Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer.

Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer.

Using volunteers to improve access to community rehabilitation in palliative care: the St Christopher's Living Well at Home Team.

Background: UK hospices often provide outpatient rehabilitation services for people with advanced progressive illness. However, some people are unable to travel, leading to inequity in rehabilitation access. Objectives: The Living Well at Home Team (LWAHT) at St Christopher's Hospice aimed to evaluate whether using volunteers to support rehabilitation in peoples' homes improved the reach of rehabilitation for people living in underserved localities and if it supported people to optimise their functional independence. Methods: This service improvement project evaluated hospice rehabilitation uptake during the implementation of volunteer-supported community rehabilitation. Following assessment by an LWAHT therapist, eligible people were matched with a trained volunteer who supported four to eight rehabilitation sessions in the person's home. The evaluation assessed uptake of the rehabilitation sessions. Mobility, wellbeing, and goal attainment outcomes were assessed by the Life-Space Assessment (LSA), General Health Questionnaire (GHQ), and Goal Attainment Scale (GAS), respectively. Results: In the first year, 183 patients were referred to the LWAHT; 123 were assessed and 96 received rehabilitation including 56 who were matched with a volunteer. Following volunteer support, patients reported significant improvements in mobility [LSA median 20 (IQR, 3.5-27.8)], general health [GHQ -2 (-5.25 to 0)], and achievement of goals [GAS T-score +8 (0-18.4)]. Conclusions: It was feasible to support community rehabilitation using hospice volunteers for people with advanced progressive illness. The LWAHT service also increased the uptake of hospice centre-based rehabilitation. Further work should test efficacy and identify patients requiring additional professional input. Key message: This is the first known study reporting on the use of trained rehabilitation volunteers to extend the reach of hospice rehabilitation services. People with limited access to the hospice, because of geographical location or personal circumstances, valued and benefited from tailored rehabilitation supported by the volunteers in their own homes.

The incidence, characteristics and in-hospital mortality of non-ventilator-associated hospital-acquired pneumonia in regional Queensland: A retrospective descriptive study.

OBJECTIVE: The aim of this study was to determine the incidence, characteristics and in-hospital mortality of non-ventilator-associated hospital-acquired pneumonia (NV-HAP) in a regional (Modified Monash Model 2) Australian hospital. METHODS: All cases with NV-HAP were obtained from the Business Analysis and Decision Support (BADS) Unit between 1st January 2013 and 31st December 2018. Medical records were reviewed, and data pertaining to incidence, characteristics (age and gender), length of stay, co-morbidities (measured using the Charlson Comorbidity Index) and in-hospital mortality were extracted. Incidence rate was calculated as a proportion of NV-HAP cases per 1000 bed-days. DESIGN: A retrospective study design was used to review all cases of NV-HAP between 1 January 2013 and 31 December 2018 at a single regional Australian hospital. Using the Modified Monash Model (MMM), our regional setting is classified as a regional centre (MMM-2). SETTING: Rockhampton Hospital, Australia. PARTICIPANTS: Patient cases. MAIN OUTCOME MEASURES: Incidence rate, Incidence proportion, mortality. RESULTS: A total of 501 cases were identified with an incidence rate of 0.98 cases per 1000 bed-days over the study period 2013-2018. Cases with NV-HAP had a median age of 78.2 years (interquartile range 18.8), a median length of stay of 13.0 days (interquartile range 12.0) and a median Charlson Comorbidity Index score of 3.0 out of 39 (interquartile range 3.0), and a greater proportion was male (n = 297, 57%). The in-hospital mortality rate for NV-HAP cases was 18.9%. CONCLUSION: This study revealed an overall incidence rate of 0.98 cases per 1000 bed-days from 2013 to 2018 in a regional Australian hospital. In addition, this study provided the descriptive characteristics for patients with NV-HAP at our regional hospital.

Shortening time for access to alcohol drives up front-loading behavior, bringing consumption in male rats to the level of females.

BACKGROUND: Incentives to promote drinking ("happy hour") can encourage faster rates of alcohol consumption, especially in women. Sex differences in drinking dynamics may underlie differential health vulnerabilities relating to alcohol in women versus men. Herein, we used operant procedures to model the happy hour effect and gain insight into the alcohol drinking dynamics of male and female rats. METHODS: Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which rats had access to alcohol (self-administration session length). Rats were tested twice within the 12 h of the dark cycle, first at 2 h (early phase of the dark cycle, "early sessions") and then again at 10 h into the dark cycle (late phase of the dark cycle, "late sessions") with an 8-h break between the two sessions in the home cage. RESULTS: Adult females consumed significantly more alcohol (g/kg) than males in the 30-min sessions with the FR1 schedule of reinforcement when tested late in the dark cycle. Front-loading of alcohol was the primary factor driving higher consumption in females. Changing the schedule of reinforcement from FR1 to FR3 reduced total consumption. Notably, this manipulation had minimal effect on front-loading behavior in females, whereas front-loading behavior was significantly reduced in males when more effort was required to access alcohol. Compressing drinking access to 15 min to model a happy hour drove up front-loading behavior, generating alcohol drinking patterns in males that were similar to patterns in females (faster drinking and higher intake). CONCLUSIONS: This strategy could be useful for exploring sex differences in the neural mechanisms underlying alcohol drinking and related health vulnerabilities. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.

Heart failure-the experience of living with end-stage heart failure and accessing care across settings.

BACKGROUND: Heart failure is a complex clinical syndrome affecting an increasing number of the ageing population. Patients and carers require increasing input from specialist palliative care services to both manage symptoms and access support in the last year of life. An integrated clinical service between the local cardiology team at Princess Royal University Hospital and the palliative care team at St. Christopher's Hospice was piloted for patients with end-stage heart failure in Bromley in Kent, UK. This study explored views of patients and carers who participated in the integrated pilot service. METHODS: A qualitative study was conducted in which a convenience sample of patients and carers were invited to participate in focus groups: two bereaved carer groups (n=2, n=2); one patient group (n=4), held between 14th December 2018 and 18th January 2019. Participants were asked to describe their experiences of care received facilitated by a topic guide. Interviews were recorded, transcribed and coded using thematic analysis to identify common themes. RESULTS: Four patients (2:2 M:F) aged between 70 to 87 years and four female carers whom had cared for patients aged between 70 to 96 years who were since deceased, participated in this study. Overall, the service was positively received, and responses were mapped into four key areas; being diagnosed and living with heart failure, referral to palliative care, key helpful components of the care received and finally, unhelpful components of the new service in terms of care. Common themes emerged including understanding of heart failure and its trajectory, communication around palliative care, having a 'broker' for the system, recognition of carer's needs, service responsiveness, and feeling 'in control'. CONCLUSIONS: This qualitative study highlighted important considerations when developing an integrated heart failure and palliative care service. Education about heart failure for patients and carers, but also the integrated multidisciplinary team is crucial to improving detection of deterioration and facilitating communication around Advance Care Planning. The value of the 'expert-carer' should also be promoted and supported in chronic conditions. We recommend a focus on development of integrated services that enable joined-up care or single point of contact for patients and carers.

Alcohol drinking during early adolescence activates microglial cells and increases frontolimbic Interleukin-1 beta and Toll-like receptor 4 gene expression, with heightened sensitivity in male rats compared to females.

Adolescent drinking is risky because neural circuits in the frontal lobes are undergoing maturational processes important for cognitive function and behavioral control in adulthood. Previous studies have shown that myelinated axons in the medial prefrontal cortex (mPFC) are particularly sensitive to alcohol drinking, especially in males. Pro-inflammatory mediators like toll-like receptor 4 (TLR4) and interleukin-1 beta (IL1b) have been implicated in alcohol induced-inflammation and demyelination; thus, herein we test the hypothesis that voluntary alcohol drinking early in adolescence elicits a pro-inflammatory state that is more pronounced in the brain of males compared to females. Adolescent male and female Wistar rats self-administered sweetened alcohol or sweetened water from postnatal days 28-42 and separate sets of brains were processed for 1) immunolabeling for ionized calcium-binding adapter molecule 1 to analyze microglial cell morphology, or 2) qPCR analysis of gene expression of pro-inflammatory mediators. Binge drinking alcohol activated microglia in the mPFC and hippocampus of both males and females, suggesting that voluntary alcohol exposure initiates an inflammatory response. Il1b mRNA was upregulated in the mPFC of both sexes. Conversely, Tlr4 mRNA levels were elevated after drinking only in males, which could explain more robust effects of alcohol on myelin in this region in developing males compared to females. Il1b mRNA changes were not observed in the hippocampus, but alcohol elevated Tlr4 mRNA in both sexes, highlighting regional specificity in inflammatory responses to alcohol. Overall, these findings give insight into potential mechanisms by which low-to-moderate voluntary alcohol intake impacts the developing brain. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.

Cervical ripening at home or in-hospital-prospective cohort study and process evaluation (CHOICE) study: a protocol.

INTRODUCTION: The aim of the cervical ripening at home or in-hospital-prospective cohort study and process evaluation (CHOICE) study is to compare home versus in-hospital cervical ripening to determine whether home cervical ripening is safe (for the primary outcome of neonatal unit (NNU) admission), acceptable to women and cost-effective from the perspective of both women and the National Health Service (NHS). METHODS AND ANALYSIS: We will perform a prospective multicentre observational cohort study with an internal pilot phase. We will obtain data from electronic health records from at least 14 maternity units offering only in-hospital cervical ripening and 12 offering dinoprostone home cervical ripening. We will also conduct a cost-effectiveness analysis and a mixed methods study to evaluate processes and women/partner experiences. Our primary sample size is 8533 women with singleton pregnancies undergoing induction of labour (IOL) at 39+0 weeks' gestation or more. To achieve this and contextualise our findings, we will collect data relating to a cohort of approximately 41 000 women undergoing IOL after 37 weeks. We will use mixed effects logistic regression for the non-inferiority comparison of NNU admission and propensity score matched adjustment to control for treatment indication bias. The economic analysis will be undertaken from the perspective of the NHS and Personal Social Services (PSS) and the pregnant woman. It will include a within-study cost-effectiveness analysis and a lifetime cost-utility analysis to account for any long-term impacts of the cervical ripening strategies. Outcomes will be reported as incremental cost per NNU admission avoided and incremental cost per quality adjusted life year gained. RESEARCH ETHICS APPROVAL AND DISSEMINATION: CHOICE has been funded and approved by the National Institute of Healthcare Research Health Technology and Assessment, and the results will be disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN32652461.

Sex Differences in the Neurobiology of Alcohol Use Disorder.

Sex differences may play a critical role in modulating how chronic or heavy alcohol use impacts the brain to cause the development of alcohol use disorder (AUD). AUD is a multifaceted and complex disorder driven by changes in key neurobiological structures that regulate executive function, memory, and stress. A three-stage framework of addiction (binge/intoxication; withdrawal/negative affect; preoccupation/anticipation) has been useful for conceptualizing the complexities of AUD and other addictions. Initially, alcohol drinking causes short-term effects that involve signaling mediated by several neurotransmitter systems such as dopamine, corticotropin releasing factor, and glutamate. With continued intoxication, alcohol leads to dysfunctional behaviors that are thought to be due in part to alterations of these and other neurotransmitter systems, along with alterations in neural pathways connecting prefrontal and limbic structures. Using the three-stage framework, this review highlights examples of research examining sex differences in drinking and differential modulation of neural systems contributing to the development of AUD. New insights addressing the role of sex differences in AUD are advancing the field forward by uncovering the complex interactions that mediate vulnerability.

Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats.

Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7-9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28-42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II-V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking.

Establishing key criteria to define and compare models of specialist palliative care: A mixed-methods study using qualitative interviews and Delphi survey.

BACKGROUND: Specialist palliative care services have various configurations of staff, processes and interventions, which determine how care is delivered. Currently, there is no consistent way to define and distinguish these different models of care. AIM: To identify the core components that characterise and differentiate existing models of specialist palliative care in the United Kingdom. DESIGN: Mixed-methods study: (1) semi-structured interviews to identify criteria, (2) two-round Delphi study to rank/refine criteria, and (3) structured interviews to test/refine criteria. SETTING/PARTICIPANTS: Specialist palliative care stakeholders from hospice inpatient, hospital advisory, and community settings. RESULTS: (1) Semi-structured interviews with 14 clinical leads, from eight UK organisations (five hospice inpatient units, two hospital advisory teams, five community teams), provided 34 preliminary criteria. (2) Delphi study: Round 1 (54 participants): thirty-four criteria presented, seven removed and seven added. Round 2 (30 participants): these 34 criteria were ranked with the 15 highest ranked criteria, including setting, type of care, size of service, diagnoses, disciplines, mode of care, types of interventions, 'out-of-hours' components (referrals, times, disciplines, mode of care, type of care), external education, use of measures, bereavement follow-up and complex grief provision. (3) Structured interviews with 21 UK service leads (six hospice inpatients, four hospital advisory and nine community teams) refined the criteria from (1) and (2), and provided four further contextual criteria (team purpose, funding, self-referral acceptance and discharge). CONCLUSION: In this innovative study, we derive 20 criteria to characterise and differentiate models of specialist palliative care - a major paradigm shift to enable accurate reporting and comparison in practice and research.

Huntingtin associates with the actin cytoskeleton and α-actinin isoforms to influence stimulus dependent morphology changes.

One response of cells to growth factor stimulus involves changes in morphology driven by the actin cytoskeleton and actin associated proteins which regulate functions such as cell adhesion, motility and in neurons, synaptic plasticity. Previous studies suggest that Huntingtin may be involved in regulating morphology however, there has been limited evidence linking endogenous Huntingtin localization or function with cytoplasmic actin in cells. We found that depletion of Huntingtin in human fibroblasts reduced adhesion and altered morphology and these phenotypes were made worse with growth factor stimulation, whereas the presence of the Huntington's Disease mutation inhibited growth factor induced changes in morphology and increased numbers of vinculin-positive focal adhesions. Huntingtin immunoreactivity localized to actin stress fibers, vinculin-positive adhesion contacts and membrane ruffles in fibroblasts. Interactome data from others has shown that Huntingtin can associate with α-actinin isoforms which bind actin filaments. Mapping studies using a cDNA encoding α-actinin-2 showed that it interacts within Huntingtin aa 399-969. Double-label immunofluorescence showed Huntingtin and α-actinin-1 co-localized to stress fibers, membrane ruffles and lamellar protrusions in fibroblasts. Proximity ligation assays confirmed a close molecular interaction between Huntingtin and α-actinin-1 in human fibroblasts and neurons. Huntingtin silencing with siRNA in fibroblasts blocked the recruitment of α-actinin-1 to membrane foci. These studies support the idea that Huntingtin is involved in regulating adhesion and actin dependent functions including those involving α-actinin.

Myelination of Axons Corresponds with Faster Transmission Speed in the Prefrontal Cortex of Developing Male Rats.

Myelination of prefrontal circuits during adolescence is thought to lead to enhanced cognitive processing and improved behavioral control. However, while standard neuroimaging techniques commonly used in human and animal studies can measure large white matter bundles and residual conduction speed, they cannot directly measure myelination of individual axons or how fast electrical signals travel along these axons. Here we focused on a specific population of prefrontal axons to directly measure conduction velocity and myelin microstructure in developing male rats. An in vitro electrophysiological approach enabled us to isolate monosynaptic projections from the anterior branches of the corpus callosum (corpus callosum-forceps minor, CCFM) to the anterior cingulate subregion of the medial prefrontal cortex (Cg1) and to measure the speed and direction of action potentials propagating along these axons. We found that a large number of axons projecting from the CCFM to neurons in Layer V of Cg1 are ensheathed with myelin between pre-adolescence [postnatal day (PD)15] and mid-adolescence (PD43). This robust increase in axonal myelination is accompanied by a near doubling of transmission speed. As there was no age difference in the diameter of these axons, myelin is likely the driving force behind faster transmission of electrical signals in older animals. These developmental changes in axonal microstructure and physiology may extend to other axonal populations as well, and could underlie some of the improvements in cognitive processing between childhood and adolescence.

Goldilocks Mastectomy with Bilateral In Situ Nipple Preservation Via Dermal Pedicle.

Patients who don't want or can't have formal breast reconstruction after mastectomy surgery can be considered for a Goldilocks mastectomy, where the breast fullness is recreated from what is left behind after the gland tissue is removed from underneath the skin in a breast reduction pattern. A Goldilocks mastectomy does not require the use of implants or tissue transfer from other parts of the body and may be completed in a single surgery. This is best suited for larger breasted women who are willing to have much smaller breasts as a result. Previously, it was a challenge to be able to preserve the nipples when this operation was performed; however, this article describes a patient who had a bilateral Goldilocks mastectomy for right breast cancer who was able to save her nipples by keeping the blood flow in place from the surrounding skin. Conventional breast reconstruction after mastectomy is a challenge for larger breasted women. The Goldilocks mastectomy technique was designed to make best use of the redundant lower pole skin and subcutaneous fat to recreate a breast mound without a prosthetic implant or autologous tissue transfer. In its original description, the Goldilocks mastectomy did not include a means for nipple preservation. In this report, we describe the further refinement of the Goldilocks procedure that preserves the nipple areolar complex using a dermal pedicle. A patient with large pendulous breasts and right breast carcinoma underwent a bilateral Goldilocks nipple-sparing mastectomy and immediate reconstruction without an implant or flap.

Menstrual Education and Personal Hygiene Supplies to Empower Young Women in Haiti.

Recent studies report that Haitian women are concerned about unmet women's health issues. The Days for Girls (DfG) International program features women's health education and personal hygiene kits to ensure women understand the process of menstruation and sanitary hygiene practices. The aim was to train Haitian seamstresses to produce the DfG kits during an in-country workshop and investigate the perceived benefit of the DfG program in young women who used the DfG kits. Posttest only design was used to measure the effectiveness of DfG workshop and postsurvey to study perception of women using DfG kits. It was found that the workshop participants demonstrated an understanding of the DfG program (90% average). Forty-four young women (89.8%) who used the DfG hygiene kits for 2 months agreed that there is a need for feminine hygiene programs in Haiti and that the kits were easy to use and clean (97.1% and 92.1%, respectively). The DfG program could provide a cost-effective feminine hygiene program for Haiti and decrease waste from traditional hygiene products.

Burden of Psychosocial and Cognitive Impairment in Patients With Atrial Fibrillation.

BACKGROUND: Impairments in psychosocial status and cognition relate to poor clinical outcomes in patients with atrial fibrillation (AF). However, how often these conditions co-occur and associations between burden of psychosocial and cognitive impairment and quality of life (QoL) have not been systematically examined in patients with AF. METHODS: A total of 218 patients with symptomatic AF were enrolled in a prospective study of AF and psychosocial factors between May 2013 and October 2014 at the University of Massachusetts Medical Center. Cognitive function, depression, and anxiety were assessed at baseline and AF-specific QoL was assessed 6 months after enrollment using validated instruments. Demographic and clinical information were obtained from a structured interview and medical record review. RESULTS: The mean age of the study participants was 63.5 ± 10.2 years, 35% were male, and 81% had paroxysmal AF. Prevalences of impairment in 1, 2, and 3 psychosocial/cognitive domains (eg, depression, anxiety, or cognition) were 75 (34.4%), 51 (23.4%), and 16 (7.3%), respectively. Patients with co-occurring psychosocial/cognitive impairments (eg, >1 domain) were older, more likely to smoke, had less education, and were more likely to have heart failure (all P < 0.05). Compared with participants with no psychosocial/cognitive impairments, AF-specific QoL at 6 months was significantly poorer among participants with baseline impairment in 2 (B = -13.6, 95% CI: -21.7 to -5.4) or 3 (B = -15.1, 95% CI: -28.0 to -2.2) psychosocial/cognitive domains. CONCLUSION: Depression, anxiety, and impaired cognition were common in our cohort of patients with symptomatic AF and often co-occurred. Higher burden of psychosocial/cognitive impairment was associated with poorer AF-specific QoL.

Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context.

Post-traumatic stress disorder (PTSD) affects 7.7 million Americans. One diagnostic criterion for PTSD is avoidance of stimuli that are related to the traumatic stress. Using a predator odor stress conditioned place aversion (CPA) model, rats can be divided into groups based on stress reactivity, as measured by avoidance of the odor-paired context. Avoider rats, which show high stress reactivity, exhibit persistent avoidance of stress-paired context and escalated alcohol drinking. Here, we examined the potential role of corticotropin-releasing factor (CRF), a neuropeptide that promotes anxiety-like behavior in mediating avoidance and escalated alcohol drinking after stress. CRF is expressed in the medial prefrontal cortex (mPFC). The dorsal and ventral sub-regions of the mPFC (dmPFC and vmPFC) have opposing roles in stress reactivity and alcohol drinking. We hypothesized that vmPFC CRF-CRFR1 signaling contributes functionally to stress-induced avoidance and escalated alcohol self-administration. In Experiment 1, adult male Wistar rats were exposed to predator odor stress in a CPA paradigm, indexed for avoidance of odor-paired context, and brains processed for CRF-immunoreactive cell density in vmPFC and dmPFC. Post-stress, Avoiders exhibited higher CRF cell density in vmPFC, but not the dmPFC. In Experiment 2, rats were tested for avoidance of a context repeatedly paired with intra-vmPFC CRF infusions. In Experiment 3, rats were stressed and indexed, then tested for the effects of intra-vmPFC CRFR1 antagonism on avoidance and alcohol self-administration. Intra-vmPFC CRF infusion produced avoidance of a paired context, and intra-vmPFC CRFR1 antagonism reversed avoidance of a stress-paired context, but did not alter post-stress alcohol self-administration. These findings suggest that vmPFC CRF-CRFR1 signaling mediates avoidance of stimuli paired with traumatic stress.