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This paper compares community responses to Ebola and Covid-19 in two regions of southern and eastern Sierra Leone with reference to the theory of institutional dynamics proposed by the anthropologist Mary Douglas. Institutions, Douglas argued, are conveyed by styles of thought, shaped by the ways human communities, through everyday practices, reinforce systems of classification and denotation. Pandemic advice to 'follow the science' proved problematic, since there is no single institution of science, and institutions never stand alone but are bundled with other institutions, reflecting the manifold and intertwined practices of human social life. The paper explores some of the ways a traumatic epidemic of Ebola Virus Disease in Sierra Leone shaped a distinctive local response to this deadly infectious disease in the absence of an effective vaccine. This local approach emphasised social rules based on ideas about sequestration and testing. Communities then proposed to continue this rules-based approach to the pandemic of Covid-19 and showed little initial enthusiasm for vaccination. With Ebola, the adoption of rules resulted in dramatic drops in infection rates. But Covid-19 spreads in different ways, and good results from the application of social rules were much less apparent. The paper shows how communities began to grapple with this new situation. In some cases, vaccine hesitation was overcome by treating the requirement for vaccination as a new form of social discipline. More generally, it is concluded that epidemiologists need to pay specific attention to institutions and institutional dynamics in order to better understand and anticipate public reactions to new disease threats.

Background: Health is increasingly affected by multiple types of crises. Community engagement is recognised as being a critical element in successful crisis response, and a number of conceptual frameworks and global guideline documents have been produced. However, little is known about the usefulness of such documents and whether they contain sufficient information to guide effective community engagement in crisis response. We undertake a scoping review to examine the usefulness of conceptual literature and official guidelines on community engagement in crisis response using a realist-informed analysis [exploring contexts, mechanisms, and outcomes(CMOs)]. Specifically, we assess the extent to which sufficient detail is provided on specific health crisis contexts, the range of mechanisms (actions) that are developed and employed to engage communities in crisis response and the outcomes achieved. We also consider the extent of analysis of interactions between the mechanisms and contexts which can explain whether successful outcomes are achieved or not., Scope and Findings: We retained 30 documents from a total of 10,780 initially identified. Our analysis found that available evidence on context, mechanism and outcomes on community engagement in crisis response, or some of their elements, was promising, but few documents provided details on all three and even fewer were able to show evidence of the interactions between these categories, thus leaving gaps in understanding how to successfully engage communities in crisis response to secure impactful outcomes. There is evidence that involving community members in all the steps of response increases community resilience and helps to build trust. Consistent communication with the communities in time of crisis is the key for effective responses and helps to improve health indicators by avoiding preventable deaths., Conclusions: Our analysis confirms the complexity of successful community engagement and the need for strategies that help to deal with this complexity to achieve good health outcomes. Further primary research is needed to answer questions of how and why specific mechanisms, in particular contexts, can lead to positive outcomes, including what works and what does not work and how to measure these processes., (© 2024. The Author(s).)

The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug's beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action., (© 2024. The Author(s).)

Abstract: This study, completed at an sexually transmitted infection (STI) clinic in 2019 to 2020, evaluated patient preferences for telemedicine, express, and standard visits. Active PrEP users preferred telemedicine and express visits, patients with prior STIs preferred express visits, and cisgender women preferred standard visits. Configuring STI clinic visit types requires shared decision making and individualization., Competing Interests: Conflict of Interest and Sources of Funding: All authors have no conflict of interest to disclose in relation to this study. J.Z. is supported by the National Institute of Allergy and Infectious Diseases of the National Institute of Health under award number K23AI150278., (Copyright © 2023 American Sexually Transmitted Diseases Association. All rights reserved.)

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation., (© 2023. The Author(s).)

Hillebrandt, David, Anil Gurtoo, Thomas Kupper, Paul Richards, Volker Schöffl, Pankaj Shah, Rianne van der Spek, Nikki Wallis, and Jim Milledge. UIAA Medical Commission recommendations for mountaineers, hillwalkers, trekkers, and rock and ice climbers with diabetes. High Alt Med Biol . 24: 110-126.-The object of this advice article is not only to give the diabetic mountaineer general guidance but also to inform his or her medical team of practical aspects of care that may not be standard for nonmountaineers. The guidelines are produced in seven sections. The first is an introduction to the guidelines, and the second is an introduction to this medical problem and is designed to be read and understood by diabetic patients and their companions. The third section is for use in an emergency in mountains. The fourth is for rock, ice, and competition climbers operating in a less remote environment. These initial sections are deliberately written in simple language. The fifth and sixth sections are written for clinicians and those with skills to read more technical information, and the seventh looks at modern technology and its pros and cons in diabetes management in a remote area. Sections One and Two could be laminated and carried when in the mountains, giving practical advice.

Understanding the drivers of fisheries bycatch is essential for limiting its impacts on vulnerable species. Here we present a model to estimate the relative magnitude of sea turtle bycatch in major coastal fisheries across the southeastern US based on spatiotemporal variation in fishing effort and the simulated distributions of juvenile Kemp's ridley ( Lepidochelys kempii ) and green ( Chelonia mydas ) sea turtles recruiting from oceanic to nearshore habitats. Over the period modeled (1996-2017), bycatch in recreational fisheries was estimated to be greater than the sum of bycatch that occurred in commercial fisheries that have historically been considered high risks to turtles (e.g., those using trawls, gillnets, and bottom longlines). Prioritizing engagement with recreational anglers to reduce bycatch could be especially beneficial to sea turtle populations. Applying lessons learned from efforts to protect turtles in commercial fisheries may help meet the challenges that arise from the large, diffuse recreational fishing sector., Competing Interests: We declare we have no competing interests., (© 2023 The Author(s).)

HIV pre-exposure prophylaxis (PrEP) effectively reduces new HIV diagnoses. High rates of incident bacterial sexually transmitted infections (STIs) have been observed in patients eligible for and adherent to PrEP. Observational studies generally report low long-term retention in PrEP care. Limited data exist on the rates of bacterial STI diagnosis upon re-engagement with PrEP services. We conducted a retrospective chart review within the HIV prevention program of an urban academic medical center in New York City. Eligible patients started PrEP from 2015 to 2019, then resumed PrEP services after a gap in care of at least 180 days. Demographic, clinical, and laboratory data were used to characterize the patient population and rates of bacterial STI diagnosis at re-engagement. In total, 286 patients were identified, with 316 qualifying re-engagement visits. Twenty-nine percent of patients had continued PrEP during the care gap, and 30% reported discontinuing medication due to a perceived change in risk. A new STI was diagnosed at 19% of re-engagement visits. There was no statistically significant difference in rates of new STI between individuals returning on or off PrEP, nor between those with perceived lower risk and those without. Individuals who fall out of PrEP services and subsequently re-engage remain at high risk of bacterial STI during the gap in care, regardless of whether PrEP medication is continued or the patient perceives themselves to be at lower HIV acquisition risk. Providers should strongly encourage patients discontinuing PrEP to remain engaged in sexual health services. Alternatives to clinic-based PrEP care must still include regular bacterial STI screening.

Purpose: The prospective Neoadjuvant Breast Registry Symphony Trial compared the 80-gene molecular subtyping signature with clinical assessment by immunohistochemistry and/or fluorescence in situ hybridization in predicting pathologic complete response (pCR) and 5-year outcomes in patients with early-stage breast cancer., Methods: Standard-of-care neoadjuvant chemotherapy combined with trastuzumab or trastuzumab plus pertuzumab was given to patients with human epidermal growth factor receptor 2 (HER2)-positive tumors (n = 295). pCR was the primary end point, with secondary end points of distant metastasis-free survival and overall survival at 5 years., Results: Among clinically defined HER2-positive (cHER2) tumors, the 80-gene assay identified 29.5% (87 of 295) as Luminal-Type (cHER2/gLuminal), 14.9% (44 of 295) as Basal-Type (cHER2/gBasal), and 55.6% (164 of 295) as HER2-Type (cHER2/genomically classified as HER2 [gHER2]). Patients with cHER2/gHER2 tumors had a higher pCR rate (61.6%) compared with non-gHER2 tumors (26.7%; P < .001). Dual targeting for cHER2/gHER2 tumors yielded a higher pCR rate (75%) compared with those treated with single HER2-targeted therapy (54%; P = .006). For cHER2/gBasal tumors, the 42.9% pCR rate observed with dual targeting was not different from that with trastuzumab alone (46.4%; P = .830). Among those with cHER2/gBasal tumors, 5-year distant metastasis-free survival (68.6%; 95% CI, 49.1 to 81.9) was significantly worse than in patients with cHER2/gLuminal tumors (88.9%; 95% CI, 78.0 to 94.6) and cHER2/gHER2 tumors (87.4%; 95% CI, 80.2 to 92.2; P = .010), with similar corresponding overall survival differences., Conclusion: The 80-gene assay identified meaningful genomic diversity in patients with cHER2 disease. Patients with cHER2/gHER2 tumors, who benefitted most from dual HER2-targeted therapy, accounted for approximately half of the cHER2 cohort. Genomically Luminal tumors had low pCR rates but good 5-year outcomes. cHER2/gBasal tumors derived no benefit from dual therapy and had significantly worse 5-year prognosis; these patients merit special consideration in future trials., Competing Interests: Pat W. WhitworthEmployment: Integra LifeSciences (I)Leadership: Integra LifeSciences (I)Stock and Other Ownership Interests: Targeted Medical Education Inc, Integra LifeSciences (I)Honoraria: Puma BiotechnologyConsulting or Advisory Role: ImpediMed, Prelude Therapeutics, Becton DickinsonResearch Funding: Prelude Therapeutics, Agendia, MedneonTravel, Accommodations, Expenses: Targeted Medical Education Inc Peter D. BeitschEmployment: InvitaeLeadership: Targeted Medical Education IncStock and Other Ownership Interests: Targeted Medical Education Inc, InvitaeResearch Funding: InvitaeExpert Testimony: Dune Medical Devices, ImpediMedUncompensated Relationships: Medneon Paul D. RichardsStock and Other Ownership Interests: NanoViricidesResearch Funding: Carrick Therapeutics (Inst) James V. PellicaneStock and Other Ownership Interests: PreludeDxHonoraria: Agendia, PreludeDxSpeakers' Bureau: Agendia, PreludeDx Beth B. DupreeLeadership: Caliber MedicalStock and Other Ownership Interests: Videra SurgicalHonoraria: Medtronic, Perimeter Medical William DooleyLeadership: Shaga Medical LLCStock and Other Ownership Interests: Shaga MedicalResearch Funding: Agendia, XoftPatents, Royalties, Other Intellectual Property: patent pending—microendoscopy system Shiyu WangEmployment: Agendia Patricia DauerEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Andrea R. MenicucciEmployment: Agendia Erin B. YoderEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Lisa E. BlumencranzEmployment: Agendia William AudehEmployment: AgendiaLeadership: AgendiaStock and Other Ownership Interests: AgendiaConsulting or Advisory Role: Celanese, Private HealthResearch Funding: AgendiaTravel, Accommodations, Expenses: AgendiaNo other potential conflicts of interest were reported.

Despite an expanding literature on Ebola-response, few studies detail or reflect on the responses of diverse systems of care. Little is known about how, why or in what ways, strategies of ill-health management were enacted locally, how health-systems power, authority and hierarchy were perceived and contested, or how other social systems, institutions and relationships shaped the response. This paper presents an interdisciplinary analysis of local responses in two early affected districts in Sierra Leone. Drawing on anthropological theories of social ordering and assemblage, we present an analysis of contrasting infection chains in three extended case studies from Bo and Moyamba districts. In contrast to previous scholarship which has understood local actions as being reactive (supporting or obstructing) to a national Ebola response, we show that local arrangements lead and shape responses. Our cases show how multiple, entangled, dynamic and co-existing systems of care influence these responses. Some individuals and communities collaborated with health authorities on measures like reporting and quarantine, others actively opposed them, or played an intermediary role. Collectively, formal health systems actors, local authorities and ordinary citizens negotiated and enacted new arrangements. These arrangements involved compromise and sometimes power was reconfigured. They were also shaped by wider political and historical contexts and by availability or absence of formal healthcare resources. Our research shows the critical importance of understanding how institutions and people involved in healthcare enact diverse "systems of care" and thereby shape Ebola response. Most importantly, our work underlines the need for alignment between formal health-systems and wider social, cultural, political and economic forms of organisation at family and community levels to improve crisis-response and promote sustainable care. In particular, health systems responders need to identify and engage with key brokers - or arrangers - in frontline care systems, with whom mutually acceptable, and effective, reconfigurations of care can be achieved., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status., Methods: The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18-90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors., Results: MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype., Conclusion: Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer., (© 2022. The Author(s).)

Global debates about vaccines as a key element of pandemic response and future preparedness in the era of Covid-19 currently focus on questions of supply, with attention to global injustice in vaccine distribution and African countries as rightful beneficiaries of international de-regulation and financing initiatives such as COVAX. At the same time, vaccine demand and uptake are seen to be threatened by hesitancy, often attributed to an increasingly globalised anti-vaxx movement and its propagation of misinformation and conspiracy, now reaching African populations through a social media 'infodemic'. Underplayed in these debates are the socio-political contexts through which vaccine technologies enter and are interpreted within African settings, and the crucial intersections between supply and demand. We explore these through a 'vaccine anxieties' framework attending to both desires for and worries about vaccines, as shaped by bodily, societal and wider political understandings and experiences. This provides an analytical lens to organise and interpret ethnographic and narrative accounts in local and national settings in Uganda and Sierra Leone, and their (dis)connections with global debates and geopolitics. In considering the socially-embedded reasons why people want or do not want Covid-19 vaccines, and how this intersects with the dynamics of vaccine supply, access and distribution in rapidly-unfolding epidemic situations, we bring new, expanded insights into debates about vaccine confidence and vaccine preparedness., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This article shares findings on COVID-19 in Africa across 2020 to examine concepts and practices of epidemic preparedness and response. Amidst uncertainties about the trajectory of COVID-19, the stages of emergency response emerge in practice as interconnected. We illustrate how complex dynamics manifest as diverse actors interpret and modify approaches according to contexts and experiences. We suggest that the concept of "intersecting precarities" best captures the temporalities at stake; that these precarities include the effects of epidemic control measures; and that people do not just accept but actively negotiate these intersections as they seek to sustain their lives and livelihoods.

Multiplex polymerase chain reaction testing for gastrointestinal pathogens was performed on a longitudinal cohort of 110 men who have sex with men taking human immunodeficiency virus preexposure prophylaxis. At least 1 pathogen was detected among 50 (45%) participants, with some participants testing positive for the same pathogen on multiple consecutive visits over a period of months., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Approximately 20% of UK women aged 70+ with early breast cancer receive primary endocrine therapy (PET) instead of surgery. PET reduces surgical morbidity but with some survival decrement. To complement and utilize a treatment dependent prognostic model, we investigated the cost-effectiveness of surgery plus adjuvant therapies versus PET for women with varying health and fitness, identifying subgroups for which each treatment is cost-effective., Methods: Survival outcomes from a statistical model, and published data on recurrence, were combined with data from a large, multicenter, prospective cohort study of over 3400 UK women aged 70+ with early breast cancer and median 52-month follow-up, to populate a probabilistic economic model. This model evaluated the cost-effectiveness of surgery plus adjuvant therapies relative to PET for 24 illustrative subgroups: Age {70, 80, 90} × Nodal status {FALSE (F), TRUE (T)} × Comorbidity score {0, 1, 2, 3+}., Results: For a 70-year-old with no lymph node involvement and no comorbidities (70, F, 0), surgery plus adjuvant therapies was cheaper and more effective than PET. For other subgroups, surgery plus adjuvant therapies was more effective but more expensive. Surgery plus adjuvant therapies was not cost-effective for 4 of the 24 subgroups: (90, F, 2), (90, F, 3), (90, T, 2), (90, T, 3)., Conclusion: From a UK perspective, surgery plus adjuvant therapies is clinically effective and cost-effective for most women aged 70+ with early breast cancer. Cost-effectiveness reduces with age and comorbidities, and for women over 90 with multiple comorbidities, there is little cost benefit and a negative impact on quality of life., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The Democratic Republic of Congo (DRC) presents a challenging context in which to respond to public health crises. Its 2018-2020 Ebola outbreak was the second largest in history. Lessons were known from the previous West African outbreak. Chief among these was the recognition that local action and involvement are key to establishing effective epidemic-response. It remains unclear whether and how this was achieved in DRC's Ebola response. Additionally, there is a lack of scholarship on how to build resilience (the ability to adapt or transform under pressure) in crisis-response. In this article, we critically review literature to examine evidence on whether and how communities were involved, trust built, and resilience strengthened through adaptation or transformation of DRC's 2018-2020 Ebola response measures. Overall, we found limited evidence that the response adapted to engage and involve local actors and institutions or respond to locally expressed concerns. When adaptations occurred, they were shaped by national and international actors rather than enabling local actors to develop locally trusted initiatives. Communities were "engaged" to understand their perceptions but were not involved in decision-making or shaping responses. Few studies documented how trust was built or analyzed power dynamics between different groups in DRC. Yet, both these elements appear to be critical in building effective, resilient responses. These failures occurred because there was no willingness by the national government or international agencies to concede decision-making power to local people. Emergency humanitarian response is entrenched in highly medicalized, military style command and control approaches which have no space for decentralizing decision-making to "non-experts". To transform humanitarian responses, international responders can no longer be regarded as "experts" who own the knowledge and control the response. To successfully tackle future humanitarian crises requires a transformation of international humanitarian and emergency response systems such that they are led, or shaped, through inclusive, equitable collaboration with local actors., Competing Interests: The authors report no conflicts of interest for this work., (© 2021 Mayhew et al.)

Background: The gut-brain axis, which mediates bidirectional communication between the gastrointestinal system and central nervous system (CNS), plays a fundamental role in multiple areas of physiology including regulating appetite, metabolism, and gastrointestinal function. The biology of the gut-brain axis is central to the efficacy of glucagon-like peptide-1 (GLP-1)-based therapies, which are now leading treatments for type 2 diabetes (T2DM) and obesity. This success and research to suggest a much broader role of gut-brain circuits in physiology and disease has led to increasing interest in targeting such circuits to discover new therapeutics. However, our current knowledge of this biology is limited, largely because the scientific tools have not been available to enable a detailed mechanistic understanding of gut-brain communication., Scope of Review: In this review, we provide an overview of the current understanding of how sensory information from the gastrointestinal system is communicated to the central nervous system, with an emphasis on circuits involved in regulating feeding and metabolism. We then describe how recent technologies are enabling a better understanding of this system at a molecular level and how this information is leading to novel insights into gut-brain communication. We also discuss current therapeutic approaches that leverage the gut-brain axis to treat diabetes, obesity, and related disorders and describe potential novel approaches that have been enabled by recent advances in the field., Major Conclusions: The gut-brain axis is intimately involved in regulating glucose homeostasis and appetite, and this system plays a key role in mediating the efficacy of therapeutics that have had a major impact on treating T2DM and obesity. Research into the gut-brain axis has historically largely focused on studying individual components in this system, but new technologies are now enabling a better understanding of how signals from these components are orchestrated to regulate metabolism. While this work reveals a complexity of signaling even greater than previously appreciated, new insights are already being leveraged to explore fundamentally new approaches to treating metabolic diseases., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

During the COVID-19 pandemic in New York City, NewYork-Presbyterian Hospital provided HIV prevention patients with gonorrhea/chlamydia testing kits at home. This report describes the program implementation to provide other sexual health clinics with a roadmap in adapting to a "new normal" in providing comprehensive sexual health care virtually to patients.

Background: The 2013-15 Ebola epidemic in West Africa was the largest so far recorded, and mainly affected three adjacent countries, Guinea, Liberia and Sierra Leone. The worst affected country (in terms of confirmed cases) was Sierra Leone. The present paper looks at the epidemic in Sierra Leone. The epidemic in this country was a concatenation of local outbreaks. These local outbreaks are not well characterized through analysis using standard numerical techniques. In part, this reflects difficulties in record collection at the height of the epidemic. This paper offers a different approach, based on application of field-based techniques of social investigation that provide a richer understanding of the epidemic., Methods: In a post-epidemic study (2016-18) of two districts (Bo and Moyamba) we use ethnographic data to reconstruct local infection pathways from evidence provided by affected communities, cross-referenced to records of the epidemic retained by the National Ebola Response Commission, now lodged in the Ebola Museum and Archive at Njala University. Our study documents and discusses local social and contextual factors largely missing from previously published studies., Results: Our major finding is that the epidemic in Sierra Leone was a series of local outbreaks, some of which were better contained than others. In those that were not well contained, a number of contingent factors helps explain loss of control. Several numerical studies have drawn attention to the importance of local heterogeneities in the Sierra Leone Ebola epidemic. Our qualitative study throws specific light on a number of elements that explain these heterogeneities: the role of externalities, health system deficiencies, cultural considerations and local coping capacities., Conclusions: Social issues and local contingencies explain the spread of Ebola in Sierra Leone and are key to understanding heterogeneities in epidemiological data. Integrating ethnographic research into epidemic-response is critical to properly understand the patterns of spread and the opportunities to intervene. This conclusion has significant implications for future interdisciplinary research and interpretation of standard numerical data, and consequently for control of epidemic outbreaks., Competing Interests: The authors have declared that no competing interests exist.

Background: Concern has been expressed over how well Africa is prepared to cope with the pandemic of Covid-19. Will rural populations with low levels of education know how to apply community-based infection control? We undertook fieldwork in two villages in central Sierra Leone to gain insight into how rural people faced with Covid-19 assess epidemic infection risks., Methods: Two communities were selected based on prior contrasted exposure to Ebola Virus Disease-one with substantial number of cases and the other having resisted infection through strong community sequestration measures. We assessed understanding of infection risks via an experimental game. This asked players to express a preference for one of two diseases, one resembling Ebola with lower risk of infection and the other resembling Covid-19 with lower risk of death. Players were not told the identity of the diseases., Results: In total 107 adult villagers played the game (58% women). Half (52%) preferred the disease model with lower risk of infection, 29% preferred the model with lower risk of death, while 21% saw the combined risk of infection and death as being equivalent. Differences in reactions between the two locations were small despite different experiences of Ebola. Asked to explain their choices 48% of players cited information on infection risks modelled by the game and 31% stated that their choices reflected awareness of the need for personal action and respect for local regulations. We concluded that villagers thoughtfully assess disease risks and that some are good intuitive statisticians., Conclusions: Results suggest rural people in Sierra Leone retain the lessons of experience from the Ebola outbreak of 2014-15 and will be able to apply these lessons to a new infectious disease for which have no prior practical experience. Our expectation is that rural populations will understand Covid-19 control measures, thus reducing need for draconian enforcement., Competing Interests: The authors have declared that no competing interests exist.

During the 2014-2015 Ebola epidemic in Sierra Leone, people were required by law to call a trained "safe burial" team to dispose of the body of a person who had died from Ebola. It took days for a team to arrive, however, due to limited resources and rural travel obstacles, so some villagers felt obliged to bury their loved ones themselves. Even with timely arrival of a team, there can be cultural priorities that deserve attention. One man's case discussed in this article suggests the need for Ebola responders to consider villagers' perspectives and possibilities for compromise., (© 2020 American Medical Association. All Rights Reserved.)

The paper considers local responses to the introduction of an Ebola Treatment Centre in eastern Sierra Leone during the West African epidemic of 2014-15. Our study used qualitative methods consisting of focus groups and interviews, to gather responses from patients, members of the families of survivors and deceased victims of the disease, social liaison workers from the centre, and members of the general public. The data indicate that scepticism and resistance were widespread at the outset, but that misconceptions were replaced, in the minds of those directly affected by the disease, by more positive later assessments. Social workers, and social contacts of families with workers in the centre, helped reshape these perceptions, but a major factor was direct experience of the disease. This is apparent in the positive endorsements by survivors and families who had members taken to the facility. Even relatives of deceased victims agreed that the case-handling centre was valuable. However, we also present evidence of continuing scepticism in the minds of members of the general public, who continue to suspect that Ebola was a crisis manufactured for external benefit. Our conclusions stress the importance of better connectivity between communities and Ebola facilities to facilitate experiential learning. There is also a need to address the wider cognitive shock caused by a well-funded Ebola health initiative arriving in communities with a long history of inadequate health care. Restoring trust in medicine requires Ebola Virus Disease to be re-contextualized within a broader framework of concern for the health of all citizens., Competing Interests: The authors have declared that no competing interests exist.

Population monitoring must be accurate and reliable to correctly classify population status. For sea turtles, nesting beach surveys are often the only population-level surveys that are accessible. However, process and observation errors, compounded by delayed maturity, obscure the relationship between trends on the nesting beach and the population. We present a simulation-based tool, monitoring strategy evaluation (MoSE), to test the relationships between monitoring data and assessment accuracy, using green sea turtles, Chelonia mydas, as a case study. To explore this first application of MoSE, we apply different treatments of population impacts to virtual true populations, and sample the nests or nesters, with observation error, to test if the observation data can be used to diagnose population status accurately. Based on the observed data, we examine population trend and compare it to the known values from the operating model. We ran a series of scenarios including harvest impacts, cyclical breeding probability, and sampling biases, to see how these factors impact accuracy in estimating population trend. We explored the necessary duration of monitoring for accurate trend estimation and the probability of a false trend diagnosis. Our results suggest that disturbance type and severity can have important and persistent effects on the accuracy of population assessments drawn from monitoring nesting beaches. The underlying population phase, age classes disturbed, and impact severity influenced the accuracy of estimating population trend. At least 10 yr of monitoring data is necessary to estimate population trend accurately, and >20 yr if juvenile age classes were disturbed and the population is recovering. In general, there is a greater probability of making a false positive trend diagnosis than a false negative, but this depends on impact type and severity, population phase, and sampling duration. Improving detection rates to 90% does little to lower probability of a false trend diagnosis with shorter monitoring spans. Altogether, monitoring strategies for specific populations may be tailored based on the impact history, population phase, and environmental drivers. The MoSE is an important framework for analysis through simulation that can comprehensively test population assessments for accuracy and inform policy recommendations regarding the best monitoring strategies., (Published 2019. This article has been contributed by U.S. Government employees and their work is in the public domain in the USA.)

Conservation planning for protected species often relies on estimates of life-history parameters. A commonly used parameter is the instantaneous maximum population growth rate ( r max ) that can be used to limit removals and design recovery targets. Estimation of r max can be challenging because of limited availability of species- and population-specific data and life-history information. We applied a method proposed by Neil and Lebreton, originally developed for birds, to loggerhead turtles. The method uses age-at-first-reproduction and adult survival to estimate r max . We used a variety of datasets and matrix population models to confirm an allometric assumption required by the method, and to generate estimates of age-at-first-reproduction and adult survival. A meta-analysis was applied to parameters from reported growth curves, which were then combined with the size distribution of neophyte nesters to derive estimates of age-at-first-reproduction. Adult survival rates were obtained from an existing matrix population model. Monte Carlo simulation was then used to combine the estimates of the allometric coefficients, age-at-first-reproduction, and adult survival to obtain a probability distribution of approximate r max values. Estimated annual maximum population growth rates averaged 0.024, with a mode of 0.017 and a 95% highest density interval of 0.006-0.047. These estimates were similar to values reported by others using different methods and captured the variability in positive, annual change estimates across nesting beach sites for the northwest Atlantic loggerhead population. The use of life-history parameters has a long history in wildlife and fisheries management and conservation planning. Our estimates of r max , while having some biases and uncertainty, encompassed values presently used in recovery planning for loggerhead turtles and offer additional information for the management of endangered and threatened species., Competing Interests: None declared.

Background: In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR + /HER2 - advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2., Patients and Methods: Postmenopausal women with HR + /HER2 - ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS., Results: Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia., Conclusion: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR + /HER2 - ABC., (Copyright © 2019. Published by Elsevier Inc.)

Background: HIV pre-exposure prophylaxis (PrEP) reduces incident HIV infections, but efficacy depends on adherence and retention, among other factors. Substance use disorders, unmet mental health needs, and demographic factors are associated with nonadherence in HIV-infected patients; we studied whether these affect PrEP retention in care., Methods: To investigate potential risk factors disengagement in a comprehensive HIV prevention program, we conducted a retrospective cohort analysis of individuals starting tenofovir-emtricitabine between January 1, 2015, and November 30, 2017. The primary outcome was adherence to the initial 3-visit schedule after PrEP initiation., Results: The cohort was predominantly African American (23%) and Hispanic (46%). Race, ethnicity, substance use, patient health questionnaire 9 score, insurance, and housing status were not associated with retention at the third follow-up visit. Age <30, PrEP initiation in 2017, PrEP initiation in the sexual health clinic, and PrEP same-day start were associated with lower retention; male gender at birth, transition from post-exposure prophylaxis (PEP) to PrEP, feeling that they could benefit from, or participating in mental health services were associated with increased retention. Overall, retention in HIV preventative care at the first follow-up visit (68%) and third follow-up visit (35%) after PrEP initiation was low., Conclusion: Clinic services and ancillary services (such as mental health) may facilitate retention in care. In this study, select social and behavioral determinants of health were not found to be linked to retention. Focused investigation of reasons for dropout may elucidate the challenges to maintaining individuals in PrEP care and direct resource allocation to those in greatest need.

Enteroendocrine cells (EECs) produce hormones such as glucagon-like peptide 1 and peptide YY that regulate food absorption, insulin secretion, and appetite. Based on the success of glucagon-like peptide 1-based therapies for type 2 diabetes and obesity, EECs are themselves the focus of drug discovery programs to enhance gut hormone secretion. The aim of this study was to identify the transcriptome and peptidome of human EECs and to provide a cross-species comparison between humans and mice. By RNA sequencing of human EECs purified by flow cytometry after cell fixation and staining, we present a first transcriptomic analysis of human EEC populations and demonstrate a strong correlation with murine counterparts. RNA sequencing was deep enough to enable identification of low-abundance transcripts such as G-protein-coupled receptors and ion channels, revealing expression in human EECs of G-protein-coupled receptors previously found to play roles in postprandial nutrient detection. With liquid chromatography-tandem mass spectrometry, we profiled the gradients of peptide hormones along the human and mouse gut, including their sequences and posttranslational modifications. The transcriptomic and peptidomic profiles of human and mouse EECs and cross-species comparison will be valuable tools for drug discovery programs and for understanding human metabolism and the endocrine impacts of bariatric surgery., (© 2019 by the American Diabetes Association.)

Purpose: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1)., Methods: Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS)., Results: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine., Conclusions: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.

Purpose: The phase 3 MONALEESA-2 study demonstrated that addition of ribociclib (RIB) to letrozole (LET) significantly improved progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Here, we evaluated duration of response (DoR), tumor shrinkage, PFS by treatment-free interval (TFI), and health-related quality of life (HRQoL)., Methods: Postmenopausal women (N = 668) with HR+ , HER2- ABC and no prior systemic therapy for ABC were randomized to RIB (600 mg/day; 3 weeks on/1 week off) plus LET (2.5 mg/day; continuous) or placebo (PBO) plus LET. Primary end point was PFS; HRQoL was the secondary end point; DoR was exploratory end point and PFS by TFI was post hoc analysis., Results: Of 501 pts with measurable disease and confirmed complete or partial response, median DoR was 26.7 months (95% CI, 24.0-NR) in the RIB arm versus 18.6 months (95% CI, 14.8-23.1) in the PBO arm. At 8 weeks, more pts in the RIB arm (32%) versus the PBO arm (17%) experienced best percentage change ≥ 60%. The average pain reduction was greater in the RIB arm (26%) versus the PBO arm (15%). PFS benefit was seen with RIB vs PBO, irrespective of TFI., Conclusion: RIB plus LET versus PBO plus LET is associated with earlier and more durable tumor response, greater degree of tumor shrinkage and pain reduction, and PFS benefit irrespective of TFI. These data further support RIB plus LET as a first-line treatment option for postmenopausal women with HR+ , HER2- ABC.

Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels., (© 2017 by the American Diabetes Association.)

Variation in the shell coiling, or chirality, of land snails provides an opportunity to investigate the potential for "single-gene" speciation, because mating between individuals of opposite chirality is believed not possible if the snails mate in a face-to-face position. However, the evidence in support of single-gene speciation is sparse, mostly based upon single-gene mitochondrial studies and patterns of chiral variation between species. Previously, we used a theoretical model to show that as the chiral phenotype of offspring is determined by the maternal genotype, occasional chiral reversals may take place and enable gene flow between mirror image morphs, preventing speciation. Here, we show empirically that there is recent or ongoing gene flow between the different chiral types of Japanese Euhadra species. We also report evidence of mating between mirror-image morphs, directly showing the potential for gene flow. Thus, theoretical models are suggestive of gene flow between oppositely coiled snails, and our empirical study shows that they can mate and that there is gene flow in Euhadra . More than a single gene is required before chiral variation in shell coiling can be considered to have created a new species.

Background: Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping., Methods: Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment., Results: In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%)., Conclusions: The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

Introduction: While breast cancer outcomes are improving steadily in younger women due to advances in screening and improved therapies, there has been little change in outcomes among the older age group. It is inevitable that comorbidities/frailty rates are higher, which may increase the risks of some breast cancer treatments such as surgery and chemotherapy, many older women are healthy and may benefit from their use. Adjusting treatment regimens appropriately for age/comorbidity/frailty is variable and largely non-evidence based, specifically with regard to rates of surgery for operable oestrogen receptor-positive disease and rates of chemotherapy for high-risk disease., Methods and Analysis: This multicentre, parallel group, pragmatic cluster randomised controlled trial (RCT) (2015-18) reported here is nested within a larger ongoing 'Age Gap Cohort Study' (2012-18RP-PG-1209-10071), aims to evaluate the effectiveness of a complex intervention of decision support interventions to assist in the treatment decision making for early breast cancer in older women. The interventions include two patient decision aids (primary endocrine therapy vs surgery/antioestrogen therapy and chemotherapy vs no chemotherapy) and a clinical treatment outcomes algorithm for clinicians., Ethics and Dissemination: National and local ethics committee approval was obtained for all UK participating sites. Results from the trial will be submitted for publication in international peer-reviewed scientific journals., Iras Reference: 115550., Trial Registration Number: European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2015-004220-61;Pre-results. Sponsor's Protocol Code Number Sheffield Teaching Hospitals STH17086. ISRCTN 32447*., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Identification of the Mondo glucose-responsive transcription factors family, including the MondoA and MondoB/ChREBP paralogs, has shed light on the mechanism whereby glucose affects gene transcription. They have clearly emerged, in recent years, as key mediators of glucose sensing by multiple cell types. MondoA and ChREBP have overlapping yet distinct expression profiles, which underlie their downstream targets and separate roles in regulating genes involved in glucose metabolism. MondoA can restrict glucose uptake and influences energy utilization in skeletal muscle, while ChREBP signals energy storage through de novo lipogenesis in liver and white adipose tissue. Because Mondo proteins mediate metabolic adaptations to changing glucose levels, a better understanding of cellular glucose sensing through Mondo proteins will likely uncover new therapeutic opportunities in the context of the imbalanced glucose homeostasis that accompanies metabolic diseases such as type 2 diabetes and cancer. Here, we provide an overview of structural homologies, transcriptional partners as well as the nutrient and hormonal mechanisms underlying Mondo proteins regulation. We next summarize their relative contribution to energy metabolism changes in physiological states and the evolutionary conservation of these pathways. Finally, we discuss their possible targeting in human pathologies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes. The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload. In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events. In the present report, we detail findings from the final analysis at 5 years. We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not. Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease. Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy. Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Use of antiangiogenic agents in treatment of metastatic breast cancer (MBC) remains controversial. We evaluated the efficacy and safety of ramucirumab and eribulin versus eribulin alone as third- to fifth-line therapy in women with advanced breast cancer., Patients and Methods: In this randomized (1:1), open-label, phase II study, US women aged 18 years or older with 2 to 4 previous chemotherapy regimens for locally recurrent or MBC, previous anthracycline and taxane treatment, and Eastern Cooperative Oncology Group performance status of 0 or 1 received ramucirumab with eribulin or eribulin alone in 21-day cycles (eribulin 1.4 mg/m 2 intravenously on days 1 and 8; ramucirumab 10 mg/kg intravenously on day 1). Randomization was stratified according to previous antiangiogenic therapy and triple-negative status. The primary end point was progression-free survival (PFS) in the intention to treat population., Results: One hundred forty-one women were randomized to ramucirumab with eribulin (n = 71) or eribulin alone (n = 70). Median PFS for ramucirumab with eribulin was 4.4 months (95% confidence interval [CI], 3.1-6.7) compared with 4.1 months (95% CI, 3.2-5.6) for eribulin (hazard ratio [HR], 0.83; 95% CI, 0.56-1.23; P = .35). Median overall survival in patients who received ramucirumab with eribulin was 13.5 months (95% CI, 10.4-17.9) compared with 11.5 months (95% CI, 9.0-17.3) in patients who received eribulin alone (HR, 0.91; 95% CI, 0.59-1.41; P = .68); objective response rate was 21% (13 of 62 patients) for the combination and 28% (17 of 60 patients) for eribulin alone. No unexpected toxicity was identified for the combination., Conclusion: Ramucirumab combined with eribulin did not significantly improve PFS in advanced MBC., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hillebrandt, David, Paul Richards, Andy Clark, and Dominique Jean. Zika virus advice for mountaineers: A UIAA Medcom consensus advice sheet. High Alt Med Biol. 17:70-71, 2016.-With the current media coverage of the spread of Zika virus from Africa and Asia to Central and South America and its possible relationship with fetal abnormalities, UIAA Medcom has produced an advice sheet for mountaineers visiting risk areas.

Acute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic β-cell dysfunction. However, the mechanisms by which human β-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human β-cell line EndoC-βH2, we demonstrate that β-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human β-cells. Using gain- and loss-of-function studies, we provide evidence that the β-cell enriched transcription factor RFX6 is a major regulator of GPR68. Further, we show that acidic pH stimulates the production and secretion of the chemokine IL-8 by β-cells through NF-кB activation. Blocking of GPR68 or NF-кB activity severely attenuated acidification induced IL-8 production. Thus, we provide mechanistic insights into GPR68 mediated β-cell response to acidic microenvironment, which could be a new target to protect β-cell against acidosis induced inflammation.

Background: The prospective Neoadjuvant Breast Symphony Trial (NBRST) study found that MammaPrint/BluePrint functional molecular subtype is superior to conventional immunohistochemistry/fluorescence in situ hybridization subtyping for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. The purpose of this substudy was to determine if the rate of pCR is affected by tumor size., Methods: The NBRST study includes breast cancer patients who received neoadjuvant chemotherapy. MammaPrint/BluePrint subtyping classified patients into four molecular subgroups: Luminal A, Luminal B, HER2 (human epidermal growth factor receptor 2), and Basal type. Probability of pCR (ypT0/isN0) as a function of tumor size and molecular subgroup was evaluated., Results: A total of 608 patients were evaluable with overall pCR rates of 28.5 %. Luminal A and B patients had significantly lower rates of pCR (6.1 and 8.7 %, respectively) than either basal (37.1 %) or HER2 (55.0 %) patients (p < 0.001). The probability of pCR significantly decreased with tumor size >5 cm [p = 0.022, odds ratio (OR) 0.58, 95 % confidence interval (CI) 0.36, 0.93]. This relationship was statistically significant in the Basal (p = 0.026, OR 0.46, 95 % CI 0.23, 0.91) and HER2 (p = 0.039, OR 0.36, 95 % CI 0.14, 0.95) subgroups. In multivariate logistic regression analyses, the dichotomized tumor size variable was not significant in any of the molecular subgroups., Discussion: Even though tumor size would intuitively be a clinical determinant of pCR, the current analysis showed that the adjusted OR for tumor size was not statistically significant in any of the molecular subgroups. Factors significantly associated with pCR were PR status, grade, lymph node status, and BluePrint molecular subtyping, which had the strongest correlation.

Unlabelled: Glucagon-like peptide-1 (GLP-1) acts as a satiety signal and enhances insulin release. This study examined how GLP-1 production from intestinal L-cells is modified by dietary changes., Methods: Transgenic mouse models were utilized in which L-cells could be purified by cell specific expression of a yellow fluorescent protein, Venus. Mice were fed on chow or 60% high fat diet (HFD) for 2 or 16 weeks. L-cells were purified by flow cytometry and analysed by microarray and quantitative RT-PCR. Enteroendocrine cell populations were examined by FACS analysis, and GLP-1 secretion was assessed in primary intestinal cultures., Results: Two weeks HFD reduced the numbers of GLP-1 positive cells in the colon, and of GIP positive cells in the small intestine. Purified small intestinal L-cells showed major shifts in their gene expression profiles. In mice on HFD for 16 weeks, significant reductions were observed in the expression of L-cell specific genes, including those encoding gut hormones (Gip, Cck, Sct, Nts), prohormone processing enzymes (Pcsk1, Cpe), granins (Chgb, Scg2), nutrient sensing machinery (Slc5a1, Slc15a1, Abcc8, Gpr120) and enteroendocrine-specific transcription factors (Etv1, Isl1, Mlxipl, Nkx2.2 and Rfx6). A corresponding reduction in the GLP-1 secretory responsiveness to nutrient stimuli was observed in primary small intestinal cultures., Conclusion: Mice fed on HFD exhibited reduced expression in L-cells of many L-cell specific genes, suggesting an impairment of enteroendocrine cell function. Our results suggest that a western style diet may detrimentally affect the secretion of gut hormones and normal post-prandial signaling, which could impact on insulin secretion and satiety., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing 'L-cell' and the GIP-producing 'K-cell'., (© 2016 Society for Endocrinology.)

Objective: Up to 40% of women over 70 years with primary operable breast cancer in the UK are treated with primary endocrine therapy (PET) as an alternative to surgery. A variety of factors are important in determining treatment for older breast cancer patients. This study aimed to identify the patient and tumor factors associated with treatment allocation in this population., Methods: Prospectively collected data on treatment received (surgery vs. PET) were analysed with multivariable logistic regression using the variables age, modified Charlson Comorbidity Index (CCI), activities of daily living (ADL) score, Mini-Mental State Examination (MMSE) score, HER2 status, tumour size, grade and nodal status., Results: Data were available for 1,122 cancers in 1,098 patients recruited between February 2013 and June 2015 from 51 UK hospitals. About 78% of the population were treated surgically, with the remainder being treated with PET. Increasing patient age at diagnosis, increasing CCI score, large tumor size (5 cm or more) and dependence in one or more ADL categories were all strongly associated with non-surgical treatment (P<0.05)., Conclusion: Increasing comorbidity, large tumor size and reduced functional ability are associated with reduced likelihood of surgical treatment of breast cancer in older patients. However, age itself remains a significant factor for non-surgical treatment; reinforcing the need for evidence-based guidelines.

We investigated the extent that the 2010 Deepwater Horizon oil spill potentially affected oceanic-stage sea turtles from populations across the Atlantic. Within an ocean-circulation model, particles were backtracked from the Gulf of Mexico spill site to determine the probability of young turtles arriving in this area from major nesting beaches. The abundance of turtles in the vicinity of the oil spill was derived by forward-tracking particles from focal beaches and integrating population size, oceanic-stage duration and stage-specific survival rates. Simulations indicated that 321 401 (66 199-397 864) green (Chelonia mydas), loggerhead (Caretta caretta) and Kemp's ridley (Lepidochelys kempii) turtles were likely within the spill site. These predictions compared favourably with estimates from in-water observations recently made available to the public (though our initial predictions for Kemp's ridley were substantially lower than in-water estimates, better agreement was obtained with modifications to mimic behaviour of young Kemp's ridley turtles in the northern Gulf). Simulations predicted 75.2% (71.9-76.3%) of turtles came from Mexico, 14.8% (11-18%) from Costa Rica, 5.9% (4.8-7.9%) from countries in northern South America, 3.4% (2.4-3.5%) from the United States and 1.6% (0.6-2.0%) from West African countries. Thus, the spill's impacts may extend far beyond the current focus on the northern Gulf of Mexico., (© 2015 The Authors.)

Mental health professionals who provide medicolegal services need to be aware of the very important differences between clinical and retained expert/forensic roles. This column offers a distinction between clinical and forensic roles in terms of responsibilities, objectives, and guiding ethical principles. Existing professional guidelines and other views from the medical literature that discourage the mixing of such roles are reviewed. The conflation of clinical and forensic roles and the attendant risks are considered, in terms of both competing interests and the possible ethical threat associated with assuming a dual role. Knowingly or unwittingly assuming a dual role is potentially harmful to the therapeutic alliance, threatens the expert's objectivity, and may jeopardize a patient's legal case. Guidance is offered as to how to avoid conflating clinical and forensic roles when compelled to provide medicolegal services.

The Gulf of Mexico is one of the most ecologically and economically valuable marine ecosystems in the world and is affected by a variety of natural and anthropogenic phenomena including climate, hurricanes, coastal development, agricultural runoff, oil spills, and fishing. These complex and interacting stressors, together with the highly dynamic nature of this ecosystem, present challenges for the effective management of its resources. We analyze a compilation of over 100 indicators representing physical, biological, and economic aspects of the Gulf of Mexico and find that an ecosystem-wide reorganization occurred in the mid-1990s. Further analysis of fishery landings composition data indicates a major shift in the late 1970s coincident with the advent of US national fisheries management policy, as well as significant shifts in the mid-1960s and the mid-1990s. These latter shifts are aligned temporally with changes in a major climate mode in the Atlantic Ocean: the Atlantic Multidecadal Oscillation (AMO). We provide an explanation for how the AMO may drive physical changes in the Gulf of Mexico, thus altering higher-level ecosystem dynamics. The hypotheses presented here should provide focus for further targeted studies, particularly in regard to whether and how management should adjust to different climate regimes or states of nature. Our study highlights the challenges in understanding the effects of climatic drivers against a background of multiple anthropogenic pressures, particularly in a system where these forces interact in complex and nonlinear ways., (© 2015 John Wiley & Sons Ltd.)