Search

Abstract Objective There are few multinational studies on gestational trophoblastic neoplasia (GTN) treatment outcomes in South America. The purpose of this study was to assess the clinical presentation, treatment outcomes, and factors associated with chemoresistance in low-risk postmolar GTN treated with first-line single-agent chemotherapy in three South American centers. Methods Multicentric, historical cohort study including women with International Federation of Gynecology and Obstetrics (FIGO)-staged low-risk postmolar GTN attending centers in Argentina, Brazil, and Colombia between 1990 and 2014. Data were obtained on patient characteristics, disease presentation, and treatment response. Logistic regression was used to assess the relationship between clinical factors and resistance to first-line single-agent treatment. A multivariate analysis of the clinical factors significant in univariate analysis was performed. Results A total of 163 women with low-risk GTN were included in the analysis. The overall rate of complete response to first-line chemotherapy was 80% (130/163). The rates of complete response to methotrexate or actinomycin-D as first-line treatment, and actinomycin-D as second-line treatment postmethotrexate failure were 79% (125/157), 83% (⅚), and 70% (23/33), respectively. Switching to second-line treatment due to chemoresistance occurred in 20.2% of cases (33/163). The multivariate analysis demonstrated that patients with a 5 to 6 FIGO risk score were 4.2-fold more likely to develop resistance to first-line single-agent treatment (p= 0.019). Conclusion 1) At presentation, most women showed clinical characteristics favorable to a good outcome, 2) the overall rate of sustained complete remission after first-line single-agent treatment was comparable to that observed in developed countries, 3) a FIGO risk score of 5 or 6 is associated with development of resistance to first-line single-agent chemotherapy.

Until recently, the influence of basal liquid water on the evolution of buried glaciers in Mars' mid latitudes was assumed to be negligible because the latter stages of Mars' Amazonian period (3 Ga to present) have long been thought to have been similarly cold and dry to today. Recent identifications of several landforms interpreted as eskers associated with these young (100s Ma) glaciers calls this assumption into doubt. They indicate basal melting (at least locally and transiently) of their parent glaciers. Although rare, they demonstrate a more complex mid-to-late Amazonian environment than was previously understood. Here, we discuss several open questions posed by the existence of glacier-linked eskers on Mars, including on their global-scale abundance and distribution, the drivers and dynamics of melting and drainage, and the fate of meltwater upon reaching the ice margin. Such questions provide rich opportunities for collaboration between the Mars and Earth cryosphere research communities.

Introduction In the UK, approximately 4.3 million adults have asthma, with one-third experiencing poor asthma control, affecting their quality of life, and increasing their healthcare use. Interventions promoting emotional/behavioural self-management can improve asthma control and reduce comorbidities and mortality. Integration of online peer support into primary care services to foster self-management is a novel strategy. We aim to co-design and evaluate an intervention for primary care clinicians to promote engagement with an asthma online health community (OHC). Our protocol describes a ‘survey leading to a trial’ design as part of a mixed-methods, non-randomised feasibility study to test the feasibility and acceptability of the intervention.Methods and analysis Adults on the asthma registers of six London general practices (~3000 patients) will be invited to an online survey, via text messages. The survey will collect data on attitudes towards seeking online peer support, asthma control, anxiety, depression, quality of life, information on the network of people providing support with asthma and demographics. Regression analyses of the survey data will identify correlates/predictors of attitudes/receptiveness towards online peer support. Patients with troublesome asthma, who (in the survey) expressed interest in online peer support, will be invited to receive the intervention, aiming to reach a recruitment target of 50 patients. Intervention will involve a one-off, face-to-face consultation with a practice clinician to introduce online peer support, sign patients up to an established asthma OHC, and encourage OHC engagement. Outcome measures will be collected at baseline and 3 months post intervention and analysed with primary care and OHC engagement data. Recruitment, intervention uptake, retention, collection of outcomes, and OHC engagement will be assessed. Interviews with clinicians and patients will explore experiences of the intervention.Ethics and dissemination Ethical approval was obtained from a National Health Service Research Ethics Committee (reference: 22/NE/0182). Written consent will be obtained before intervention receipt and interview participation. Findings will be shared via dissemination to general practices, conference presentations and peer-reviewed publications.Trial registration number NCT05829265.

IntroductionCoordinated alignment of the eyes during gaze fixation and eye movements are an important component of normal visual function. We have previously described the coordinated behavior of convergence eye movements and pupillary responses using a 0.1 Hz binocular disparity-driven sine profile and a step profile. The goal of this publication is to further characterize ocular vergence-pupil size coordination over a wider range of frequencies of ocular disparity stimulation in normal subjects.MethodsBinocular disparity stimulation is generated by presentation of independent targets to each eye on a virtual reality display, while eye movements and pupil size are measured by an embedded video-oculography system. This design allows us to study two complimentary analyses of this motion relationship. First, a macroscale analysis describes the vergence angle of the eyes in response to binocular disparity target movement and pupil area as a function of the observed vergence response. Second, a microscale analysis performs a piecewise linear decomposition of the vergence angle and pupil relationship to permit more nuanced findings.ResultsThese analyses identified three main features of controlled coupling of pupil and convergence eye movements. First, a near response relationship operates with increasing prevalence during convergence (relative to the “baseline” angle); the coupling is higher with increased convergence in this range. Second, the prevalence of “near response”-type coupling decreases monotonically in the diverging direction; the decrease persists after the targets move (converge back) from maximum divergence toward the baseline positions, with a minimum prevalence of near response segments near the baseline target position. Third, an opposite polarity pupil response is infrequent, but tends to be more prevalent when the vergence angles are at maximum convergence or divergence for a sinusoidal binocular disparity task.DiscussionWe suggest that the latter response is an exploratory “range-validation” when binocular disparity is relatively constant. In a broader sense, these findings describe operating characteristics of the near response in normal subjects and form a basis for quantitative assessments of function in conditions such as convergence insufficiency and mild traumatic brain injury.

While thiocarbonyl-stabilised phosphonium ylides generally react upon flash vacuum pyrolysis by the extrusion of Ph3PS to give alkynes in an analogous way to their carbonyl-stabilised analogues, two examples with a hydrogen atom on the ylidic carbon are found to undergo a quite different process. The net transfer of a phenyl group from P to S gives (Z)-configured 1-diphenylphosphino-2-(phenylsulfenyl)alkenes in a novel isomerisation process via intermediate λ5-1,2-thiaphosphetes. These prove to be versatile hemilabile ligands with a total of seven complexes prepared involving five different transition metals. Four of these are characterised by X-ray diffraction with two involving the bidentate ligand forming a five-membered ring metallacycle and two with the ligand coordinating to the metal only through phosphorus.

Background/objectivesPersons with Alzheimer disease and related dementias (ADRDs) require comprehensive care that spans health systems and community-based organizations. This study examined the clinical outcomes of a comprehensive dementia care program and identified subgroups who were more likely to benefit.DesignObservational, baseline and 1 year after intervention.SettingUrban, academic medical center.ParticipantsA total of 554 persons with dementia and their caregivers who had 1-year follow-up evaluations and data on clinical outcomes.InterventionHealth system-based comprehensive dementia care management program using nurse practitioner dementia care managers.MeasurementsPatient measures included the Mini-Mental State Examination (MMSE), the Functional Activities Questionnaire, Basic and Instrumental Activities of Daily Living scales, the Cornell Scale for Depression in Dementia, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity. Caregiver measures included the Modified Caregiver Strain Index, the Patient Health Questionnaire-9, NPI-Q Distress, and the Dementia Burden Scale-Caregiver). We used established minimal clinically important differences and lowest tertiles of baseline symptoms to define improving symptoms and maintaining low symptoms as clinical benefit for patients and caregivers.ResultsAt year 1, persons with ADRD improved on all scales, except MMSE and functional status measures; caregivers improved on all scales. Using validated instruments, 314/543 (58%) of patients, 282/447 (63%) of caregivers, and 376/501 (75%) of patients or caregivers demonstrated clinical benefit. In adjusted multivariate models, at year 1, more behavioral symptoms and fewer depression symptoms at baseline were associated with patient improvement; and fewer baseline depression symptoms were associated with maintaining low behavioral symptoms. Male caregiver sex, higher baseline caregiver burden, and caring for patients with fewer baseline depression symptoms were associated with caregiver improvement. Male caregiver sex and patients with fewer depression symptoms, fewer behavioral symptoms, and more functional impairment at baseline were associated with caregivers maintaining low burden at 1 year.ConclusionsHealth system-based comprehensive dementia care management is a promising approach to improving clinical outcomes, with benefits for both patients and caregivers. J Am Geriatr Soc 67:2267-2273, 2019.

Objective: Medical interventions that do not offer the patient meaningful benefit due to inconsistency with prognoses are often considered “inappropriate” by clinicians. We described the clinical details and resource utilisation of patients who were assessed as receiving inappropriate treatment. Design: Chart abstraction was performed on 123 patients who were assessed by their critical care physician as having received inappropriate treatment to document clinical characteristics, diagnostic testing, life-sustaining treatments and nursing assessments of daily pain and level of consciousness. Results: The mean age was 67 and on admission, 41% had cancer and 25% had advanced pulmonary disease. At least one of the following three conditions was noted in 57% of the patients: severe neurological injury, overwhelming sepsis or irreversible respiratory failure. Patients were less likely to be alert (OR 0.39, CI 0.16–0.91, p = 0.03) on days they were assessed as receiving inappropriate critical care. After they were assessed as receiving inappropriate critical care, they received 172 imaging studies, 151 procedures, 522 days of mechanical ventilation (excludes one patient who received 1020 days of mechanical ventilation), 254 days of vasopressors, 226 days of hemodialysis and 10 attempts at cardiopulmonary resuscitation. Conclusions: Patients assessed as receiving inappropriate critical care receive resource-intensive medical care, largely while non-alert.

Introduction: Varying intensity of advance care planning (ACP) interventions at the population level has not been compared among seriously ill patients in primary care. This project will implement, test, and disseminate real-world scalable ACP interventions among primary care clinics across three University of California Health systems. The three ACP interventions are (1) distribution of an advance directive (AD) with targeted ACP messaging, (2) the AD, messaging, plus prompting patients to engage with the Prepare For Your Care website (PREPARE), and (3) the AD, messaging, PREPARE, plus Care Coordinator engagement with patients and clinicians. Methods: We will identify a population cohort of seriously ill primary care patients and implement the ACP interventions using electronic health record (EHR) patient portals and postal mailings. Forty-five clinics across the three health systems will be cluster randomized to one of the three ACP interventions. The primary outcome for the population cohort is AD or Physician Orders for Life-Sustaining Treatment documentation in the EHR. A subset of the population cohort will be surveyed to assess patient-centered outcomes, including care consistent with goals at baseline, 12 months, and 24 months. Caregivers will be interviewed if patients are unable to be surveyed or die. ACP documentation, goal concordant care, and among decedents, health care utilization will be compared among intervention arms. Study Implementation: Challenges and Contributions: The project is guided by a Study Advisory Group and Community Advisory Groups at each site to ensure rigorous patient-centered methods and consistency of implementation. Intervention fidelity will be evaluated using the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework. Challenges to implementation of this three-site health system trial and to intervention fidelity stem from site/clinic/system cultures, increasing attention to end-of-life care from payers and regulators, and growing pressures by health systems to implement ACP interventions. Stakeholder engagement is required to ensure consistent interventions across sites.

Background/objectivesAlthough Alzheimer disease and other dementias are life limiting, only a minority of these patients or their proxy decision makers participate in advance care planning. We describe end-of-life care preferences and acute care and hospice use in the last 6 months of life for persons enrolled in a comprehensive dementia care management program.DesignObservational, retrospective cohort.SettingUrban, academic medical center.ParticipantsA total of 322 persons enrolled in dementia care management after July 1, 2012, who died before July 1, 2016.InterventionDementia care comanagement model using nurse practitioners partnered with primary care providers and community organizations to provide comprehensive dementia care, including advance care planning.MeasurementsAdvance care preferences, use of Physician Orders for Life Sustaining Treatment (POLST), hospice enrollment, and hospitalizations and emergency department (ED) visits in the last 6 months of life obtained from electronic health record data.ResultsNearly all decedents (99.7%, N = 321) had a goals-of-care conversation documented (median = 3 conversations; interquartile range = 2-4 conversations), and 64% had advance care preferences recorded. Among those with recorded preferences, 88% indicated do not resuscitate, 48% limited medical interventions, and 35% chose comfort-focused care. Most patients (89%) specified limited artificial nutrition, including withholding feeding tubes. Over half (54%) had no hospitalizations or ED visits in the last 6 months of life, and intensive care unit stays were rare (5% of decedents). Overall, 69% died on hospice. Decedents who had completed a POLST were more likely to die in hospice care (74% vs 62%; P = .03) and die at home (70% vs 59%; P = .04).ConclusionsEnrollees in a comprehensive dementia care comanagement program had high engagement in advance care planning, high rates of hospice use, and low acute care utilization near the end of life. Wider implementation of such programs may improve end-of-life care for persons with dementia. J Am Geriatr Soc 67:443-448, 2019.

Importance:An estimated 4 to 5 million Americans have Alzheimer disease or another dementia. Objective:To determine the health care utilization and cost outcomes of a comprehensive dementia care program for Medicare fee-for-service beneficiaries. Design, Setting, and Participants:In this case-control study, we used a quasiexperimental design to compare health care utilization and costs for 1083 Medicare fee-for-service beneficiaries enrolled in the University of California Los Angeles Health System Alzheimer and Dementia Care program between July 1, 2012, and December 31, 2015, with those of 2166 similar patients with dementia not participating in the program. Patients in the comparison cohort were selected using the zip code of residence as a sampling frame and matched with propensity scores, which included demographic characteristics, comorbidities, and prior-year health care utilization. We used Medicare claims data to compare utilization and cost outcomes for the 2 groups. Interventions:Patients in the dementia care program were comanaged by nurse practitioners and physicians, and the program consisted of structured needs assessments of patients and their caregivers, creation and implementation of individualized dementia care plans with input from primary care physicians, monitoring and revising care plans, referral to community organizations for dementia-related services and support, and access to a clinician for assistance and advice 24 hours per day, 7 days per week. Main Outcomes and Measures:Admissions to long-term care facilities; average difference-in-differences per quarter over the 3-year intervention period for all-cause hospitalization, emergency department visits, 30-day hospital readmissions, and total Medicare Parts A and B costs of care. Program costs were included in the cost estimates. Results:Program participants (n = 382 men, n = 701 women; mean [SD] age, 82.10 [7.90] years; age range 54-101 years) were less likely to be admitted to a long-term care facility (hazard ratio, 0.60; 95% CI, 0.59-0.61) than those not participating in the dementia care program (n = 759 men, n = 1407 women; mean [SD] age, 82.42 [8.50] years; age range, 34-103 years). There were no differences between groups in terms of hospitalizations, emergency department visits, or 30-day readmissions. The total cost of care to Medicare, excluding program costs, was $601 less per patient per quarter (95% CI, -$1198 to -$5). After accounting for the estimated program costs of $317 per patient per quarter, the program was cost neutral for Medicare, with an estimated net cost of -$284 (95% CI, -$881 to $312) per program participant per quarter. Conclusions and Relevance:Comprehensive dementia care may reduce the number of admissions to long-term care facilities, and depending on program costs, may be cost neutral or cost saving. Wider implementation of such programs may help people with dementia stay in their communities.

Considerable progress has been made in recent years towards the identification and characterisation of novel subtype-selective modulators of nicotinic acetylcholine receptors (nAChRs). In particular, this has focussed on modulators of α7 nAChRs, a nAChR subtype that has been identified as a target for drug discovery in connection with a range of potential therapeutic applications. This review focusses upon α7-selective modulators that bind to receptor sites other than the extracellular ‘orthosteric’ agonist binding site for the endogenous agonist acetylcholine (ACh). Such compounds include those that are able to potentiate responses evoked by orthosteric agonists such as ACh (positive allosteric modulators; PAMs) and those that are able to activate α7 nAChRs by direct allosteric activation in the absence of an orthosteric agonist (allosteric agonists or ‘ago-PAMs’). There has been considerable debate about the mechanism of action of α7-selective PAMs and allosteric agonists, much of which has centred around identifying the location of their binding sites on α7 nAChRs. Based on a variety of experimental evidence, including recent structural data, there is now clear evidence indicating that at least some α7-selective PAMs bind to an inter-subunit site located in the transmembrane domain. In contrast, there are differing hypotheses about the site or sites at which allosteric agonists bind to α7 nAChRs. It will be argued that the available evidence supports the conclusion that direct allosteric activation by allosteric agonists/ago-PAMs occurs via the same inter-subunit transmembrane site that has been identified for several α7-selective PAMs.

Introduction A significant environmental risk factor for neurodegenerative disease is traumatic brain injury (TBI). However, it is not clear how TBI results in ongoing chronic neurodegeneration. Animal studies show that systemic inflammation is signalled to the brain. This can result in sustained and aggressive microglial activation, which in turn is associated with widespread neurodegeneration. We aim to evaluate systemic inflammation as a mediator of ongoing neurodegeneration after TBI.Methods and analysis TBI-braINFLAMM will combine data already collected from two large prospective TBI studies. The CREACTIVE study, a broad consortium which enrolled >8000 patients with TBI to have CT scans and blood samples in the hyperacute period, has data available from 854 patients. The BIO-AX-TBI study recruited 311 patients to have acute CT scans, longitudinal blood samples and longitudinal MRI brain scans. The BIO-AX-TBI study also has data from 102 healthy and 24 non-TBI trauma controls, comprising blood samples (both control groups) and MRI scans (healthy controls only). All blood samples from BIO-AX-TBI and CREACTIVE have already been tested for neuronal injury markers (GFAP, tau and NfL), and CREACTIVE blood samples have been tested for inflammatory cytokines. We will additionally test inflammatory cytokine levels from the already collected longitudinal blood samples in the BIO-AX-TBI study, as well as matched microdialysate and blood samples taken during the acute period from a subgroup of patients with TBI (n=18).We will use this unique dataset to characterise post-TBI systemic inflammation, and its relationships with injury severity and ongoing neurodegeneration.Ethics and dissemination Ethical approval for this study has been granted by the London—Camberwell St Giles Research Ethics Committee (17/LO/2066). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of larger observational and experimental medicine studies assessing the role and management of post-TBI systemic inflammation.

Introduction Outcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are at an increased occupational risk of TBI, with high rates of complex polytrauma including TBI characterising the UK campaign in Afghanistan. The ArmeD SerVices TrAuma and RehabilitatioN OutComE (ADVANCE)-TBI substudy will describe the patterns, associations and long-term outcomes of TBI in the established ADVANCE cohort.Methods and analysis The ADVANCE cohort comprises 579 military personnel exposed to major battlefield trauma requiring medical evacuation, and 566 matched military personnel without major trauma. TBI exposure has been captured at baseline using a standardised interview and registry data, and will be refined at first follow-up visit with the Ohio State Method TBI interview (a National Institute of Neurological Disorders and Stroke TBI common data element). Participants will undergo blood sampling, MRI and detailed neuropsychological assessment longitudinally as part of their follow-up visits every 3–5 years over a 20-year period. Biomarkers of injury, neuroinflammation and degeneration will be quantified in blood, and polygenic risk scores calculated for neurodegeneration. Age-matched healthy volunteers will be recruited as controls for MRI analyses. We will describe TBI exposure across the cohort, and consider any relationship with advanced biomarkers of injury and clinical outcomes including cognitive performance, neuropsychiatric symptom burden and function. The influence of genotype will be assessed. This research will explore the relationship between military head injury exposure and long-term outcomes, providing insights into underlying disease mechanisms and informing prevention interventions.Ethics and dissemination The ADVANCE-TBI substudy has received a favourable opinion from the Ministry of Defence Research Ethics Committee (ref: 2126/MODREC/22). Findings will be disseminated via publications in peer-reviewed journals and presentations at conferences.