Search

The COVID-19 pandemic has affected human life in unprecedented ways. Lives of older persons and their families have been especially adversely affected. Eleven Caregiver Resource Centers (CRCs) support family caregivers across the state of California, providing services such as assessment, counseling and respite. This presentation is part of a larger evaluation study and addresses the impact of the COVID-19 pandemic on family caregivers and systems supporting them. We interviewed directors, clinical staff and family consultants (n=35) from CRCs across diverse communities and geography in California, conducting semi-structured focus group interviews by Zoom. Questions explored perceptions of staff about effects on caregivers and implications for systems of support for caregivers. Interviews were transcribed and analyzed using the Dedoose software. Caregiver effects included increased isolation, higher stress, loss of support, neglected health needs, and accelerated technology adoption. Caregivers at particular risk were those facing multiple demands and experiencing compromised resources under the pandemic, such as closure of adult day care. System effects included challenges with hastened virtual delivery, disruption in services, and new opportunities to serve clients virtually. Community resources, such as internet connectivity, exacerbated disparities for family caregivers. We make recommendations to mitigate these challenges including technology platforms to support service delivery and education, training and preparedness for both caregivers and providers. These recommendations are relevant to the ongoing COVID-19 pandemic and adaptable to other crisis situations such as natural disasters.

Objective: To relate a novel test of identifying and recalling odor percepts to biomarkers of Alzheimer's Disease (AD) in well-characterized elderly individuals, ranging from cognitively normal to demented. Methods: 183 participants (cognitively normal: n=70, subjective cognitive concerns: n=74, Mild Cognitive Impairment (MCI): n=29, AD dementia: n=10) were administered novel olfactory tests: the Odor Percept IDentification (OPID) and the Percepts of Odor Episodic Memory (POEM) tests. Univariate cross-sectional analyses of performance across diagnoses; logistic regression modeling including covariates of age, gender, education, APOE genotype, and neuropsychological test scores; and linear mixed modeling of longitudinal cognitive scores were performed. Amyloid deposition and MRI volumetrics were analyzed in a subset of participants. Results: Accuracy of identification and episodic memory of odor percepts differed significantly across diagnosis and age, with progressively worse performance across degrees of impairment. Among the participants who were cognitively normal or had subjective cognitive concerns, poorer than expected performance on the POEM test (based on the same individual's performance on the OPID and odor discrimination tests) was associated with higher frequencies of the APOE e4 allele, thinner entorhinal cortices, and worse longitudinal trajectory of Logical Memory scores. Interpretation: Selective impairment of episodic memory of odor percepts, relative to identification and discrimination of odor percepts revealed by this novel POEM battery, is associated with biomarkers of AD in a well-characterized pre-MCI population. These affordable, non-invasive olfactory tests offer potential to identify clinically normal individuals who have greater likelihood of future cognitive decline. This article is protected by copyright. All rights reserved.

The aim of the present study was to describe incidences of restrictive interventions and the association of methamphetamine use at an acute adult inpatient mental health unit in metropolitan Melbourne, Victoria, Australia. A total of 232 consecutive consumer admissions to the inpatient unit across a 3-month period were described for illicit substance use and the use of restrictive interventions (seclusion, mechanical restraint, and physical restraint) prior to and during admission. Of all admissions, 25 (10.8%) involved consumers subjected to a restrictive intervention. Methamphetamine use was either self-reported or detected by saliva test for 71 (30.6%) consumers. Following multivariate analyses, methamphetamine use (odds ratio (OR): 7.83, 95% confidence interval (CI): 2.33-26.31) and restrictive intervention in the emergency department prior to admission (OR: 8.85, 95% CI: 2.83-27.70) were significant independent predictors of the use of restrictive interventions after inpatient admission. Anecdotal observations provided by clinical mental health staff that consumers intoxicated with methamphetamine appear to require restrictive intervention more frequently than other consumers was confirmed with the results of the current study. As the state of Victoria in Australia is on a pathway to the elimination of the use of restrictive interventions in mental health services, clinicians need to develop management strategies that provide specialist mental health care using the least-restrictive interventions. Although 26.8% of methamphetamine users were secluded after admission, restrictive interventions should not be the default management strategy for consumers who present with self-report or positive screen for methamphetamine use.

Prostate cancer is characterized by a dependence upon androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) is the accepted treatment for progressive prostate cancer. Although ADT is usually initially effective, acquired resistance termed castrate-resistant prostate cancer (CRPC) develops. PTEN and TP53 are two of the most commonly deleted or mutated genes in prostate cancer, the compound loss of which is enriched in CRPC. To interrogate the metabolic alterations associated with survival following ADT, we used an orthotopic model of Pten/Tp53 null prostate cancer. Metabolite profiles and associated regulators were compared in tumors from androgen-intact mice and in tumors surviving castration. AR inhibition led to changes in the levels of glycolysis and tricarboxylic acid (TCA) cycle pathway intermediates. As anticipated for inhibitory reciprocal feedback between AR and PI3K/AKT signaling pathways, pAKT levels were increased in androgen-deprived tumors. Elevated mitochondrial hexokinase 2 (HK2) levels and enzyme activities also were observed in androgen-deprived tumors, consistent with pAKT-dependent HK2 protein induction and mitochondrial association. Competitive inhibition of HK2-mitochondrial binding in prostate cancer cells led to decreased viability. These data argue for AKT-associated HK2-mediated metabolic reprogramming and mitochondrial association in PI3K-driven prostate cancer as one survival mechanism downstream of AR inhibition.

Summary Aims The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). Methods In this phase-2, double-blind (DB), double-dummy, placebo- and active-controlled study, patients (40–80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. Results As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. Conclusion Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated. Trial registration: ClinicalTrials.gov: NCT01094262.

Central brain network connections greatly contribute to overall network efficiency. Here we examined whether small vessel disease (SVD) related white matter alterations in central brain network connections have a greater impact on executive functioning than alterations in non-central brain network connections. Brain networks were reconstructed from diffusion-weighted MRI scans in 72 individuals (75 ± 8 years) with cognitive impairment and SVD on MRI. The centrality of white matter connections in the network was defined using graph theory. The association between the fractional anisotropy (FA) of central versus non-central connections, executive functioning, and markers of SVD was evaluated with linear regression and mediation analysis. Lower FA in central network connections was more strongly associated with impairment in executive functioning than FA in non-central network connections (r = 0.41 vs. r = 0.27; P 50%–10% connections). Higher SVD burden was associated with lower FA in central as well as non-central network connections. However, only central network FA mediated the relationship between white matter hyperintensity volume and executive functioning [change in regression coefficient after mediation (95% CI): −0.15 (−0.35 to −0.02)]. The mediation effect was not observed for FA alterations in non-central network connections [−0.03 (−0.19 to 0.04)]. These findings suggest that the centrality of network connections, and thus their contribution to global network efficiency, appears to be relevant for understanding the relationship between SVD and cognitive impairment. Hum Brain Mapp 37:2446–2454, 2016.

Syrinx has been reported in 25–85 % of children with Chiari malformation type I (CMI), and it is most commonly cervical in location. As a result, cervical MRI is routinely included in an evaluation for CMI. Isolated thoracic syrinx without involvement of the cervical cord in this population is uncommon but clinically important because its presence may influence the decision to operate, surgical techniques employed, or interpretation of follow-up imaging. The purpose of this study was to determine the incidence of isolated thoracic syrinx in a large group of children evaluated for CMI. We retrospectively reviewed all patients under 21 years of age who were evaluated for CMI at Columbia University/Morgan Stanley Children’s Hospital of New York from 1998 to 2013. All patients underwent MRI of the entire spine as part of the CMI evaluation, regardless of whether surgery was planned. The proportion of patients exhibiting isolated thoracic syrinx was determined. Presenting signs, symptoms, and imaging findings were then studied in an attempt to identify any clinical features associated with isolated thoracic syrinx. We identified 266 patients evaluated over the study period. One-hundred thirty-two patients (50 %) presented with a syrinx, and 12 patients (4.5 % of all patients evaluated and 9.1 % of all patients with a syrinx) had an isolated thoracic syrinx. Demographic variables, clinical presentation, and extent of tonsillar ectopia showed great heterogeneity in this group, and no factor was consistently associated with isolated thoracic syrinx. Isolated thoracic syrinx is an uncommon but clinically significant finding in children with CMI. Our data demonstrate that the presence of a CMI-related thoracic syrinx cannot be reliably predicted clinically and is therefore likely to be missed in patients who do not undergo complete spinal cord imaging. MRI of the entire spinal cord should be considered for all children undergoing initial evaluation for CMI.

In this article, I investigate the way forms of writing construct temporal frameworks for processing information into knowledge in the works of Francis Bacon. Baconian science looks to the distant future even as it requires immediately useful information. One means of processing information is narrative. I argue that the New Atlantis , Bacon’s utopian narrative, functions similarly to modern scientific hypothesis, projecting beyond the current state of knowledge to imagine how things might be. The New Atlantis thus presents a solution to the problem of deriving knowledge from incomplete information: because knowledge is not a discrete object to be collected, but something produced over time, fiction can shape our understanding of the truth, as long as we understand that knowledge to be perennially incomplete and provisional.

Graphical abstract, Historically, the routine use of laboratory automation solutions has been prohibitively expensive for many laboratories. As legacy hardware has begun to emerge on the secondary market, automation is becoming an increasingly affordable option to augment workflow in virtually any laboratory. To assess the utility of legacy liquid handling in stem cell differentiation, a used liquid handling robot was purchased at auction to automate a stem cell differentiation protocol that gives rise to CD14 + CD45+ mononuclear cells. To maintain sterility, the automated liquid handling robot was housed in a custom constructed HEPA filtered enclosure. A custom cell scraper and a disposable filter box were designed and 3D printed to permit the robot intricate cell culture actions required by the protocol. All files for the 3D printed labware are uploaded and are freely available. • A used liquid handling robot was used to automate an hESC to monocyte differentiation protocol. • The robot-performed protocol induced monocytes as effectively as human technicians. • Custom 3D printed labware was made to permit certain cell culture actions and are uploaded for free access.

Hearing loss is the most common sensory deficit in developed societies. Hearing impairment in children, particularly of prelingual onset, has been shown to negatively affect educational achievement, future employment and earnings, and even life expectancy. Sensorineural hearing loss (SNHL), which refers to defects within the cochlea or auditory nerve itself, far outweighs conductive causes for permanent hearing loss in both children and adults. The causes of SNHL in children are heterogeneous, including both congenital and acquired causes. This article identifies potential mechanisms of intervention both at the level of the hair cell and the spiral ganglion neurons.

342 Background: The differential aggressiveness of potentially independent prostate cancer clones remains largely unknown. Appropriate prostate cancer staging using mpMRI and biopsy tissue can be confounded by sampling error. To date, there has been no understanding of whether clonal variability influences management decisions for localized prostate tumors. We sought to identify the sensitivity and genomic profile of distinct localized tumors from a patient following systemic intense neoadjuvant androgen deprivation therapy (ADT). Methods: A 66-year-old man with high risk prostate cancer enrolled in a Phase 2 study of intense neoadjuvant ADT (goserelin + enzalutamide; inADT). Baseline mpMRI showed a single semi-contiguous lesion encompassing the right apical-mid PZ extending into the left distal apical PZ. MR/US-fusion targeted biopsy was performed before 6 months of inADT. A second mpMRI was performed before radical prostatectomy. Whole exome sequencing on microdissected tumor foci identified somatic mutations and copy number alterations, which were further used with immunohistochemistry to assess tumor clonal architecture and genomic/phenotypic evolution of treatment resistant tumor. Results: We found two clonally independent tumors exhibited intrinsic heterogeneity at baseline which correlated with response or resistance. Biopsies of distinct left- and right-sided tumors showed differing histologies. mpMRI and pathology showed near complete response of the left-sided tumor and substantial resistance of the right-sided tumor, which exhibited a large intraductal component. Histology and whole exome data highlighted a divergence in the status of PTEN and TP53, tumor suppressor genes implicated in prostate cancer progression. Conclusions: These data highlight that even nascent prostate cancer is heterogenous and neoadjuvant therapeutic strategies will need to consider this for clinical optimization. Evolutionary trajectories that resulted in tumor heterogeneity in this case likely contributed to our observation that two independent prostate tumor nodules with distinct genetic alterations responded differently to neoadjuvant intense ADT. Clinical trial information: NCT02430480.

Background and Objectives Online service delivery options have the potential to increase access to informational resources among caregivers to older adults. However, it is unknown which caregivers will use online-delivered services over usual service delivery modes (e.g., by phone) when both options are available in social service settings. This is important for service providers to know when making decisions that best serve their communities. Research Design and Methods Guided by Andersen’s model of health service utilization, we used step-wise logistic regression models to compare the characteristics of caregivers who used an online information service called FCA CareJourney (FCA CJ) with those who accessed the same services using the usual mode of service delivery (N = 540). Online and usual-care services were available through two social service organizations in California. Results In all, 13.7% of clients used FCA CJ to receive services online. Enabling characteristics were the main predictors of using online-delivered services. Caregivers employed part-time had 3.82 times the odds of using online-delivered services compared to those employed full-time (odds ratio [OR] = 3.82; 95% confidence interval [CI]: 1.58–9.22). Caregivers who learned about services from health care providers had 2.91 times the odds of using FCA CJ as those who learned about services through social services (OR = 2.91; 95% CI: 1.28–6.62). Even among those who learned about services online, 62.2% still accessed services using usual delivery modes. Discussion and Implications Based on differences in the characteristics of caregivers using different service delivery modes and the low uptake of online-delivered services, we suggest online service delivery should supplement, not replace, usual delivery modes in social service settings. At the same time, user rates of online service delivery are likely modifiable. Given the potential for online-delivered programming to expand access to information services for caregivers, we recommend further examination into the effects of marketing online service delivery options to caregivers in novel ways.

Summary Background High resource expenditure on acute care is a challenge for mental health services aiming to focus on supporting recovery, and relapse after an acute crisis episode is common. Some evidence supports self-management interventions to prevent such relapses, but their effect on readmissions to acute care following a crisis is untested. We tested whether a self-management intervention facilitated by peer support workers could reduce rates of readmission to acute care for people discharged from crisis resolution teams, which provide intensive home treatment following a crisis. Methods We did a randomised controlled superiority trial recruiting participants from six crisis resolution teams in England. Eligible participants had been on crisis resolution team caseloads for at least a week, and had capacity to give informed consent. Participants were randomly assigned to intervention and control groups by an unmasked data manager. Those collecting and analysing data were masked to allocation, but participants were not. Participants in the intervention group were offered up to ten sessions with a peer support worker who supported them in completing a personal recovery workbook, including formulation of personal recovery goals and crisis plans. The control group received the personal recovery workbook by post. The primary outcome was readmission to acute care within 1 year. This trial is registered with ISRCTN, number 01027104. Findings 221 participants were assigned to the intervention group versus 220 to the control group; primary outcome data were obtained for 218 versus 216. 64 (29%) of 218 participants in the intervention versus 83 (38%) of 216 in the control group were readmitted to acute care within 1 year (odds ratio 0·66, 95% CI 0·43–0·99; p=0·0438). 71 serious adverse events were identified in the trial (29 in the treatment group; 42 in the control group). Interpretation Our findings suggest that peer-delivered self-management reduces readmission to acute care, although admission rates were lower than anticipated and confidence intervals were relatively wide. The complexity of the study intervention limits interpretability, but assessment is warranted of whether implementing this intervention in routine settings reduces acute care readmission. Funding National Institute for Health Research.

Chinese and American philanthropists have more in common than one might think.

Great ideas for social impact are dying on the vine because organizations lack the tools they need to grow. With the right strategies in place, any nonprofit can lay the foundation for success.

How nonprofit organizations can do a better job with their data.

We need to equip the next generation with the tools they need to deliver on good intentions.

Antibody-drug conjugates (ADCs) are an emerging class of biopharmaceuticals. As such, there are no specific guidelines addressing impurity limits and qualification requirements. The current ICH guidelines on impurities, Q3A (Impurities in New Drug Substances), Q3B (Impurities in New Drug Products), and Q6B (Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products) do not adequately address how to assess small molecule impurities in ADCs. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) formed an impurities working group (IWG) to discuss this issue. This white paper presents a strategy for evaluating the impact of small molecule impurities in ADCs. This strategy suggests a science-based approach that can be applied to the design of control systems for ADC therapeutics. The key principles that form the basis for this strategy include the significant difference in molecular weights between small molecule impurities and the ADC, the conjugation potential of the small molecule impurities, and the typical dosing concentrations and dosing schedule. The result is that exposure to small impurities in ADCs is so low as to often pose little or no significant safety risk.

Immune pressure exerted by MHC class I-restricted cytotoxic T cells drives the development of viral escape mutations, thereby regulating HIV disease progression. Nonetheless, the relationship between host immunity and HIV central nervous system (CNS) disease remains poorly understood. The simian immunodeficiency virus (SIV) macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate cell-mediated immunity regulating SIV CNS disease progression, we compared the incidence of SIV encephalitis and the influence of MHC class I allele expression on the development of CNS disease in rhesus macaques (Macaca mulatta) versus pigtailed macaques (Macaca nemestrina). After inoculation with the immunosuppressive swarm SIV/DeltaB670 and the neurovirulent molecular clone SIV/17E-Fr, pigtailed macaques progressed more rapidly to AIDS, had higher plasma and cerebrospinal fluid (CSF) viral loads, and were more likely to progress to SIV-associated encephalitis (SIVE) compared to rhesus macaques. In addition, MHC class I alleles were neuroprotective in both species (Mamu-A*001 in rhesus macaques and Mane-A1*084:01:01 in pigtailed macaques); animals expressing these alleles were less likely to develop SIV encephalitis and correspondingly had lower viral replication in the brain. Species-specific differences in susceptibility to SIV disease demonstrated that cell mediated immune responses are critical to SIV CNS disease progression.

The purpose of this research was to identify characteristics of redesignated National League for Nursing Centers of Excellence in Nursing Education that represent the intersection between quality and excellence. A qualitative content analysis of six final applications submitted for redesignation disclosed essential resources that supported students, faculty, and staff and identified six characteristics: connections through relationships, communities of learning and service, support for students and faculty, connections through technology, use of innovation, and a systems focus. The systematic focus on excellence in teaching and learning identified in this research represents best practices from exemplary schools worthy of emulation by other nursing education programs.

Acute stroke treatments reduce the risk of post-stroke disability. These treatments, tissue plasminogen activator (tPA) and intra-arterial treatment, are highly time-dependent; thus, one of the main barriers to treatment is pre-hospital delay. Stroke preparedness is defined as the ability to recognize stroke symptoms and the intent to activate emergency medical services (EMS). This review describes types of acute stroke treatment and preparedness interventions, including recent mass media interventions to increase acute stroke treatment rates, and adult and youth community interventions to increase stroke preparedness. The mass media campaigns show mixed results regarding acute stroke treatment rates, possibly attributed to the various media platforms utilized and resources available. The adult and youth community interventions reveal an overall increase in stroke symptom recognition and behavioral intent to call EMS. However, most of these community interventions were not grounded in health behavior theory, and they were tested in single group, pre-post test study designs that assessed behavioral rather than clinical outcomes. The delivery of stroke preparedness information by youth to adults, for example via home assignments, is a promising and innovative approach to stroke preparedness. Mass media and community interventions show promise to increase stroke preparedness and acute stroke treatment rates. The development of health behavior theory-based interventions that are tested via scientifically rigorous study designs are needed to prioritize which interventions should be disseminated to culturally and socially similar communities.

Background. Treatment decision tools have been developed in many fields of medicine, including psychiatry, however benefits for patients have not been sustained once the support is withdrawn. We have developed a web-based computerised clinical decision support tool (CDST), which can provide patients and clinicians with continuous, up-to-date, personalised information about the efficacy and tolerability of competing interventions. To test the feasibility and acceptability of the CDST we conducted a focus group study, aimed to explore the views of clinicians, patients and carers. Methods. The CDST was developed in Oxford. To tailor treatments at an individual level, the CDST combines the best available evidence from the scientific literature with patient preferences and values, and with patient medical profile to generate personalised clinical recommendations. We conducted three focus groups comprising of three different participant types: consultant psychiatrists, participants with mental health diagnosis and/or experience of caring for someone with a mental health diagnosis, and primary care practitioners and nurses. Each 1-hour focus group started with a short visual demonstration of the CDST. To standardise the discussion during the focus groups, we used the same topic guide that covered themes relating to the acceptability and usability of the CDST. Focus groups were recorded and any identifying participant details were anonymised. Data were analysed thematically and managed using the Framework method and the constant comparative method. Results. The focus groups took place in Oxford between October 2016 and January 2017. Overall 31 participants attended (12 consultants, 11 primary care practitioners and 8 patients or carers). The main themes that emerged related to CDST applications in clinical practice, communication, conflicting priorities and record keeping. CDST was considered a useful clinical decision support, with recognised value in promoting clinician-patient collaboration and contributing to the development of personalised medicine. One major benefit of the CDST was perceived to be the open discussion about the possible side-effects of medications. Participants from all the three groups, however, universally commented that the terminology and language presented on the CDST were too medicalised, potentially leading to ethical issues around consent to treatment. Conclusions. The CDST can improve communication pathways between patients, carers and clinicians, identifying care priorities and providing an up-to-date platform for implementing evidence-based practice, with regard to prescribing practices.

This study was designed to evaluate the efficacy and safety of fulranumab, a fully human monoclonal antibody directed against nerve growth factor (NGF), for pain relief in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). In this multicenter, double-blind study, adults with IC/BPS (i.e., interstitial cystitis symptom index [ICSI] total score ≥8) accompanied by chronic, moderate-to-severe pain were randomized to fulranumab 9 mg or matching placebo, administered subcutaneously at weeks 1, 5, and 9. The primary efficacy endpoint was change from baseline to study endpoint (week 12 or at withdrawal) in average daily pain intensity score. Key secondary endpoints included change from baseline to study endpoint in worst pain intensity score, ICSI total score, Pelvic Pain and Urgency/Frequency total score, Patient Perception of Bladder Condition score, and global response assessment. This study was terminated prematurely based on concern that this class may be associated with rapidly progressing osteoarthritis or osteonecrosis. Thirty-one patients (of the targeted 70 patients) were randomized, 17 to placebo and 14 to fulranumab, with 15 and 10 patients, respectively, receiving all 3 doses of double-blind treatment. In ANOVA analyses, there was no statistically significant difference between treatment groups for the primary endpoint (LS mean difference [95% CI] vs. placebo, −0.2 [−1.52, 1.10]) or any of the secondary endpoints. Fulranumab was well tolerated, with no patient discontinuing due to an adverse event or experiencing a joint-related serious adverse event over a 26-week follow-up period. No events related to the neurologic or motor systems were reported. Efficacy was not demonstrated in the present study with the single dose tested and a limited sample size, leading to lack of statistical power. These findings do not exclude the possibility that fulranumab would provide clinical benefit in a larger study and/or specific populations (phenotypes) in this difficult to treat pain condition. NCT01060254 , registered January 29, 2010.

Why the process of creating a theory of change matters, and a five-step guide to success.

A new generation of wealth is making a difference using powerful technology, inventing new financial models to better leverage capital, and rigorously focusing on getting proven results.

Sporadic and geographically widespread reports of parasites affecting the Belted Kingfisher (Megaceryle alcyon) have been published but few have described details of the pathology. A female, adult kingfisher was found dead in a heavily wooded area of a zoo in Maryland, USA. At necropsy, numerous sexually dimorphic, 4.4-40.5-cm adult Monopetalonema alcedinis nematodes were found tightly wound within the coelomic cavity between organs and completely filling the caudal thoracic and abdominal air sacs. Abundant, 30-60-µm diameter, larvated, thick-walled ova were found in the bronchi and parabronchi, within the mesentery, and in the serosa of multiple coelomic organs. Monopetalonema alcedinis is a characteristic member of the superfamily Diplotriaenoidea, a group of nematodes occurring in birds and reptiles. Infective larvae within an invertebrate intermediate host are ingested and penetrate the intestine, traveling to the lungs and then into the air sacs, where the adult females release eggs. The ova are coughed up by the avian host and passed in feces. Specimens of M. alcedinis have been found in the Belted Kingfisher, although typically intensity of infection is low and infections remain asymptomatic. In contrast, we report the second documented case of high numbers of M. alcedinis resulting in pathologic changes in which parasitism contributed to host mortality.

Object Ventriculoatrial (VA) shunting is rarely used for patients with normal-pressure hydrocephalus (NPH), likely due to surgeon technical preference and case reports indicating cardiopulmonary complications. However, these complications have typically been limited to adults in whom VA shunts had been placed when they were children. Few studies have directly compared VA shunting to ventriculoperitoneal (VP) shunting in cases of NPH. Methods The authors retrospectively analyzed all NPH patients treated by a single surgeon at their center from January 2002 through December 2011. Thirty patients were treated with VA shunts (14 male) and 157 with VP shunts (86 male). The patients' mean age (± SD) at surgery was 73.7 ± 9.4 years for VA shunting and 76.0 ± 8.2 years for VP shunting; the median durations of follow-up were 42.0 months (IQR 19.2–63.6 months) and 34.2 months (IQR 15.8–67.5), respectively. Statistical analysis was performed using chi-square tests and Wilcoxon rank-sum tests. Results Perioperative and postoperative complications for VA and VP shunting cohorts, respectively, included distal revision (2.7% vs 6.6%, p = 0.45), proximal revision (2.7% vs 2.5%, p = 0.97), and postoperative seizure (2.7% vs 1.5%, p = 0.62). Shunt drainage–related subdural hematomas/hygromas developed in 8.1%/27.0% of VA shunt–treated patients versus 6.6%/26.4% of VP shunt–treated patients (p = 0.76/0.98) and were nearly always successfully managed with programmable-valve adjustment. Symptomatic intracerebral hemorrhage (1.5%) and shunt infection (2.0%) were only observed in those who underwent VP shunting. Of note, no cardiovascular complications were observed in any patient, and there were no cases of distal occlusion of the VA shunt. Conclusions The authors found no significant differences in complication rates between VA and VP shunting, and VA shunting was not associated with any cardiopulmonary complications. Thus, in the authors' experience, VA shunting is at least as safe as VP shunting for treating NPH.

Peripheral neuropathy is the most frequent neurological complication of HIV infection, affecting more than one-third of infected patients, including patients treated with antiretroviral therapy. Although emerging noninvasive techniques for corneal nerve assessments are increasingly being used to diagnose and monitor peripheral neuropathies, corneal nerve alterations have not been characterized in HIV. Here, to determine whether SIV infection leads to corneal nerve fiber loss, we immunostained corneas for the nerve fiber marker βIII tubulin. We developed and applied both manual and automated methods to measure nerves in the corneal subbasal plexus. These counting methods independently indicated significantly lower subbasal corneal nerve fiber density among SIV-infected animals that rapidly progressed to AIDS compared with slow progressors. Concomitant with decreased corneal nerve fiber density, rapid progressors had increased levels of SIV RNA and CD68-positive macrophages and expression of glial fibrillary acidic protein by glial satellite cells in the trigeminal ganglia, the location of the neuronal cell bodies of corneal sensory nerve fibers. In addition, corneal nerve fiber density was directly correlated with epidermal nerve fiber length. These findings indicate that corneal nerve assessment has great potential to diagnose and monitor HIV-induced peripheral neuropathy and to set the stage for introducing noninvasive techniques to measure corneal nerve fiber density in HIV clinical settings.

Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.

To investigate the effect of gambogic acid (GA) on the growth and cell death of castrate resistant prostate cancer (PC) with phosphate and tension homology (PTEN) and p53 genes deleted in vitro and ex vivo, and elucidate the underlying possible molecular mechanisms.PTENThe treatment of GA significantly reduced cell viability of PTENGA was a potent anti-tumor compound as for PTEN

Background: An evolving concept that contributes to the understanding of resistance to androgen deprivation therapy and/or androgen receptor (AR) antagonist in prostate cancer is the ability of the cells to bypass AR blockade and turn on compensatory hormone signaling for survival. Recent preclinical and clinical studies demonstrate that induction of GR expression confers resistance to AR-targeted therapy. Hence therapeutic strategies to overcome GR-mediated resistance are warranted. Experimental Design: Prostate cancer cell-lines and patient derived xenograft (PDX) models were exposed to the pan-AKT inhibitor ipatasertib or other PI3K/AKT- pathway inhibitors with or without AR blockade. AR and GR array determined differentially expressed AR/GR target genes. Protein expression levels were measured. Cell viability and tumor growth was determined in response to treatment. Results: AKT inhibitor as monotherapy significantly decreases cell viability across multiple prostate cancer models. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. The pan-AKT inhibitor ipatasertib as well as other inhibitors of the PI3K/AKT pathway decreased GR activity through AR-dependent and AR-independent mechanisms. Importantly, AKT inhibition, with and without AR blockade, demonstrated significant anti-tumor activity in several in vivo prostate cancer models with no noticeable toxicity. Conclusion: Inhibition of the PI3K/AKT pathway blocks GR activity and overcomes GR-mediated resistance to AR-targeted therapy. This therapeutic approach has immediate clinical relevance as ipatasertib is currently in advanced clinical development and provides a supportive tool for how to manage patients with acquired resistant to AR-targeted therapy. Citation Format: Remi M. Adelaiye-Ogala, Kathleen Kelly, David VanderWeele. Targeting of the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting the induction of glucocorticoid receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-262.

Background: Genetic alterations in lethal, metastatic prostate cancer include the loss of PTEN, translocation of the TMPRSS2 and ERG genes, upregulation of the androgen receptor (AR), and disruption of the DNA homologous repair pathway driven by mutations to BRCA1, BRCA2, and ATM. Many of these mutations can be observed while the cancer is still localized in the prostate. Here, we seek to identify genetic features indicative of therapeutic response and novel drivers of cancer progression to inform clinical practice. Methods: Using tissue from 33 patients in an intense neoadjuvant anti-androgen clinical trial at the NCI (NCT02430480), we examined genetic features that would predict exceptional or poor response to anti-androgen enzalutamide therapy. Each patient on trial presented with multiple tumor foci, allowing us to investigate the intratumoral heterogeneity across foci within individual patients, as well as investigating the tumor profiles across multiple patients. Several patients exhibited exceptional response with residual tumor burdens less than 0.5cc, while others had substantial treatment-resistant cancers. We developed a panel of 12 immunohistopathological stains and used this panel to guide laser capture microdissection on pre-treatment biopsies and spatially matched post-treatment radical prostatectomy specimens to isolate ultrapure tumor foci from each patient. DNA from these foci was used for whole exome sequencing, as somatic copy number alterations and mutations also confirm their evolutionary relationship. This enabled us to classify baseline specimens as responder or nonresponder, while examining variations in genetic features between the two cohorts. Results: To date, focal PTEN loss was observed in all nonresponders, while focal ERG staining was absent in 100% of responders and present in 60% of nonresponders. Synaptophysin positivity was rare at baseline but predicted resistance to treatment with 100% sensitivity. Intriguingly, baseline copy number profiles highlight a 6q deletion in 100% of exceptional responders, but not in the non-responders. Together, these data suggest an immunostain panel to assess oncogene and tumor suppressor alterations can predict response to anti-androgen therapy, while also suggesting a novel role of 6q in resistance to anti-androgen hormone therapy. Current studies are examining the role of 6q in response to anti-androgen therapies, which remains an area of active interest in our laboratory. Conclusions: These findings demonstrate the feasibility in identifying intratumoral heterogeneity based on prostate biomarker status both in pre-treatment and post-treatment specimens. Using these data, comprehensive molecular analysis of prostate cancer at diagnosis may better-enable physicians to predict response to anti-androgen therapy and provide tailored treatment based on gene expression status. Citation Format: Scott Wilkinson, Huihui Ye, Nicole Carrabba, Rayann Atway, Shana Y. Trostel, Thomas Hennigan, Ross Lake, Stephanie Harmon, Guinevere Chun, Baris Turkbey, Peter A. Pinto, Peter L. Choyke, Fatima Karzai, David J. VanderWeele, Kathleen Kelly, William L. Dahut, Adam G. Sowalsky. Combining genetic and histopathologic features to predict response to anti-androgen therapy in aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2510.

Contrary to the anti-proliferative interferon (IFN) signaling, IFN related DNA damage resistance signature (IRDS) has pro-survival function and is responsible for cancer cell intrinsic therapy resistance. This signature encompasses a subset of STAT1-driven genes that have been associated with breast cancer therapy resistance. Interestingly, our RNAseq analysis of organoids from FACS-sorted Pten/Tp53-null PCa luminal progenitors have revealed a robust IRDS expression. Based on our previous findings that the luminal progenitors display intrinsic resistance to androgen deprivation therapy (ADT), we hypothesized that the IRDS expression might in part account for survival of PCa cells following ADT or genotoxic therapies. Our analysis of human PCa datasets revealed IRDS as a prognostic marker for progression in the TCGA primary PCa cohort (p Citation Format: Supreet Agarwal, Kerry McGowen, Fathi Elloumi, Maggie Cam, Mike Beshiri, Eva Corey, Kathleen Kelly. Interferon signaling contributes to prostate cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-030.

Objective HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV-induced central nervous system (CNS) disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication. Design To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between simian immunodeficiency virus (SIV)-infected macaques treated with maraviroc (MVC) versus untreated SIV-infected macaques. Methods Six SIV-infected rhesus macaques were treated with MVC monotherapy for 5 months beginning 24 days postinoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, cerobrospinal fluid, and brain, and CNS expression of TNFα and CCL2 were measured by qRT-PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA. Results SIV RNA and proviral DNA levels in brain were markedly lower with MVC treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. MVC treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFα and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection. Conclusion CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined antiretroviral regimens may offer multiple neuroprotective benefits.

Nerve growth factor (NGF) is increased in chronic pain conditions. This study examined analgesic efficacy and safety of fulranumab, a fully human monoclonal anti-NGF antibody, in adults with chronic osteoarthritis pain. Patients (n=466, intent-to-treat) were randomized to receive, in addition to their current pain therapy, subcutaneous injections in 1 of 6 parallel treatment groups: placebo (n=78), fulranumab 1 mg (n=77) or 3 mg (n=79) every 4 weeks (Q4wk), 3 mg (n=76), 6 mg (n=78), or 10 mg (n=78) every 8 weeks (Q8wk). Primary efficacy results showed that fulranumab significantly reduced the average pain intensity score (Por = 0.030) from baseline to week 12 compared with placebo in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. Secondary efficacy outcomes indicated that significant improvement occurred compared with placebo at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index subscales of pain, stiffness, and physical function (P0.040) across all fulranumab groups except 1mgQ4wk, on the Brief Pain Inventory-Short Form subscales of pain intensity (Por = 0.016) and pain interference (Por = 0.030) in the 3mgQ4wk and 10mgQ8wk groups, and on the Patient Global Assessment score (Por = 0.040) in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. The most common (or = 5% of patients) treatment-emergent adverse events in overall fulranumab groups during the first 12weeks included paresthesia (7%), headache (5%), and nasopharyngitis (5%). Most neurologic-related treatment-emergent adverse events were mild or moderate and resolved at the end of week 12. Serious adverse events occurred in 3 patients, but they were not neurologically related and resolved before study completion. Fulranumab treatment resulted in statistically significant efficacy in pain measures and physical function versus placebo and was generally well tolerated.

BACKGROUND: In small series, endoscopic third ventriculostomy (ETV) has been shown to potentially have efficacy similar to that of ventriculoperitoneal shunting (VPS) for idiopathic normal-pressure hydrocephalus (iNPH). Therefore, some clinicians have advocated for ETV to avoid the potential long-term complications associated with VPS. Complication rates for these procedures vary widely based on limited small series data. OBJECTIVE: We used a nationwide database that provides a comprehensive investigation of the perioperative safety of ETV for iNPH compared with VPS. METHODS: We identified discharges with the primary diagnosis of iNPH (International Classification of Diseases, Ninth Revision code 331.5 [ICD-9]) with ICD-9 primary procedure codes for VPS (02.34) and ETV (02.2) from 2007 to 2010. We analyzed short-term safety outcomes using univariate and hierarchical logistic regression analyses. RESULTS: There were a total of 652 discharges for ETV for iNPH and 12 845 discharges for VPS for iNPH over the study period. ETV was associated with a significantly higher mortality (3.2% vs 0.5%) and short-term complication (17.9% vs 11.8%) rates than VPS despite similar mean modified comorbidity scores. On multivariate analysis, ETV alone predicted increased mortality and increased length of stay when adjusted for other patient and hospital factors. CONCLUSION: This is the first study that robustly assesses the perioperative complications and safety outcomes of ETV for iNPH. Compared with VPS, ETV is associated with higher perioperative mortality and complication rates. This consideration is important to weigh against the potential benefit of ETV: avoiding long-term shunt dependence. Prospective, randomized studies are needed.