate goal-setting, discharge planning, and quality SNF care.

Successful Community Discharge Among Older Adults With Traumatic Brain Injury in Skilled Nursing Facilities.

OBJECTIVE: To identify patient, injury, and functional status characteristics associated with successful discharge to the community following a skilled nursing facility (SNF) stay among older adults hospitalized following traumatic brain injury (TBI). SETTING: Skilled nursing facilities. PARTICIPANTS: Medicare fee-for-service beneficiaries admitted to an SNF after hospitalization for TBI. DESIGN: Retrospective cohort study using Medicare administrative data merged with the National Trauma Data Bank using a multilayered Bayesian record linkage approach. MAIN OUTCOME MEASURE: Successful community discharge: discharged alive within 100 days of SNF admission and remaining in the community for 30 days or more without dying or admission to a healthcare facility. RESULTS: Medicaid enrollment, incontinence, decreased independence with activities of daily living, and cognitive impairment were associated with lower odds of successful discharge, whereas race "other" was associated with higher odds of successful discharge. Injury factors including worse injury severity (Glasgow Coma Scale and Abbreviated Injury Scale scores) and fall-related injury mechanism were not associated with successful discharge. CONCLUSION: Among older adults with TBI who discharge to an SNF, sociodemographic and functional status characteristics are associated with successful discharge and may be useful to clinicians for discharge planning. Acute injury severity indices may have limited utility in predicting discharge disposition once a patient is admitted to an SNF for post-acute care.

Assessing Physical Function and Mobility following Pediatric Traumatic Brain Injury with the NIH Toolbox Motor Battery: A Feasibility Study.

AIMS: Traumatic brain injury (TBI) can impair physical function in children. The NIH Toolbox Motor Battery (NIHTB-M) was designed to be a brief assessment of physical function, but no studies have examined its use in children with TBI. This study aims to describe the feasibility of using the NIHTB-M to assess children with TBI. METHODS: The NIHTB-M was administered to children with TBI 2 weeks (n = 22) and/or 6 months (n = 23) following injury. This descriptive study summarizes participant performance, administration challenges, and the association between NIHTB-M scores, participant characteristics, and subjective report of physical function. RESULTS: Of the NIHTB-M domains, deficits in endurance and balance were most prevalent. Children aged 5 to 16 years could complete the assessment per administration guidelines, except for a few cases (n = 3) where orthopedic injuries limited participation. Younger children (aged 3 to 4) had difficulty following the NIHTB-M directions. Technological issues impacted balance assessment in several cases (n = 6). CONCLUSION: The NIHTB-M is brief to administer, generally well tolerated by school-aged children and, despite occasional technological challenges, is a feasible performance-based battery for assessment of children with TBI for clinical and research purposes. Additional investigation of psychometric properties and ceiling and floor effects is needed.

Which drug is best for a patient with type 2 diabetes and heart failure?

ABSTRACT: Heart failure is twice as common in men with type 2 diabetes than those without it and is almost five times greater in women with diabetes. Ideally, effective treatment for one condition also will help with the other; certainly, clinicians should not prescribe a medication that will potentially worsen one of the conditions, if avoiding it is at all possible. This article reviews the effects of diabetes medications on heart failure outcomes.

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

BACKGROUND: In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. METHODS: We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. RESULTS: Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001). CONCLUSIONS: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities.

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2). CONCLUSION: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society.

Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management.

Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7-1.0 mg/kg). Five were exposed to 200-800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.