Palliation of heart failure: value-based supportive care

Objectives: Heart failure (HF) is a prevalent condition associated with poor quality-of-life and high symptom burden. As patients reach ceilings of survival-extending interventions, their priorities may be more readily addressed through the support of palliative care services; however, the best model of care remains unestablished. We aimed to create and evaluate a cospeciality cross-boundary service model for patients with HF that better provides for their palliative care needs in the latter stages of life, while delivering a more cost-effective patient journey. Methods: In 2016, the Heart Failure Supportive Care Service (HFSCS) was established to provide patient-centred holistic support to patients with advanced HF. Patient experience questionnaires were developed and distributed in mid-2018 and end-of-2020. Indexed hospital admission data (in-patient bed days pre-referral/post-referral) were used allowing statistical comparisons by paired t-tests. Results: From 2016–2020, 236 patients were referred to the HFSCS. Overall, 75/118 questionnaires were returned. Patients felt that the HFSCS delivered compassionate care (84%) that improved symptoms and quality of life (80% and 65%). Introduction of the HFSCS resulted in a reduction in HF-related admissions: actual days 18.3 to 4 days (p<0.001), indexed days 0.05 to 0.032 days (p=0.03). Cost mapping revealed an estimated average saving of at least £10 218.36 per referral and a total estimated cost saving of approximately £2.4 million over 5 years. Conclusion: This service demonstrates that a cospeciality cross-boundary method of care delivery successfully provides the benefits of palliative care to patients with HF in a value-based manner, while meeting the priorities of care that matter to patients most

Brief Report: AIP Mutation in Pituitary Adenomas in the 18th Century and Today

From New England Journal of Medicine, Volume 364, issue 1, p.43-50. Copyright © (2011) Massachusetts Medical Society. Reprinted with permission.Gigantism results when a growth hormone–secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783,1-3 he noted an enlarged pituitary fossa. We extracted DNA from the patient’s teeth and identified a germline mutation in the aryl hydrocarbon–interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier

The sensitivity of breeding songbirds to changes in seasonal timing is linked to population change but cannot be directly attributed to the effects of trophic asynchrony on productivity

A consequence of climate change has been an advance in the timing of seasonal events. Differences in the rate of advance between trophic levels may result in predators becoming mismatched with prey availability, reducing fitness and potentially driving population declines. Such “trophic asynchrony” is hypothesized to have contributed to recent population declines of long-distance migratory birds in particular. Using spatially extensive survey data from 1983 to 2010 to estimate variation in spring phenology from 280 plant and insect species and the egg-laying phenology of 21 British songbird species, we explored the effects of trophic asynchrony on avian population trends and potential underlying demographic mechanisms. Species which advanced their laying dates least over the last three decades, and were therefore at greatest risk of asynchrony, exhibited the most negative population trends. We expressed asynchrony as the annual variation in bird phenology relative to spring phenology, and related asynchrony to annual avian productivity. In warmer springs, birds were more asynchronous, but productivity was only marginally reduced; long-distance migrants, short-distance migrants and resident bird species all exhibited effects of similar magnitude. Long-term population, but not productivity, declines were greatest among those species whose annual productivity was most greatly reduced by asynchrony. This suggests that population change is not mechanistically driven by the negative effects of asynchrony on productivity. The apparent effects of asynchrony on population trends are therefore either more likely to be strongly expressed via other demographic pathways, or alternatively, are a surrogate for species' sensitivity to other environmental pressures which are the ultimate cause of decline

Red-flag sepsis and SOFA identifies different patient population at risk of sepsis-related deaths on the general ward

Controversy exists regarding the best diagnostic and screening tool for sepsis outside the intensive care unit (ICU). Sequential organ failure assessment (SOFA) score has been shown to be superior to systemic inflammatory response syndrome (SIRS) criteria, however, the performance of “Red Flag sepsis criteria” has not been tested formally. The aim of the study was to investigate the ability of Red Flag sepsis criteria to identify the patients at high risk of sepsis-related death in comparison to SOFA based sepsis criteria. We also investigated the comparison of Red Flag sepsis to quick SOFA (qSOFA), SIRS, and national early warning score (NEWS) scores and factors influencing patient mortality. Patients were recruited into a 24-hour point-prevalence study on the general wards and emergency departments across all Welsh acute hospitals. Inclusion criteria were: clinical suspicion of infection and NEWS 3 or above in-line with established escalation criteria in Wales. Data on Red Flag sepsis and SOFA criteria was collected together with qSOFA and SIRS scores and 90-day mortality. 459 patients were recruited over a 24-hour period. 246 were positive for Red Flag sepsis, mortality 33.7% (83/246); 241 for SOFA based sepsis criteria, mortality 39.4% (95/241); 54 for qSOFA, mortality 57.4% (31/54), and 268 for SIRS, mortality 33.6% (90/268). 55 patients were not picked up by any criteria. We found that older age was associated with death with OR (95% CI) of 1.03 (1.02–1.04); higher frailty score 1.24 (1.11–1.40); DNA-CPR order 1.74 (1.14–2.65); ceiling of care 1.55 (1.02–2.33); and SOFA score of 2 and above 1.69 (1.16–2.47). The different clinical tools captured different subsets of the at-risk population, with similar sensitivity. SOFA score 2 or above was independently associated with increased risk of death at 90 days. The sequalae of infection-related organ dysfunction cannot be reliably captured based on routine clinical and physiological parameters alone

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Sepsis-related deaths in the at-risk population on the wards: attributable fraction of mortality in a large point-prevalence study

Objective Sepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments. Results 839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score ≥ 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%)

Phenological sensitivity to climate across taxa and trophic levels

Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5–2.9 days earlier on average), with substantial taxonomic variation (1.1–14.8 days earlier on average)

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course