Immune checkpoint inhibitor toxicity and associated outcomes in older patients with cancer.

INTRODUCTION: Increased immune checkpoint inhibitor (ICI) use in various advanced cancer types has led to a parallel rise in immune-related adverse events (irAEs). Despite widespread use, ICI data in older patients remains limited. We investigate irAE prevalence in older patients receiving ICI and whether irAEs and survival are associated. MATERIALS AND METHODS: Our retrospective study included patients aged ≥65 years with advanced malignancies who had ≥1 dose of ICI from January 2011 through September 2019. We evaluated irAE cases and their respective grades and assessed oncological response by progression-free survival (PFS) and overall survival (OS). RESULTS: Mean age of 210 patients was 75.0 ± 7.2 years, 58.1% were men, and most were white. IrAE prevalence was 41.4% (n = 87); 9.5% (n = 20) developed multisystem irAE. Most irAEs were grades 1 and 2 (27.6% and 49.4%, respectively), while grades 3 and 4 accounted for 17.2% and 5.8%, respectively. No grade 5 irAE occurred. Compared with patients with no irAEs, those with irAEs had improved OS (HR [hazard ratio], 0.41; 95% CI [confidence interval], 0.282-0.597; p < 0.0001) and PFS (HR, 0.311; 95% CI: 0.213-0.453; p < 0.0001). Improved OS was seen with irAE grades 1 and 2 versus grades 3 and 4 (HR, 0.344; 95% CI: 0.171-0.694; p = 0.0029). Similarly, improved PFS was seen with lower grade irAE (HR, 0.489; 95% CI: 0.247-0.965; p = 0.0391). DISCUSSION: The irAE prevalence in older patients was similar to that in younger patients. To our knowledge, this is one of few studies that confirms a positive association of irAE on both OS and PFS in older patients with cancer, and improved OS and PFS with lower versus higher grade irAE.

Establishing a national strategy for shared research resources in biomedical sciences.

Contemporary science has become increasingly multi-disciplinary and team-based, resulting in unprecedented growth in biomedical innovation and technology over the last several decades. Collaborative research efforts have enabled investigators to respond to the demands of an increasingly complex 21st century landscape, including pressing scientific challenges such as the COVID-19 pandemic. A major contributing factor to the success of team science is the mobilization of core facilities and shared research resources (SRRs), the scientific instrumentation and expertise that exist within research organizations that enable widespread access to advanced technologies for trainees, faculty, and staff. For over 40 years, SRRs have played a key role in accelerating biomedical research discoveries, yet a national strategy that addresses how to leverage these resources to enhance team science and achieve shared scientific goals is noticeably absent. We believe a national strategy for biomedical SRRs-led by the National Institutes of Health-is crucial to advance key national initiatives, enable long-term research efficiency, and provide a solid foundation for the next generation of scientists.

A Review of the Scientific Rigor, Reproducibility, and Transparency Studies Conducted by the ABRF Research Groups.

Shared research resource facilities, also known as core laboratories (Cores), are responsible for generating a significant and growing portion of the research data in academic biomedical research institutions. Cores represent a central repository for institutional knowledge management, with deep expertise in the strengths and limitations of technology and its applications. They inherently support transparency and scientific reproducibility by protecting against cognitive bias in research design and data analysis, and they have institutional responsibility for the conduct of research (research ethics, regulatory compliance, and financial accountability) performed in their Cores. The Association of Biomolecular Resource Facilities (ABRF) is a FASEB-member scientific society whose members are scientists and administrators that manage or support Cores. The ABRF Research Groups (RGs), representing expertise for an array of cutting-edge and established technology platforms, perform multicenter research studies to determine and communicate best practices and community-based standards. This review provides a summary of the contributions of the ABRF RGs to promote scientific rigor and reproducibility in Cores from the published literature, ABRF meetings, and ABRF RGs communications.

The Effects of Music-Contingent Gait Training on Cognition and Mood in Parkinson Disease: A Feasibility Study.

Background. In Parkinson disease (PD), gait impairments often coexist with nonmotor symptoms such as anxiety and depression. Biofeedback training may improve gait function in PD, but its effect on nonmotor symptoms remains unclear. This study explored the cognitive and global effects of Ambulosono, a cognitive gait training method utilizing step size to contingently control the real-time play of motivational music. Objective. This study examined the feasibility of music-contingent gait training and its effects on neuropsychological test performance and mood in persons with PD. Methods. A total of 30 participants with mild to moderate PD were semirandomized via sequential alternating assignment into an experimental training group or control music group. The training group received 12 weeks of music-contingent training, whereby music play was dependent on the user achieving a set stride length, adjusted online based on individual performance. The control group received hybrid training beginning with 6 weeks of noncontingent music walking, whereby music played continuously regardless of step size, followed by 6 weeks of music-contingent training. Global cognition, memory, executive function, attention, and working memory assessments were completed by blinded assessors at baseline, 6 weeks, and 12 weeks. Motor function, mood, and anxiety were assessed. Results. Average training adherence was 97%, with no falls occurring during training sessions. Improvements on cognitive measures were not clinically significant; however, significant decreases in depression and anxiety were observed in both groups over time (P < .05). Conclusions. Music-contingent gait training is feasible and safe in individuals with PD. Further investigation into potential therapeutic applications of this technology is recommended.

Heterosexual Self-Presentation and Other Individual- and Community-Based Correlates of HIV testing among Latino Men Who Have Sex With Men.

From 2010 to 2014, HIV diagnoses among Latino men who have sex with other men (LMSM) have increased by 14%, while diagnoses declined by 11% among white, non-Latino MSM. This health disparity is in part due to exposure to other LMSM with undiagnosed HIV infections. To effectively engage LMSM who are unaware of their serostatus, profiles of men differing in theorized determinants of HIV testing must be considered. In this retrospective study, we examined data from 546 LMSM to investigate whether hypothesized individual- (traditional masculine gender role conformity; sexual identity development status; alcohol and illicit drug use; sexual risk behaviors; perceived HIV susceptibility; and HIV stigma) and community-based (HIV prevention programming, access to health care, social support, neighborhood collective efficacy) factors were associated with differences in HIV testing. Latent profile analysis was used to identify profiles of men, and subsequent analyses examined whether profiles exhibited differential proportions of HIV testing. Four latent profiles were observed. One profile (50.3% tested) differed markedly from all other profiles (5.1 to 11% tested) in HIV testing. Characteristics of participants in this unique profile included reporting lower levels of heterosexual self-presentation, sexual identity uncertainty (and high levels of sexual identity commitment), condom use, HIV stigma, education, and perceived HIV susceptibility than all other profiles. Findings could improve HIV testing rates among LMSM by specifying ways in which public health advertisements/campaigns and community-based testing outreach efforts could be tailored to men most at-risk for transmitting HIV due to unknown serostatus.

Survey on Scientific Shared Resource Rigor and Reproducibility.

Shared scientific resources, also known as core facilities, support a significant portion of the research conducted at biomolecular research institutions. The Association of Biomolecular Resource Facilities (ABRF) established the Committee on Core Rigor and Reproducibility (CCoRRe) to further its mission of integrating advanced technologies, education, and communication in the operations of shared scientific resources in support of reproducible research. In order to first assess the needs of the scientific shared resource community, the CCoRRe solicited feedback from ABRF members via a survey. The purpose of the survey was to gain information on how U.S. National Institutes of Health (NIH) initiatives on advancing scientific rigor and reproducibility influenced current services and new technology development. In addition, the survey aimed to identify the challenges and opportunities related to implementation of new reporting requirements and to identify new practices and resources needed to ensure rigorous research. The results revealed a surprising unfamiliarity with the NIH guidelines. Many of the perceived challenges to the effective implementation of best practices (i.e., those designed to ensure rigor and reproducibility) were similarly noted as a challenge to effective provision of support services in a core setting. Further, most cores routinely use best practices and offer services that support rigor and reproducibility. These services include access to well-maintained instrumentation and training on experimental design and data analysis as well as data management. Feedback from this survey will enable the ABRF to build better educational resources and share critical best-practice guidelines. These resources will become important tools to the core community and the researchers they serve to impact rigor and transparency across the range of science and technology.

Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells.

Resident microbiota activate regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies described the functional importance and mechanisms by which gut microbiota and specific microbial components influenced the development of intestinal IL-10-producing B cells. We used fecal transplant to germ-free (GF) Il10+/EGFP reporter and Il10-/- mice to demonstrate that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory-1 cells in ex-GF mice. IL-10 in turn down-regulated microbiota-activated mucosal inflammatory cytokines. TLR2/9 ligands and enteric bacterial lysates preferentially induced IL-10 production and regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell co-transfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2, MyD88 and PI3K-dependent fashion. In vitro studies implicated PI3Kp110δ and AKT downstream signaling. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88 and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.

Utility of the Addenbrooke's Cognitive Examination in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that primarily affects motor neurons. Cognitive changes are reported in 25%-50% of patients, secondary to frontotemporal involvement. The objective of this study was to evaluate the utility of a screening tool, the Addenbrooke's Cognitive Examination (ACE), in ALS patients. METHODS: In this retrospective cross-sectional study, performance on the ACE was compared between 55 ALS patients and 49 healthy controls. The validation of the ACE in ALS patients was explored using a neuropsychometric battery. Correlations between the ACE and clinical variables such as the ALS Functional Rating Scale-Revised (ALSFRS-R) and forced vital capacity were computed. RESULTS: A higher percentage of patients were below cut-off scores, although this remained non-significant between the patient and control groups. The ACE did not reveal significant differences between ALS patients and controls. The scores on the ACE displayed moderate correlations with our neuropsychometric battery for some domains, whereas others showed poor or no associations. Poor ACE Total was associated with lower ALSFRS-R and finger-tapping scores. CONCLUSIONS: Performance on the ACE was comparable between patients and controls. Associations with motor function pose a challenge to accurate interpretation of ACE performance. It is likely that patients with poor cognition have greater disability, or that poor ACE performance reflects reduced motor ability to perform the task. This raises concern for the utility of the ACE as a screening tool in ALS patients, especially since recent versions of the ACE continue to include motor-based tasks.

Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms.

BACKGROUND: We apply recently recommended Parkinson's disease mild cognitive impairment (PD-MCI) classification criteria from the movement disorders society (MDS) to PD patients and controls and compare diagnoses to that of short global cognitive scales at baseline and over time. We also examine baseline prevalence of neuropsychiatric symptoms across different definitions of MCI. METHODS: 51 PD patients and 50 controls were classified as cognitively normal, MCI, or demented using MDS criteria (1.5 or 2.0 SD below normative values), Clinical Dementia Rating Scale (CDR), and the Dementia Rating Scale (DRS). All subject had parallel assessment with the Neuropsychiatric inventory (NPI). RESULTS: We confirmed that PD-MCI (a) is frequent, (b) increases the risk of PDD, and (c) affects multiple cognitive domains. We highlight the predictive variability of different criteria, suggesting the need for further refinement and standardization. When a common dementia outcome was used, the Level II MDS optimal testing battery with impairment defined as two SD below norms in 2+ tests performs the best. Neuropsychiatric symptoms were more common in PD across all baseline and longitudinal cognitive classifications. CONCLUSIONS: Our results advance previous findings on the utility of MDS PD-MCI criteria for PD patients and controls at baseline and over time. Additionally, we emphasize the possible utility of other cognitive scales and neuropsychiatric symptoms.

Improving American Healthcare Through "Clinical Lab 2.0": A Project Santa Fe Report.

Project Santa Fe was established both to provide thought leadership and to help develop the evidence base for the valuation of clinical laboratory services in the next era of American healthcare. The participants in Project Santa Fe represent major regional health systems that can operationalize laboratory-driven innovations and test their valuation in diverse regional marketplaces in the United States. We provide recommendations from the inaugural March 2016 meeting of Project Santa Fe. Specifically, in the transition from volume-based to value-based health care, clinical laboratories are called upon to provide programmatic leadership in reducing total cost of care through optimization of time-to-diagnosis and time-to-effective therapeutics, optimization of care coordination, and programmatic support of wellness care, screening, and monitoring. This call to action is more than working with industry stakeholders on the basis of our expertise; it is providing leadership in creating the programs that accomplish these objectives. In so doing, clinical laboratories can be effectors in identifying patients at risk for escalation in care, closing gaps in care, and optimizing outcomes of health care innovation. We also hope that, through such activities, the evidence base will be created for the new value propositions of integrated laboratory networks. In the very simplest sense, this effort to create "Clinical Lab 2.0" will establish the impact of laboratory diagnostics on the full 100% spend in American healthcare, not just the 2.5% spend attributed to in vitro diagnostics. In so doing, our aim is to empower regional and local laboratories to thrive under new models of payment in the next era of American health care delivery.

Policy Measures and Reimbursement for Emergency Medical Imaging in the Era of Payment Reform: Proceedings From a Panel Discussion of the 2015 Academic Emergency Medicine Consensus Conference.

The Affordable Care Act (ACA) of 2010 is expanding the use of quality measurement and promulgating new payment models that place downward pressure on health care utilization and costs. As emergency department (ED) computed tomography utilization has tripled in the past decade, stakeholders have identified advanced imaging as an area where quality and efficiency measures should expand. On May 12, 2015, Academic Emergency Medicine convened a consensus conference titled "Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization." As part of the conference, a panel of health care policy leaders and emergency physicians discussed the effect of the ACA and other quality programs on ED diagnostic imaging, specifically the way that quality metrics may affect ED care and how ED diagnostic imaging fits in the broader strategy of the U.S. government. This article discusses the content of the panel's presentations.

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum.

Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.

Parasite maturation and host serum iron influence the labile iron pool of erythrocyte stage Plasmodium falciparum.

Iron is a critical and tightly regulated nutrient for both the malaria parasite and its human host. The importance of the relationship between host iron and the parasite has been underscored recently by studies showing that host iron supplementation may increase the risk of falciparum malaria. It is unclear what host iron sources the parasite is able to access. We developed a flow cytometry-based method for measuring the labile iron pool (LIP) of parasitized erythrocytes using the nucleic acid dye STYO 61 and the iron sensitive dye, calcein acetoxymethyl ester (CA-AM). This new approach enabled us to measure the LIP of P. falciparum through the course of its erythrocytic life cycle and in response to the addition of host serum iron sources. We found that the LIP increases as the malaria parasite develops from early ring to late schizont stage, and that the addition of either transferrin or ferric citrate to culture media increases the LIP of trophozoites. Our method for detecting the LIP within malaria parasitized RBCs provides evidence that the parasite is able to access serum iron sources as part of the host vs. parasite arms race for iron.

Evaluation and purchase of an analytical flow cytometer: some of the numerous factors to consider.

When purchasing a flow cytometer, the decision of which brand, model, specifications, and accessories may be challenging. The decisions should initially be guided by the specific applications intended for the instrument. However, many other factors need to be considered, which include hardware, software, quality assurance, support, service, and price and recommendations from colleagues. These issues are discussed to help guide the purchasing process.

The impact of education on provider attitudes toward family-witnessed resuscitation.

INTRODUCTION: The majority of acute care facilities have not developed policies or guidelines to facilitate family presence during cardiopulmonary resuscitation. Prior studies have shown that the personal beliefs and attitudes of hospital personnel involved in resuscitation efforts are the primary reasons family presence is not offered. METHODS: This 2-phase, before/after study was conducted in a 388-bed academic trauma center, and in a 143-bed community hospital in eastern Washington State in 2008. In phase I, a convenience sample of physicians and registered nurses from both facilities were surveyed about their opinions and beliefs regarding family-witnessed resuscitation (FWR). Spearman's rho and independent t-tests were used to compare support of FWR between and within roles and practice location subgroups. In phase II of the study, clinician subgroups in the community hospital were re-surveyed following an educational program that used evidence-based information. Independent t-test and one-way ANOVA were used to compare pre and post-education mean scores of subgroups on indicators of effective teaching strategies and improved FWR support. RESULTS: Opinions on FWR vary within and between practice roles and locations, with the strongest variable of support being prior experience with FWR. Following FWR education, mean scores improved for survey variables chosen as indicators of FWR support and teaching effectiveness. DISCUSSION: When CPR providers are presented with FWR education, their opinion-based beliefs may be modified, decreasing barriers to family witnessed resuscitation and improving overall support of FWR as an extension of family-centered care.

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia.

Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age- and sex-matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1-weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss.

Partnership for Families Program: philanthropy for in vitro fertilization patients.

OBJECTIVE: To describe our Partnership for Families Program, which was established to provide second in vitro fertilization (IVF) cycles for couples who pay for one IVF cycle, do not get pregnant and cannot afford a second IVF cycle. In addition, this program provides funding for fertility-sparing procedures for financially needy cancer patients. STUDY DESIGN: Retrospective description of the Partnership for Families' first 5 years of operation. RESULTS: In its 5 years of operation, the Partnership for Families Program has provided 137 infertile couples with a second IVF cycle, resulting in 68 ongoing or delivered pregnancies. It has also provided funding for 19 fertility-sparing procedures for cancer patients. CONCLUSION: Because of the high costs of IVF, alternative funding sources, specifically philanthropy, must be explored to provide increased access to IVF. The Partnership for Families Program, started by patients in a single practice, has in 5 years provided over 151 infertile and cancer patients IVF or egg-freezing cycles that they otherwise could not have afforded. This is a program that can be emulated by other fertility centers.

Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism.

OBJECTIVES: To determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients. DESIGN: Forty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinson's Disease Rating Scale, separated into dopamine responsive and dopamine non-responsive signs) and neuropsychological testing (memory: California Verbal Learning Test (CVLT)) and a composite of index of executive function (EF): Stroop Interference, Trail Making Test Part B, and digit ordering. All underwent volumetric MRI scans analyzed using voxel-based morphometry (VBM). Group comparisons, and the correlations between MRI gray and white matter volume and motor and cognitive measures were controlled for age, sex and intracranial volume. Cerebellar volume was independently measured using a validated extraction method. RESULTS: Patients and controls were matched for demographics and global cognitive measures. VBM indicated significant gray matter (GM) atrophy in the cerebellum in PD and was confirmed independently. Poor memory was associated with GM atrophy in the left (uncus, middle temporal and fusiform gyri) and right temporal lobes and left putamen. Dopamine non-responsive motor signs and EF were associated with caudate atrophy. EF was also associated with GM atrophy in the middle temporal gyri, the left precuneus and cerebellum. CONCLUSIONS: Cortical and striatal atrophy were associated with dopamine non-responsive motor signs and cognitive impairment and provide a morphologic correlate for progression of PD. Cerebellar atrophy was found in older PD patients.

CD28 costimulation is essential for human T regulatory expansion and function.

The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8-12 days of culture with CD28 costimulation in the presence of rapamycin resulted in >1000-fold expansion of Tregs in <3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.

Age and dementia-associated atrophy predominates in the hippocampal head and amygdala in Parkinson's disease.

The hippocampus (HC) and amygdala (AG) decrease in volume with age and in Parkinson's disease (PD) with (PDD) and without dementia. We compared 44 PD to 44 age, sex and education-matched subjects without PD (non-PD) and 13 PDD subjects. T1-weighted MR images were used to manually segment the head, body and tail of the HC and the AG. HC volumes, corrected to intracranial volume, were smaller in PDD than non-PD (p=0.04), reflected predominantly by head atrophy. Right AG volumes were smaller in PD compared to non-PD (p=0.03). HC volumes in older (>70), but not younger, non-demented PD differed from non-PD (HC, p=0.02; head, p=0.03). Age correlated negatively with overall HC (r=-0.43, p=0.004) and head (r=-0.48, p=0.001) in PD, but not in non-PD. In PD, left HC head volumes correlated with recall, but not recognition scores on the CVLT-II (r=0.35, p=0.02) and BVMT-R (r=0.35, p=0.02); AG volumes correlated with CVLT-II recall (r=0.35, p=0.02). No correlations were found in non-PD (p>0.4). In conclusion, functionally meaningful age-associated hippocampal and amygdala atrophy occurs in PD.