To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance.
We conducted a ...multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests.
The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction.
GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health.
...when adjusting for age and sex, there remained no significant association between obesity (vs nonobesity) and receiving 2+ doses (odds ratio 1.22; 95% CI 0.77-1.93; P = .40).  n (%) P value ...Overall (N = 321) 1 Dose (n = 267) 2+ Doses (n = 54) Demographic and anthropomorphic characteristics     Age (y), median (IQR) 8.8 (3.0-16.2) 8.2 (2.9-16.3) 11.8 (4.5-15.6) .27      Males 151 (47) 128 (48) 23 (4) .47  BMI category    .82 Underweight 27 (8) 24 (9) 3 (6)  Healthy weight 168 (52) 139 (52) 29 (54)  Overweight 57 (18) 48 (18) 9 (17)  Obese 69 (22) 56 (21) 13 (24)   Medical/reaction historylow *     Known allergy to reaction trigger 171 (54) 137 (52) 34 (63) .14 Specific trigger causing reaction     Peanuts 84 (26) 65 (25) 17 (33) .26 Tree nuts 72 (24) 65 (25) 11 (21) .55 Fruits and vegetables 20 (6) 14 (5) 6 (12) .10 Shellfish 24 (8) 23 (9) 1 (2) .09 Fish 12 (4) 11 (4) 1 (2) .43 Milk products 40 (13) 36 (14) 4 (8) .22 Eggs 18 (6) 13 (5) 5 (10) .20 Wheat 2 (1) 2 (1) 0 (0) .53 Other food 48 (15) 38 (15) 10 (19) .41 Insect sting 10 (3) 8 (3) 2 (4) .79 Anaphylaxis symptoms     Cutaneous 299 (93) 248 (93) 51 (94) .68 Gastrointestinal 153 (48) 133 (50) 20 (37) .09 Respiratory 262 (82) 213 (80) 49 (91) .06 Cardiovascular 21 (7) 18 (7) 3 (6) .75  ED treatment summary     Time to administration of first dose of epinephrine (min)dagger 21 (9-50) 20 (10-50) 27 (7-55) .76 First epinephrine dose given (mg)double dagger 0.30 (0.15-0.30) 0.30 (0.15-0.30) 0.30 (0.25-0.30) .050 Adjunctive medications given     Antihistamine 210 (64) 173 (65) 37 (69) .60 Steroid 183 (84) 157 (85) 26 (79) .38 β-agonist 88 (27) 65 (24) 23 (43) .006 Table I Demographic characteristics, medical history, and treatment summary of patients presenting to the ED with anaphylaxis due to food or insect sting who received at least 1 epinephrine treatmentlow * BMI, Body mass index; IQR, intraquartile range.
Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in ...patients with
or
germline mutation-associated early breast cancer.
We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with
or
germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.
A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval CI, 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.
Among patients with high-risk, HER2-negative early breast cancer and germline
or
pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).
Mutant mouse models related to schizophrenia have been based primarily on the pathophysiology of schizophrenia, the known effects of antipsychotic drugs, and candidate genes for schizophrenia. ...Sensorimotor gating deficits in schizophrenia patients, as indexed by measures of prepulse inhibition of startle (PPI), have been well characterized and suggested to meet the criteria as a useful endophenotype in human genetic studies. PPI refers to the ability of a non-startling “prepulse” to inhibit responding to the subsequent startling stimulus or “pulse.” Because of the cross-species nature of PPI, it has been used primarily in pharmacological animal models to screen putative antipsychotic medications. As techniques in molecular genetics have progressed over the past 15 years, PPI has emerged as a phenotype used in assessing genetic mouse models of relevance to schizophrenia. In this review, we provide a selected overview of the use of PPI in mouse models of schizophrenia and discuss the contribution and usefulness of PPI as a phenotype in the context of genetic mouse models. To that end, we discuss mutant mice generated to address hypotheses regarding the pathophysiology of schizophrenia and candidate genes (i.e., hypothesis driven). We also briefly discuss the usefulness of PPI in phenotype-driven approaches in which a PPI phenotype could lead to “bottom up” approaches of identifying novel genes of relevance to PPI (i.e., hypothesis generating).
The spatiotemporal structure of the human microbiome
, proteome
and metabolome
reflects and determines regional intestinal physiology and may have implications for disease
. Yet, little is known ...about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals
. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.
The authors summarize the recent developments in speckle-tracking echocardiography (STE), a relatively new technique that can be used in conjunction with two-dimensional or three-dimensional ...echocardiography for resolving the multidirectional components of left ventricular (LV) deformation. The tracking system is based on grayscale B-mode images and is obtained by automatic measurement of the distance between 2 pixels of an LV segment during the cardiac cycle, independent of the angle of insonation. The integration of STE with real-time cardiac ultrasound imaging overcomes some of the limitations of previous work in the field and has the potential to provide a unified framework to more accurately quantify the regional and global function of the left ventricle. STE holds promise to reduce interobserver and intraobserver variability in assessing regional LV function and to improve patient care while reducing health care costs through the early identification of subclinical disease. Following a brief overview of the approach, the authors pool the initial observations from clinical studies on the development, validation, merits, and limitations of STE.
Cognitive deficits in schizophrenia are among the core symptoms of the disease, correlate with functional outcome, and are not well treated with current antipsychotic therapies. In order to bring ...together academic, industrial, and governmental bodies to address this great 'unmet therapeutic need', the NIMH sponsored the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Through careful factor analysis and consensus of expert opinion, MATRICS identified seven domains of cognition that are deficient in schizophrenia (attention/vigilance, working memory, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition) and recommended a specific neuropsychological test battery to probe these domains. In order to move the field forward and outline an approach for translational research, there is a need for a "preclinical MATRICS" to develop a rodent test battery that is appropriate for drug development. In this review, we outline such an approach and review current rodent tasks that target these seven domains of cognition. The rodent tasks are discussed in terms of their validity for probing each cognitive domain as well as a brief overview of the pharmacology and manipulations relevant to schizophrenia for each task.
A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) ...(2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
Aims/hypothesis
We hypothesised that progression of islet autoimmunity and type 1 diabetes mellitus differs among races/ethnicities in at-risk individuals.
Methods
In this study, we analysed the data ...from the Type 1 Diabetes TrialNet Pathway to Prevention Study. We studied 4873 non-diabetic, autoantibody-positive relatives of individuals with type 1 diabetes followed prospectively (11% Hispanic, 80.9% non-Hispanic white NHW, 2.9% non-Hispanic black NHB and 5.2% non-Hispanic other NHO). Primary outcomes were time from single autoantibody positivity confirmation to multiple autoantibody positivity, and time from multiple autoantibody positivity to type 1 diabetes mellitus diagnosis.
Results
Conversion from single to multiple autoantibody positivity was less common in Hispanic individuals than in NHW individuals (HR 0.66 95% CI 0.46, 0.96,
p
= 0.028) adjusting for autoantibody type, age, sex, Diabetes Prevention Trial Type 1 Risk Score and
HLA-DR3-DQ2/DR4-DQ8
genotype. In participants who screened positive for multiple autoantibodies (
n
= 2834), time to type 1 diabetes did not differ by race/ethnicity overall (
p
= 0.91). In children who were <12 years old when multiple autoantibody positivity was determined, being overweight/obese had differential effects by ethnicity: type 1 diabetes risk was increased by 36% in NHW children (HR 1.36 95% CI 1.04, 1.77,
p
= 0.024) and was nearly quadrupled in Hispanic children (HR 3.8 95% CI 1.6, 9.1,
p
= 0.0026). We did not observe this interaction in participants who were ≥12 years old at determination of autoantibody positivity, although this group size was limited. No significant differential risks were observed between individuals of NHB and NHW ethnicity.
Conclusions/interpretation
The risk and rate of progression of islet autoimmunity were lower in Hispanic compared with NHW at-risk individuals, while significant differences in the development of type 1 diabetes were limited to children <12 years old and were modified by BMI.
We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic ...relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457,
= 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml;
= 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1
TIGIT
CD8
T cells (
= 0.44,
= 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8
T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy.
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