With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently ...know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.
Although blacks receive lower doses of hemodialysis than whites, their survival when receiving dialysis treatment is better than that for whites. Previous studies of the relationship between the dose ...of dialysis and patient survival have not controlled for differences in patient characteristics.
To examine the association of mortality with the dose of hemodialysis for clusters of patients categorized by race and sex.
Retrospective analysis of laboratory data and mortality outcomes from 1994, using a national database of hemodialysis patients.
A total of 18144 black and white patients receiving hemodialysis 3 times weekly who either lived the entire year receiving hemodialysis or died.
The fractional reduction of urea in a single dialysis session as the measured hemodialysis dose (urea reduction ratio URR) after controlling for race, sex, age, and diabetes mellitus. Mortality was determined by strata of URRs and albumin and creatinine levels.
Across all age categories, blacks had lower URRs than whites, and men had lower URRs than women. In an age-adjusted model for evaluating interactions among URRs, race, sex, and diabetes, the association of URR with mortality risk was weak among blacks, particularly black men. After adjustment for age and diabetes, death probability curves were most steep for white women with URR values less than 60%. The death probability curves were least steep for black men. There was no meaningful difference between death probability and albumin or creatinine concentration among the race by sex clusters.
Using URR, the usual measure of hemodialysis dose, the assumption that the association between dialysis dose and survival is uniform across demographic groups appears incorrect. Comparisons of the quality of dialysis patient care should not rely on URR alone to predict patient survival.
ABSTRACT We present results of a stellar occultation by the Jupiter Trojan asteroid Patroclus and its nearly equal size moon, Menoetius. The geocentric mid-time of the event was 2013 October 21 ...06:43:02 UT. Eleven sites out of 36 successfully recorded an occultation. Seven chords across Patroclus yielded an elliptical limb fit of 124.6 by 98.2 km. There were six chords across Menoetius that yielded an elliptical limb fit of 117.2 by 93.0 km. There were three sites that got chords on both objects. At the time of the occultation we measured a separation of 664.6 km (0.247 arcsec) and a position angle for Menoetius of 265 7 measured eastward from J2000 north. Combining this occultation data with previous light curve data, the axial ratios of both objects are 1.3 : 1.21 : 1, indicative of a mostly oblate ellipsoid with a slight asymmetry in its equatorial projection. The oblate shape is not an equilibrium shape for the current rotation period, but would be if it were rotating with an ∼8 h period. This faster period is consistent with a pre-evolved state of the system with an orbital separation that is 50% smaller. Our best estimate of the system density is 0.88 g cm−3.
Amivantamab plus carboplatin–pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced ...non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial.
A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab–lazertinib–chemotherapy, chemotherapy, or amivantamab–chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab–lazertinib–chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.
All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively. Consistent PFS results were seen by investigator assessment (HR 0.41 and 0.38 for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab–chemotherapy had lower rates of hematologic AEs than amivantamab–lazertinib–chemotherapy.
Amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab–lazertinib–chemotherapy regimen.
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•Amivantamab–chemotherapy improved PFS and intracranial PFS versus chemotherapy.•Amivantamab–lazertinib–chemotherapy improved PFS and intracranial PFS versus chemotherapy.•Predominant AEs in the amivantamab-containing arms were hematologic, EGFR, and MET related.•MARIPOSA-2 is the first study to demonstrate improved PFS versus chemotherapy after disease progression on osimertinib.
Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy ...(HT) where possible benefits include a delay in the onset of dementia—yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self‐reported HT use on brain volume in 562 elderly women (71–94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate‐adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.
Declining estrogen levels for women in all stages of menopause can affect memory and risk of Alzheimer's Disease (AD), emphasizing a role for hormone therapy (HT). Effects may differ due to several factors including lifestyle and cardiovascular risk, genetic makeup, and timing and duration of HT. We addressed this hypothesis using self‐reported HT in 562 elderly women with mixed cognitive status, covarying for aforementioned factors. Voxelwise regression showed HT use as correlated with higher brain volume regardless of cognitive status
Abstract Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships ...between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. ...Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
Complications related to inadequate volume management are common during hemodialysis. This trial tested the hypothesis that availability of an intradialytic blood volume monitoring (IBVM) device ...improves fluid removal, reducing morbidity. A six-center, randomized trial with 6 mo of intervention comparing IBVM using Crit-Line versus conventional clinical monitoring was conducted. The average rate of non-access-related hospitalizations was compared across treatment groups using Poisson regression. Mortality analysis used the Kaplan Meier method. A total of 227 patients were randomized to Crit-Line, and 216 were randomized to conventional monitoring. Both groups had similar baseline characteristics. During the study, no differences in weight, BP, or number of dialysis-related complications were observed. There were 120 and 81 non-access-related hospitalizations in the Crit-Line and conventional monitoring groups. The adjusted risk ratio for non-access-related and access-related hospitalization was 1.61 (95% confidence interval 1.15 to 2.25; P = 0.01) and 1.52 (95% confidence interval 1.02 to 2.28; P = 0.04) for the Crit-Line monitoring group. Mortality was 8.7% in the Crit-Line monitoring group and 3.3% in the conventional group (P = 0.021). Standardized mortality ratios comparing the Crit-Line and conventional monitoring groups to the prevalent hemodialysis population were 0.77 (NS) and 0.26 (P < 0.001). Hospitalization rates were 1.51 and 1.03 events/yr in the Crit-Line and standard monitoring groups, compared with 2.01 for the prevalent hemodialysis population. IBVM was associated with higher nonvascular and vascular access-related hospitalizations and mortality compared with conventional monitoring. The atypically low hospitalization and mortality rates for the conventional monitoring group suggest that these findings should be generalized to the US hemodialysis population with caution.
Cardiovascular disease is an important cause of mortality among patients with chronic kidney disease (CKD). This study describes associations between CKD, cardiac revascularization strategies, and ...mortality among patients with CKD and cardiovascular disease. All patients undergoing cardiac catheterization at Duke University Medical Center (1995 to 2000) with documented stenosis > or =75% of at least one coronary artery and available creatinine data were included. CKD was staged using creatinine clearance (CrCl) derived from the Cockcroft-Gault formula (normal, > or = 90 ml/min; mild, 60 to 89 ml/min; moderate, 30 to 59 ml/min; severe, 15 to 29 ml/min). Cox proportional-hazard regression estimated the relationship between clinical variables, including CrCl and percutaneous coronary artery intervention (PCI), coronary artery bypass grafting (CABG), medical management, and patient survival. There were 4584 patients included, and 24% had CrCl <60 ml/min. Each 10-ml/min decrement in CrCl was associated with an increase in mortality (hazard ratio, 1.14; P < 0.0001). CABG was associated with a survival benefit among patients with both normal renal function and patients with CKD compared with medical management. In patients with normal renal function, CABG was not associated with survival benefit over PCI. However, in patients with CKD, CABG was associated with improved survival. PCI was associated with a survival benefit compared with medical management among patients with normal, mildly, and moderately impaired renal function. Among patients with severe CKD, PCI was not associated with improved survival. CABG is associated with greater mortality reduction than PCI in severe CKD.
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