Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.

BACKGROUND: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. METHODS: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. RESULTS: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. CONCLUSION: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.

BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

Bridging the Age Gap: a prognostic model that predicts survival and aids in primary treatment decisions for older women with oestrogen receptor-positive early breast cancer.

BACKGROUND: A prognostic model was developed and validated using cancer registry data. This underpins an online decision support tool, informing primary treatment choice for women aged 70 years or older with hormone receptor-positive early breast cancer. METHODS: Data from women diagnosed between 2002 and 2010 in the English Northern and Yorkshire and West Midlands regions were used to develop the model. Primary treatment options of surgery with adjuvant endocrine therapy or primary endocrine therapy were compared. Models predicting the hazard of breast cancer-specific mortality and hazard of other-cause mortality were combined to derive survival probabilities. The model was validated externally using data from the Eastern Cancer Registration and Information Centre. RESULTS: The model was developed using data from 23 842 women, and validated externally on a data set from 14 526 patients. The overall model calibration was good. At 2 and 5 years, predicted mortality from breast cancer and other causes differed from the observed rate by less than 1 per cent. At 5 years, there were slight overpredictions in breast cancer mortality (2629 predicted versus 2556 observed deaths; P = 0·142) and mortality from all causes (6399 versus 6320 respectively; P = 0·583). The discrepancy varied between subgroups. Model discrimination was 0·75 or above for all mortality measures. CONCLUSION: A prognostic model for older women with oestrogen receptor-positive early breast cancer was developed and validated in the present study. This forms a basis for an online decision support tool (https://agegap.shef.ac.uk/).

ANTECEDENTES: Se ha desarrollado y validado un modelo pronóstico utilizando datos del registro de cáncer. Ello ha permitido ofrecer una herramienta online para facilitar la toma de decisiones respecto a la elección del tratamiento inicial en mujeres mayores de 70 años con cáncer de mama precoz y receptores de hormonas positivos. MÉTODOS: Se incluyeron un total de 23.842 mujeres, diagnosticadas entre 2002 y 2010 en las regiones del Norte, Yorkshire y West Midlands inglesas que cumplieron con los criterios de inclusión. Se compararon dos opciones de tratamiento: cirugía primaria asociada a tratamiento endocrino adyuvante o tratamiento primario endocrino. Para estimar la probabilidad de supervivencia se combinaron modelos predictivos para el riesgo de mortalidad específica por cáncer de mama y para el riesgo de mortalidad por otras causas. Se realizó una validación externa con datos del Eastern Cancer Registration and Information Center (n = 14.526). RESULTADOS: La calibración global del modelo fue buena. A los 2 y 5 años, la mortalidad anticipada por cáncer de mama y por otras causas difería de la observada en menos del 1%. A los 5 años, hubo una ligera sobrevaloración de la predicción de mortalidad por cáncer de mama (prevista versus real: 2.629 versus 2.556, P = 0,78) y de la mortalidad por todas las causas (6.399 versus 6.320, P = 0,14). Esta discrepancia varió entre subgrupos. La capacidad discriminativa del modelo fue del 0,75 o superior para todas las medidas de mortalidad. CONCLUSIÓN: En este estudio, se desarrolló y validó un modelo pronóstico para mujeres mayores con cáncer de mama precoz positivo para receptores de estrógenos. Esta herramienta que facilita la toma de decisiones está disponible online (https://agegap.shef.ac.uk/).

Breast cancer surgery in older women: outcomes of the Bridging Age Gap in Breast Cancer study.

BACKGROUND: Breast cancer surgery in older women is variable and sometimes non-standard owing to concerns about morbidity. Bridging the Age Gap in Breast Cancer is a prospective multicentre cohort study aiming to determine factors influencing treatment selection and outcomes from surgery for older patients with breast cancer. METHODS: Women aged at least 70 years with operable breast cancer were recruited from 57 UK breast units between 2013 and 2018. Associations between patient and tumour characteristics and type of surgery in the breast and axilla were evaluated using univariable and multivariable analyses. Oncological outcomes, adverse events and quality-of-life (QoL) outcomes were monitored for 2 years. RESULTS: Among 3375 women recruited, surgery was performed in 2816 patients, of whom 24 with inadequate data were excluded. Sixty-two women had bilateral tumours, giving a total of 2854 surgical events. Median age was 76 (range 70-95) years. Breast surgery comprised mastectomy in 1138 and breast-conserving surgery in 1716 procedures. Axillary surgery comprised axillary lymph node dissection in 575 and sentinel node biopsy in 2203; 76 had no axillary surgery. Age, frailty, dementia and co-morbidities were predictors of mastectomy (multivariable odds ratio (OR) for age 1·06, 95 per cent c.i. 1·05 to 1·08). Age, frailty and co-morbidity were significant predictors of no axillary surgery (OR for age 0·91, 0·87 to 0·96). The rate of adverse events was moderate (551 of 2854, 19·3 per cent), with no 30-day mortality. Long-term QoL and functional independence were adversely affected by surgery. CONCLUSION: Breast cancer surgery is safe in women aged 70 years or more, with serious adverse events being rare and no mortality. Age, ill health and frailty all influence surgical decision-making. Surgery has a negative impact on QoL and independence, which must be considered when counselling patients about choices.

ANTECEDENTES: La cirugía del cáncer de mama en mujeres mayores es variable y, a veces, no estandarizada debido a las reservas que origina la morbilidad quirúrgica. Bridging the Age Gap in Breast Cancer es un estudio de cohortes, prospectivo, multicéntrico cuyo objetivo fue determinar los factores que influyen en la selección del tratamiento y en los resultados de la cirugía en pacientes mayores con cáncer de mama. MÉTODOS: Se reclutaron mujeres de > 70 años de edad con cáncer de mama operable atendidas en 56 unidades de mama del Reino Unido entre 2013-2018. Los datos sobre las características de la paciente y del tumor se correlacionaron con el tipo de cirugía en la mama y en la axila mediante análisis univariable y multivariable. Se controlaron los resultados oncológicos, los eventos adversos y los resultados en cuanto a la calidad de vida durante 2 años. RESULTADOS: De 3.375 mujeres reclutadas, se realizó una intervención quirúrgica en 2.816 pacientes. Hubo 62 tumores bilaterales, por lo que se analizan 2.854 procedimientos. La mediana de edad fue de 76 años (rango 70-95). En 1.138 pacientes se realizó una mastectomía y en 1.798 cirugía conservadora de la mama. En cuanto a la cirugía de la axila, en 575 pacientes se realizó una linfadenectomía, en 2.203 una biopsia de ganglio centinela y en 76 no se realizó ningún procedimiento. Los factores predictores de mastectomía fueron la edad, la fragilidad, la demencia y las comorbilidades (riesgo relativo, RR 1,06; i.c. del 95% 1,05-1,08), mientras que para la cirugía axilar los factores predictores fueron la fragilidad y las comorbilidades (RR 0,91; i.c. del 95% 0,87-0,96). La tasa de efectos adversos fue moderada (551/2854; 19,3%), sin mortalidad a los 30 días. La calidad de vida a largo plazo y la independencia funcional se vieron negativamente afectadas por la cirugía. CONCLUSIÓN: La cirugía de cáncer de mama es segura, con escasos efectos adversos graves y sin mortalidad. La edad, las comorbilidades y la fragilidad tienen impacto en la toma de decisiones quirúrgicas. La cirugía tiene una repercusión negativa en la calidad de vida e independencia funcional, hechos que deben ser tenidos en cuenta al aconsejar a las pacientes sobre las opciones terapéuticas.

Transportation Barriers to Health Care in the United States: Findings From the National Health Interview Survey, 1997-2017.

Objectives. To quantify the number of people in the US who delay medical care annually because of lack of available transportation and to examine the differential prevalence of this barrier for adults across sociodemographic characteristics and patient populations.Methods. We used data from the National Health Interview Survey (1997-2017) to examine this barrier over time and across groups. We used joinpoint regression analysis to identify significant changes in trends and multivariate analysis to examine correlates of this barrier for the year 2017.Results. In 2017, 5.8 million persons in the United States (1.8%) delayed medical care because they did not have transportation. The proportion reporting transportation barriers increased between 2003 and 2009 with no significant trends before or after this window within our study period. We found that Hispanic people, those living below the poverty threshold, Medicaid recipients, and people with a functional limitation had greater odds of reporting a transportation barrier after we controlled for other sociodemographic and health characteristics.Conclusions. Transportation barriers to health care have a disproportionate impact on individuals who are poor and who have chronic conditions. Our study documents a significant problem in access to health care during a time of rapidly changing transportation technology.

Capital Expenditures Increased at Rural Hospitals That Merged Between 2012 and 2015.

EXECUTIVE SUMMARY: The number of rural hospital mergers has increased substantially in recent years. A commonly reported reason for merging is to increase access to capital. However, no empirical evidence exists to show whether capital expenditures increased at rural hospitals after a merger. We used a difference-in-differences approach to determine whether total capital expenditures changed at rural hospitals after a merger. The comparison group (rural hospitals that did not merge during the 2012 through 2015 study period) was weighted using inverse probability of treatment weights. The key outcome measure was logged total capital expenditures.Merging resulted in a 26% increase in capital expenditures and also was associated with a significant improvement in plant age. The postmerger improvement in plant age may have been partially attributable to merger-related accounting changes and partially attributable to increased capital expenses, possibly on long-term asset renovations and replacement.These findings suggest that through mergers, rural hospital board members and executives who have accepted or are considering a merger may improve a hospital's ability to increase capital expenditures. Further, increased capital investments in rural hospitals may be an important signal to the community that the acquirer intends to keep the rural hospital open and continue providing some volume and level of services within the community. Future research should determine how capital is spent after a merger.

The Medicare Shared Savings Program and Outcomes for Ischemic Stroke Patients: a Retrospective Cohort Study.

BACKGROUND: Post-stroke care delivery may be affected by provider participation in Medicare Shared Savings Program (MSSP) Accountable Care Organizations (ACOs) through systematic changes to discharge planning, care coordination, and transitional care. OBJECTIVE: To evaluate the association of MSSP with patient outcomes in the year following hospitalization for ischemic stroke. DESIGN: Retrospective cohort SETTING: Get With The Guidelines (GWTG)-Stroke (2010-2014) PARTICIPANTS: Hospitalizations for mild to moderate incident ischemic stroke were linked with Medicare claims for fee-for-service beneficiaries ≥ 65 years (N = 251,605). MAIN MEASURES: Outcomes included discharge to home, 30-day all-cause readmission, length of index hospital stay, days in the community (home-time) at 1 year, and 1-year recurrent stroke and mortality. A difference-in-differences design was used to compare outcomes before and after hospital MSSP implementation for patients (1) discharged from hospitals that chose to participate versus not participate in MSSP or (2) assigned to an MSSP ACO versus not or both. Unique estimates for 2013 and 2014 ACOs were generated. KEY RESULTS: For hospitals joining MSSP in 2013 or 2014, the probability of discharge to home decreased by 2.57 (95% confidence intervals (CI) = - 4.43, - 0.71) percentage points (pp) and 1.84 pp (CI = - 3.31, - 0.37), respectively, among beneficiaries not assigned to an MSSP ACO. Among discharges from hospitals joining MSSP in 2013, beneficiary ACO alignment versus not was associated with increased home discharge, reduced length of stay, and increased home-time. For patients discharged from hospitals joining MSSP in 2014, ACO alignment was not associated with changes in utilization. No association between MSSP and recurrent stroke or mortality was observed. CONCLUSIONS: Among patients with mild to moderate ischemic stroke, meaningful reductions in acute care utilization were observed only for ACO-aligned beneficiaries who were also discharged from a hospital initiating MSSP in 2013. Only 1 year of data was available for the 2014 MSSP cohort, and these early results suggest further study is warranted. REGISTRATION: None.

Omission of surgery in older women with early breast cancer has an adverse impact on breast cancer-specific survival.

BACKGROUND: Primary endocrine therapy is used as an alternative to surgery in up to 40 per cent of women with early breast cancer aged over 70 years in the UK. This study investigated the impact of surgery versus primary endocrine therapy on breast cancer-specific survival (BCSS) in older women. METHODS: Cancer registration data for 2002-2010 were obtained from two English regions. A retrospective analysis was performed for women with oestrogen receptor (ER)-positive disease, using statistical modelling to show the effect of treatment (surgery or primary endocrine therapy) and age and health status on BCSS. Missing data were handled using multiple imputation. RESULTS: Cancer registration data on 23 961 women were retrieved. After data preprocessing, 18 730 of 23 849 women (78·5 per cent) were identified as having ER-positive disease; of these, 10 087 (53·9 per cent) had surgery and 8643 (46·1 per cent) had primary endocrine therapy. BCSS was worse in the primary endocrine therapy group than in the surgical group (5-year BCSS rate 69·4 and 89·9 per cent respectively). This was true for all strata considered, although the difference was less in the cohort with the greatest degree of co-morbidity. For older, frailer patients the hazard of breast cancer death had less relative impact on overall survival. CONCLUSION: BCSS in older women with ER-positive disease is worse if surgery is omitted. This treatment choice may contribute to inferior cancer outcomes. Selection for surgery on the basis of predicted life expectancy may permit choice of women for whom surgery confers little benefit.

Current Knowledge on Skin Cancer Prevention in Liver Transplant Recipients.

The improved survival of liver transplant recipients (LTRs) has been accompanied by a concomitant rise in long-term liver transplantation complications, including skin cancer. A recent study found that the prevalence of skin cancer among LTRs is 13.5%, a rate equivalent to that observed among kidney transplant recipients. Given the morbidity associated with skin cancer in LTRs, an individualized, multidisciplinary approach to skin cancer prevention that incorporates patient education, encourages consistent use of primary prevention methods, and ensures routine dermatologic screening should be universally adopted in this population. Chemopreventative measures should be considered in LTRs with a high skin cancer burden. Furthermore, additional studies should be performed in order to systematize these recommendations.

An interdisciplinary review of current and future approaches to improving human-predator relations.

In a world of shrinking habitats and increasing competition for natural resources, potentially dangerous predators bring the challenges of coexisting with wildlife sharply into focus. Through interdisciplinary collaboration among authors trained in the humanities, social sciences, and natural sciences, we reviewed current approaches to mitigating adverse human-predator encounters and devised a vision for future approaches to understanding and mitigating such encounters. Limitations to current approaches to mitigation include too much focus on negative impacts; oversimplified equating of levels of damage with levels of conflict; and unsuccessful technical fixes resulting from failure to engage locals, address hidden costs, or understand cultural (nonscientific) explanations of the causality of attacks. An emerging interdisciplinary literature suggests that to better frame and successfully mitigate negative human-predator relations conservation professionals need to consider dispensing with conflict as the dominant framework for thinking about human-predator encounters; work out what conflicts are really about (they may be human-human conflicts); unravel the historical contexts of particular conflicts; and explore different cultural ways of thinking about animals. The idea of cosmopolitan natures may help conservation professionals think more clearly about human-predator relations in both local and global context. These new perspectives for future research practice include a recommendation for focused interdisciplinary research and the use of new approaches, including human-animal geography, multispecies ethnography, and approaches from the environmental humanities notably environmental history. Managers should think carefully about how they engage with local cultural beliefs about wildlife, work with all parties to agree on what constitutes good evidence, develop processes and methods to mitigate conflicts, and decide how to monitor and evaluate these. Demand for immediate solutions that benefit both conservation and development favors dispute resolution and technical fixes, which obscures important underlying drivers of conflicts. If these drivers are not considered, well-intentioned efforts focused on human-wildlife conflicts will fail.

A global assessment of the social and conservation outcomes of protected areas.

Protected areas (PAs) are a key strategy for protecting biological resources, but they vary considerably in their effectiveness and are frequently reported as having negative impacts on local people. This has contributed to a divisive and unresolved debate concerning the compatibility of environmental and socioeconomic development goals. Elucidating the relationship between positive and negative social impacts and conservation outcomes of PAs is key for the development of more effective and socially just conservation. We conducted a global meta-analysis on 165 PAs using data from 171 published studies. We assessed how PAs affect the well-being of local people, the factors associated with these impacts, and crucially the relationship between PAs' conservation and socioeconomic outcomes. Protected areas associated with positive socioeconomic outcomes were more likely to report positive conservation outcomes. Positive conservation and socioeconomic outcomes were more likely to occur when PAs adopted comanagement regimes, empowered local people, reduced economic inequalities, and maintained cultural and livelihood benefits. Whereas the strictest regimes of PA management attempted to exclude anthropogenic influences to achieve biological conservation objectives, PAs that explicitly integrated local people as stakeholders tended to be more effective at achieving joint biological conservation and socioeconomic development outcomes. Strict protection may be needed in some circumstances, yet our results demonstrate that conservation and development objectives can be synergistic and highlight management strategies that increase the probability of maximizing both conservation performance and development outcomes of PAs.

Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis.

Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood-brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important role of thrombin and its major receptor in the brain, protease-activated receptor 1 (PAR1), in the pathophysiology of neurological injury, we hypothesized that PAR1 may contribute to status epilepticus (SE)-induced epileptogenesis and that its inhibition shortly after SE will have neuroprotective and antiepileptogenic effects. Adult rats subjected to lithium-pilocarpine SE were administrated with SCH79797 (a PAR1 selective antagonist) after SE termination. Thrombin and PAR1 levels and neuronal cell survival were evaluated 48h following SE. The effect of PAR1 inhibition on animal survival, interictal spikes (IIS) and electrographic seizures during the first two weeks after SE and behavioral seizures during the chronic period was evaluated. SE resulted in a high mortality rate and incidence of IIS and seizures in the surviving animals. There was a marked increase in thrombin, decrease in PAR1 immunoreactivity and hippocampal cell loss in the SE-treated rats. Inhibition of PAR1 following SE resulted in a decrease in mortality and morbidity, increase in neuronal cell survival in the hippocampus and suppression of IIS, electrographic and behavioral seizures following SE. These data suggest that the PAR1 signaling pathway contributes to epileptogenesis following SE. Because breakdown of the BBB occurs frequently in brain injuries, PAR1 inhibition may have beneficial effects in a variety of acquired injuries leading to epilepsy.

Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information.

Cognitive impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is often considered more detrimental to quality of life than seizures. While it has been previously shown that the encoding of memory during behavior is impaired in the pilocarpine model of TLE in rats, how this information is consolidated during the subsequent sleep period remains unknown. In this study, we first report marked deficits in spatial memory performance and severe cell loss in the CA1 layer of the hippocampus lower spatial coherence of firing in TLE rats. We then present the first evidence that the reactivation of behavior-driven patterns of activity of CA1 place cells in the hippocampus is intact in TLE rats. Using a template-matching method, we discovered that real-time (3-5 s) reactivation structure was intact in TLE rats. Furthermore, we estimated the entropy rate of short time scale (∼250 ms) bursting activity using block entropies and found that significant, extended temporal correlations exist in both TLE and control rats. Fitting a first-order Markov Chain model to these bursting time series, we found that long sequences derived from behavior were significantly enriched in the Markov model over corresponding models fit on randomized data confirming the presence of replay in shorter time scales. We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats.

Rural Hospital Closures: A Scoping Review of Studies Published Between 1990 and 2020.

Between 1990 and 2020, 334 rural hospitals closed in the United States, and since 2011 hospital closures have outnumbered new hospital openings. This scoping review evaluates peer-reviewed studies published since 1990 with a focus on rural hospital closures, synthesizing studies across six themes: 1) health care policy environment, 2) precursors to rural hospital closures, 3) economic impacts, 4) effects of rural hospital closures on access to care, 5) health and community impacts, and 6) definitions of rural hospitals and communities. In the 1990s, rural hospitals that closed were smaller, while rural hospitals that closed in the 2010s tended to have more beds. Many studies of the health impacts of rural hospital closures yielded null findings. However, these studies differed in their definitions of "rural hospital closure." Given the accelerated rate of hospital closures, more attention should be paid to hospitals that serve rural communities of color and low-income communities.

A critical re-evaluation of the specificity of action of perivagal capsaicin.

Perivagal application of capsaicin (1% solution) is considered to cause a selective degeneration of vagal afferent C fibres and has been used extensively to examine the site of action of many gastrointestinal (GI) neuropeptides. The actions of both capsaicin and GI neuropeptides may not be restricted to vagal afferent fibres, however, as other non-sensory neurones have displayed sensitivity to capsaicin and brainstem microinjections of these neuropeptides induce GI effects similar to those obtained upon systemic application. The aim of the present study was to test the hypothesis that perivagal capsaicin induces degeneration of vagal efferents controlling GI functions. Experiments were conducted 7-14 days after 30 min unilateral perivagal application of 0.1-1% capsaicin. Immunohistochemical analyses demonstrated that, as following vagotomy, capsaicin induced dendritic degeneration, decreased choline acetyltransferase but increased nitric oxide synthase immunoreactivity in rat dorsal motor nucleus of the vagus (DMV) neurones. Electrophysiological recordings showed a decreased DMV input resistance and excitability due, in part, to the expression of a large conductance calcium-dependent potassium current and the opening of a transient outward potassium window current at resting potential. Furthermore, the number of DMV neurones excited by thyrotrophin-releasing hormone and the gastric motility response to DMV microinjections of TRH were decreased significantly. Our data indicate that perivagal application of capsaicin induced DMV neuronal degeneration and decreased vagal motor responses. Treatment with perivagal capsaicin cannot therefore be considered selective for vagal afferent C fibres and, consequently, care is needed when using perivagal capsaicin to assess the mechanism of action of GI neuropeptides.

Altered short-term plasticity in the prefrontal cortex after early life seizures.

Seizures during development are a relatively common occurrence and are often associated with poor cognitive outcomes. Recent studies show that early life seizures alter the function of various brain structures and have long-term consequences on seizure susceptibility and behavioral regulation. While many neocortical functions could be disrupted by epileptic seizures, we have concentrated on studying the prefrontal cortex (PFC) as disturbance of PFC functions is involved in numerous co-morbid disorders associated with epilepsy. In the present work we report an alteration of short-term plasticity in the PFC in rats that have experienced early life seizures. The most robust alteration occurs in the layer II/III to layer V network of neurons. However short-term plasticity of layer V to layer V network was also affected, indicating that the PFC function is broadly influenced by early life seizures. These data strongly suggest that repetitive seizures early in development cause substantial alteration in PFC function, which may be an important component underlying cognitive deficits in individuals with a history of seizures during development.

Kgaria (Boletaceae, Boletoideae) gen. nov. in Australia: Neither a Tylopilus nor a Porphyrellus.

Kgaria is described as a new porphyrellus-like genus of Boletaceae to accommodate Tylopilus cyanogranulifer, a dark brown to dull lilac/violet, or rarely, nearly black bolete with a series of oxidation reactions progressing from blue to red then nearly black and a dark brown spore deposit. Idiosyncratic blue-green pigment encrustations (cyanogranules) and a similarly colored reaction of the hyphae located on pileus and stipe surfaces are also diagnostic. Phylogenetic analyses of nuclear large-subunit rDNA (nrLSU), translation elongation factor 1-alpha (tef-1), and the second largest subunit of RNA polymerase II (rpb2) infer Kgaria as a unique generic lineage with two species, one of which is newly described (K. similis). Tylopilus olivaceoporus, originally described at the same time and as distinct from T. cyanogranulifer, appears to be conspecific with the latter. Some darkly pigmented taxa with similar oxidation reactions that were recently described from Brazil, Guyana, and China are further supported by morphology and molecular data as discrete lineages in separate genera in subfamily Boletoideae. Citation: Halling RE, Fechner NA, Holmes G, Davoodian N (2023). Kgaria (Boletaceae, Boletoideae) gen. nov. in Australia: Neither a Tylopilus nor a Porphyrellus. Fungal Systematics and Evolution 12: 31-45. doi: 10.3114/fuse.2023.12.02.

Short-term effects of comprehensive caregiver supports on caregiver outcomes.

OBJECTIVE: To estimate the association of the Veterans Health Administration (VHA) Program of Comprehensive Assistance for Family Caregivers (PCAFC) implemented in 2011 with caregiver health and health care use. DATA SOURCES: VHA claims and electronic health records from May 2009 to May 2018. STUDY DESIGN: Using a retrospective, pre-post study design with inverse probability of treatment weights to address selection into treatment, we examine the association of PCAFC on caregivers who are veterans: (1) outpatient primary, specialty, and mental health care visits; (2) probability of uncontrolled hypertension and anxiety/depression; and (3) VHA health care costs. We compare outcomes for caregivers approved for PCAFC (treatment) to caregivers denied PCAFC (comparison). DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: In the year pre-application, we observe similar probabilities of having any VHA primary care (~36%), VHA specialty care (~24%), and VHA or VHA-purchased mental health care (~22%) for treatment and comparison caregivers. In the year post-application, treated caregivers had a 5.89 percentage point larger probability of any outpatient VHA primary care (p = 0.002) and 4.34 percentage points larger probability of any outpatient mental health care use (p = 0.014). Post-application, probabilities of having uncontrolled hypertension or diagnosed anxiety/depression were higher for both treated and comparison groups. In the second year post-application, treated caregivers had a 1.88 percentage point larger probability of uncontrolled hypertension (p = 0.019) and 4.68 percentage points larger probability of diagnosed anxiety/depression (predicted probabilities: treated = 0.30; comparison = 0.25; p = 0.005). We find no evidence of differences in VHA total costs by PCAFC status. CONCLUSIONS: Our findings that PCAFC enrollment is associated with increased health care diagnosis and service use may reflect improved access for previously unmet needs in the population of veteran caregivers for veterans in PCAFC. The costs and value of these increases can be weighed against other effects of the program to inform national policies supporting caregivers.

Spatiotemporal spread of cucurbit downy mildew in the eastern United States.

The dynamics of cucurbit downy mildew, caused by Pseudoperonospora cubensis, in the eastern United States in 2008 and 2009 were investigated based on disease records collected in 24 states as part of the Cucurbit downy mildew ipmPIPE monitoring program. The mean season-long rate of temporal disease progress across the 2 years was 1.4 new cases per day. Although cucurbit downy mildew was detected in mid-February and early March in southern Florida, the disease progressed slowly during the spring and early summer and did not enter its exponential phase until mid-June. The median nearest-neighbor distance of spread of new disease cases was ≈110 km in both years, with ≈15% of the distances being >240 km. Considering disease epidemics on all cucurbits, the epidemic expanded at a rate of 9.2 and 10.5 km per day in 2008 and 2009, respectively. These rates of spatial spread are at the lower range of those reported for the annual spread of tobacco blue mold in the southeastern United States, a disease that is also aerially dispersed over long distances. These results suggest that regional spread of cucurbit downy mildew may be limited by opportunities for establishment in the first half of the year, when fewer cucurbit hosts are available for infection. The O-ring statistic was used to determine the spatial pattern of cucurbit downy mildew outbreaks using complete spatial randomness as the null model for hypothesis testing. Disease outbreaks in both years were spatially aggregated and the extent of spatial dependence was up to 1,000 km. Results from the spatial analysis suggests that disease outbreaks in the Great Lakes and mid-Atlantic regions may be due to the spread of P. cubensis sporangia from outbreaks of the disease near the Georgia/South Carolina/North Carolina border rather than from overwintering sites in southern Florida. Space-time point pattern analysis indicated strong (P < 0.001) evidence for a space-time interaction and a space-time risk window of ≈3 to 5 months after first disease outbreak and 300 to 600 km was detected in both years. Results of this study support the hypothesis that infection of cucurbits by P. cubensis appears to be an outcome of a contagion process, and the relative large space-time window suggests that factors occurring on a large spatial scale (≈1,000 km) facilitate the spread of cucurbit downy mildew in the eastern United States.

For Rural Hospitals That Merged, Inpatient Charges Decreased and Outpatient Charges Increased: A Pre-/Post-Comparison of Rural Hospitals That Merged and Rural Hospitals That Did Not Merge Between 2005 and 2015.

PURPOSE: To determine whether inpatient and outpatient charges changed at rural hospitals after a merger. METHODS: Hospital mergers were derived from proprietary Irving Levin Associates data through manual review and validation. Hospital-level characteristics were derived from HCRIS, CMS Impact File Hospital Inpatient Prospective Payment System, Hospital MSA file, AHRF, and US Census data. A difference-in-differences approach was used to determine whether inpatient and outpatient charges changed at rural hospitals after a merger. The comparison group, rural hospitals that did not merge at any point during the sample period, was weighted using inverse probability of treatment weights. Key outcome measures were total inpatient and total outpatient charges (logged). FINDINGS: Hospitals that merged billed 17.73% more inpatient charges and 12.66% more outpatient charges at baseline compared to hospitals that did not merge. Our results indicate that merging was associated with a 3.04% decrease in inpatient charges (P < .001) and a 1.07% increase in outpatient charges (P = .082). Merging was also associated with a 4.38% decrease in total revenue, a 3.58% decrease in net patient revenue, and no change in total inpatient discharges or average daily census. CONCLUSIONS & IMPLICATIONS: Merging was strongly associated with a decrease in inpatient charges and somewhat associated with an increase in outpatient charges for rural hospitals. Future work could build upon this work to determine whether acquirers reduce or eliminate certain services at rural hospitals after a merger, and ultimately how changes in service delivery could impact patients in those rural communities.