Early human contact and housing for pigs - part 3: ability to cope with the environment.

Early experiences can have long-term impacts on stress adaptability. This paper is the last of three in a series on early experiences and stress in pigs, and reports on the effects of early human contact and housing on the ability of pigs to cope with their general environment. Using a 2 × 2 factorial design, 48 litters of pigs were reared in either a farrowing crate (FC) or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0 to 4 weeks of age. At 4 weeks of age (preweaning), C piglets that were reared in FC had considerably lower concentrations of serum brain-derived neurotrophic factor (BDNF) than piglets from the other treatment combinations. Compared to C pigs, +HC pigs had fewer injuries at 4 weeks of age. There were no clear effects of human contact on BDNF concentrations or injuries after weaning, or on basal cortisol or immunoglobulin-A concentrations, behavioural time budgets, tear staining, growth, or piglet survival. Compared to FC piglets, LP piglets showed more play behaviour and interactions with the dam and less repetitive nosing towards pen mates during lactation. There was no evidence that early housing affected pigs' behavioural time budgets or physiology after weaning. Tear staining severity was greater in LP piglets at 4 weeks of age, but this may have been associated with the higher growth rates of LP piglets preweaning. There was no effect of lactation housing on growth after weaning. Preweaning piglet mortality was higher in the loose system. The findings on BDNF concentrations, injuries and play behaviour suggest improved welfare during the treatment period in +HC and LP piglets compared to C and FC piglets, respectively. These results together with those from the other papers in this series indicate that positive human interaction early in life promotes stress adaptability in pigs. Furthermore, while the farrowing crate environment deprives piglets of opportunities for play behaviour and sow interaction, there was no evidence that rearing in crates negatively affected pig welfare or stress resilience after weaning. Whether these findings are specific to the two housing systems studied here, or can be generalised to other housing designs, warrants further research.

Low risk management intervention: Limited impact of remedial tillage on net ecosystem carbon balance at a commercial Miscanthus plantation.

Perennial bioenergy crops are a key tool in decarbonizing global energy systems, but to ensure the efficient use of land resources, it is essential that yields and crop longevity are maximized. Remedial shallow surface tillage is being explored in commercial Miscanthus plantations as an approach to reinvigorate older crops and to rectify poor establishment, improving yields. There are posited links, however, between tillage and losses in soil carbon (C) via increased ecosystem C fluxes to the atmosphere. As Miscanthus is utilized as an energy crop, changes in field C fluxes need to be assessed as part of the C balance of the crop. Here, for the first time, we quantify the C impacts of remedial tillage at a mature commercial Miscanthus plantation in Lincolnshire, United Kingdom. Net ecosystem C production based on eddy covariance flux observations and exported yield totalled 12.16 Mg C ha-1 over the 4.6 year period after tillage, showing the site functioned as a net sink for atmospheric carbon dioxide (CO2). There was no indication of negative tillage induced impacts on soil C stocks, with no difference 3 years post tillage in the surface (0-30 cm) or deep (0-70 cm) soil C stocks between the tilled Miscanthus field and an adjacent paired untilled Miscanthus field. Comparison to historic samples showed surface soil C stocks increased by 11.16 ± 3.91 Mg C ha-1 between pre (October 2011) and post tillage sampling (November 2016). Within the period of the study, however, the tillage did not result in the increased yields necessary to "pay back" the tillage induced yield loss. Rather the crop was effectively re-established, with progressive yield increases over the study period, mirroring expectations of newly planted sites. The overall impacts of remedial tillage will depend therefore, on the longer-term impacts on crop longevity and yields.

Early human contact and housing for pigs - part 1: responses to humans, novelty and isolation.

The development of fear and stress responses in animals can be influenced by early life experiences, including interactions with humans, maternal care, and the physical surroundings. This paper is the first of three reporting on a large experiment examining the effects of the early housing environment and early positive human contact on stress resilience in pigs. This first paper reports on the responses of pigs to humans, novelty, and social isolation. Using a 2 × 2 factorial design, 48 litters of pigs were reared in either a conventional farrowing crate (FC) where the sow was confined or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely throughout the farrowing and lactation period. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0-4 weeks of age. The positive handling treatment was highly effective in reducing piglets' fear of humans, based on +HC piglets showing greater approach and less avoidance of an unfamiliar person at 3 weeks of age. There was evidence that this reduction in fear of humans lasted well beyond when the treatment was applied (lactation), with +HC pigs showing greater approach and less avoidance of humans in tests at 6, 9 and 14 weeks of age. The +HC treatment also reduced piglets' fear of a novel object at 3 weeks of age, and for pigs in FC, the cortisol response after social isolation at 7 weeks of age. Rearing in FC compared to LP reduced piglets' fear of novelty at 3 weeks of age, as well as their vocalisations and cortisol response to isolation at 7 weeks of age. The FC pigs showed greater approach and less avoidance of humans compared to LP pigs at 3, 4 and 6 weeks of age, but not at 9 and 14 weeks of age. These results show that positive handling early in life can reduce pigs' fear of humans, fear of novelty and physiological stress response to social isolation. The LP pigs were reared in a more isolated environment with less overall contact with stockpeople and other pigs, which may have increased their fear responses to humans and novel situations, suggesting that different housing systems can modulate these pigs' responses.

Variation in Hospice Aide Care by Residential Setting.

Background: Hospice care frequently includes hands-on care from hospice aides, but the need for hospice aide care may vary in residential settings (e.g., assisted livings and nursing homes). Objectives: The objective of this study is to compare hospice aide use and factors associated with use across residential settings. Design: This longitudinal cohort study used data from Medicare beneficiaries in the United States enrolled in the Medicare Current Beneficiary Survey (MCBS) who died between 2010 and 2019 and had hospice claims and available residential setting data in MCBS (n = 1,915). Analysis: Decedent hospice aide use was compared by residential settings; multivariable models controlling for sociodemographic, clinical/functional, and hospice characteristics examined factors associated with hospice aide care in different residential settings. Results: Hospice aide visits were least common in the community setting (64.4% vs. 76.6% vs. 72.6% with any hospice aide visits in community, assisted living, and nursing home, respectively, p = 0.001). In adjusted models, factors associated with hospice aide visits did not significantly differ by residential settings. Conclusions: Despite staff providing hands-on support in assisted livings and nursing homes, hospice aide visits were more common in residential as opposed to community settings, and factors associated with hospice aide visits were similar among settings. To maximize the potentially positive impact of hospice aides on overall care, additional work is needed to understand when hospice aides are used and how hospice aides collaborate with families and care teams. This will help to ensure that hospice care is appropriately tailored to individual care needs in all residential settings.

Place of Death for Adults Receiving Specialist Palliative Care in Their Last 3 Months of Life: Factors Associated With Preferred Place, Actual Place, and Place of Death Congruence.

Objectives: Congruence between the preferred and actual place of death is recognised as an important quality indicator in end-of-life care. However, there may be complexities about preferences that are ignored in summary congruence measures. This article examined factors associated with preferred place of death, actual place of death, and congruence for a sample of patients who had received specialist palliative care in the last three months of life in Ireland. Methods: This article analysed merged data from two previously published mortality follow-back surveys: Economic Evaluation of Palliative Care in Ireland (EEPCI); Irish component of International Access, Rights and Empowerment (IARE I). Logistic regression models examined factors associated with (a) preferences for home death versus institutional setting, (b) home death versus hospital death, and (c) congruent versus non-congruent death. Setting: Four regions with differing levels of specialist palliative care development in Ireland. Participants: Mean age 77, 50% female/male, 19% living alone, 64% main diagnosis cancer. Data collected 2011-2015, regression model sample sizes: n = 342-351. Results: Congruence between preferred and actual place of death in the raw merged dataset was 51%. Patients living alone were significantly less likely to prefer home versus institution death (OR 0.389, 95%CI 0.157-0.961), less likely to die at home (OR 0.383, 95%CI 0.274-0.536), but had no significant association with congruence. Conclusions: The findings highlight the value in examining place of death preferences as well as congruence, because preferences may be influenced by what is feasible rather than what patients would like. The analyses also underline the importance of well-resourced community-based supports, including homecare, facilitating hospital discharge, and management of complex (eg, non-cancer) conditions, to facilitate patients to die in their preferred place.

Specialist Palliative Care Use and End-of-Life Care in Patients With Metastatic Cancer.

CONTEXT: For patients with advanced cancer, high intensity treatment at the end of life is measured as a reflection of the quality of care. Use of specialist palliative care has been promoted to improve care quality, but whether its use is associated with decreased treatment intensity on a population-level is unknown. OBJECTIVES: To determine whether receipt of specialist palliative care use is associated with differences in end-of-life quality metrics in patients with metastatic cancer. METHODS: Retrospective propensity-matched cohort of patients age ≥ 65 who died with metastatic cancer in U.S. hospitals with palliative care programs that participated in the National Palliative Care Registry in 2018-2019. Cox proportional hazards regression was used to assess the impact of specialist palliative care on use of chemotherapy in the last 14 days of life, use of intensive care unit (ICU) in the last 30 days of life, use of hospice, and hospice enrollment ≥ three days. RESULTS: After 1:2 matching, our cohort consisted of 15,878 exposed and 31,756 unexposed patients. Receipt of specialist palliative care was associated with a decrease in use of chemotherapy (adjusted hazard ratio (aHR) 0.59 [0.50-0.70]) and ICU at the end of life (aHR 0.86 [0.80-0.92]), and an increase in hospice use (aHR 1.92 [1.85-1.99]) and hospice enrollment for ≥three days (aHR 2.00 [1.93-2.07]). CONCLUSION: On a population-level, use of specialist palliative care was associated with improved metrics for quality end-of-life care for patients dying with metastatic cancer, underscoring the importance of its integration into cancer care.

Stochastic model corrections for reduced Lotka-Volterra models exhibiting mutual, commensal, competitive, and predatory interactions.

We explore model-form error and how to correct it in systems of ordinary differential equations. In particular, we focus on the Lotka-Volterra equations, which are used broadly in fields such as ecology, biology, economics, chemistry, and physics. Accounting for every object and their complex interactions with a complete model often becomes infeasible, thereby requiring reduced models. However, reduced models may omit vital relationships, resulting in discrepancies between reduced model predictions and observations from the true system. In this work, we propose a model correction framework for decreasing such discrepancies. Specifically, we embed a stochastic enrichment operator into the reduced model's system of equations. The enrichment operator is theory-informed, calibrated with observations from the complete model, and extended to extrapolative combinations of parameters and initial conditions. The complete model involves N species, while the reduced and enriched models only track M

Spatiotemporal Patterns of Hospitalizations Among Older Adults With Co-Presence of Cancer and Dementia in US Counties: 2013-2018.

We assessed the spatiotemporal patterns of hospitalization with comorbid cancer and dementia. Using the 2013-2018 inpatient claims data for Medicare fee-for-service (FFS) beneficiaries, we calculated hospitalization rates by dividing the total admissions from individuals with the co-presence of a major cancer (breast, prostate, lung, and colorectal) and dementia diagnoses with the total counts of FFS beneficiaries aged 65 or older. We identified 22 hotspots with high hospitalization rates that showed heterogeneous spatial and temporal utilization patterns. The odds of a county being a hotspot increased significantly with the county-level percentage of dual Medicare-Medicaid beneficiaries (aOR 1.05; 95% CI: 1.04-1.07) and the prevalence of cancer (aOR 1.73; 95% CI: 1.59-1.89), while decreased significantly with increasing degree of rurality (aOR .82; 95% CI: .79-.85) and decreased yearly over time (aOR .72; 95% CI: .68-.75). The identified hotspots and factors at the county-level may help understand healthcare utilization patterns and assess resource allocation for this unique patient group.

Post-PICU Cognitive and Psychological Outcomes in Children Receiving Treatments for Acute Lymphoblastic Leukemia.

OBJECTIVES: To examine neurocognitive and psychological outcomes associated with post-PICU admissions in children treated for childhood acute lymphoblastic leukemia (ALL). DESIGN: Observational study from October 2007 to March 2017. SETTING: Pediatric onco-critical care unit. PATIENTS: All patients in this study (n = 296; ages 3-21) were treated for ALL on the St. Jude Total Therapy 16 clinical trial (NCT00549848) from 2007 to 2017. Of these, 104 patients were admitted to the PICU during protocol-directed therapy. All patients completed protocol-directed neurocognitive monitoring prospectively, at the end of cancer-directed therapy. Data on PICU stays were abstracted retrospectively from the medical record. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic and critical illness variables were abstracted from institutional databases and medical records. Neurocognitive and psychosocial outcomes were prospectively obtained at the end of treatment. Children who had a PICU admission experienced significantly lower functioning compared to normative samples in several areas of cognitive functioning (working memory, processing speed, executive functions, inattention, math achievement, fine motor dexterity, and speed), daily living skills, and internalizing problems (all ps < 0.05). Compared with those without PICU admissions, patients with PICU admissions had worse performance on a measure of sustained attention (p = 0.017). The frequency of patients at risk for problems with learning and memory was significantly higher in the PICU group compared with the non-PICU group (25% vs 12%, p = 0.006). Critical illness symptom severity was not associated with neurocognitive or psychological outcomes. CONCLUSIONS: Children with ALL, with or without a PICU admission, experienced lower cognitive and psychological outcomes following treatment. Future research is needed to continue identifying risk factors for post-intensive care syndrome (PICS-p) and post-PICU cognitive and psychological impairments in pediatric patients.

Mortality Risk Factors in Pediatric Onco-Critical Care Patients and Machine Learning Derived Early Onco-Critical Care Phenotypes in a Retrospective Cohort.

OBJECTIVES: To use supervised and unsupervised statistical methodology to determine risk factors associated with mortality in critically ill pediatric oncology patients to identify patient phenotypes of interest for future prospective study. DESIGN: This retrospective cohort study included nonsurgical pediatric critical care admissions from January 2017 to December 2018. We determined the prevalence of multiple organ failure (MOF), ICU mortality, and associated factors. Consensus k-means clustering analysis was performed using 35 bedside admission variables for early, onco-critical care phenotype development. SETTING: Single critical care unit in a subspeciality pediatric hospital. INTERVENTION: None. PATIENTS: There were 364 critical care admissions in 324 patients with underlying malignancy, hematopoietic cell transplant, or immunodeficiency reviewed. MEASUREMENTS: Prevalence of multiple organ failure, ICU mortality, determination of early onco-critical care phenotypes. MAIN RESULTS: ICU mortality was 5.2% and was increased in those with MOF (18.4% MOF, 1.7% single organ failure [SOF], 0.6% no organ failure; p ≤ 0.0001). Prevalence of MOF was 23.9%. Significantly increased ICU mortality risk was associated with day 1 MOF (hazards ratio [HR] 2.27; 95% CI, 1.10-6.82; p = 0.03), MOF during ICU admission (HR 4.16; 95% CI, 1.09-15.86; p = 0.037), and with invasive mechanical ventilation requirement (IMV; HR 5.12; 95% CI, 1.31-19.94; p = 0.018). Four phenotypes were derived (PedOnc1-4). PedOnc1 and 2 represented patient groups with low mortality and SOF. PedOnc3 was enriched in patients with sepsis and MOF with mortality associated with liver and renal dysfunction. PedOnc4 had the highest frequency of ICU mortality and MOF characterized by acute respiratory failure requiring invasive mechanical ventilation at admission with neurologic dysfunction and/or severe sepsis. Notably, most of the mortality in PedOnc4 was early (i.e., within 72 hr of ICU admission). CONCLUSIONS: Mortality was lower than previously reported in critically ill pediatric oncology patients and was associated with MOF and IMV. These findings were further validated and expanded by the four derived nonsynonymous computable phenotypes. Of particular interest for future prospective validation and correlative biological study was the PedOnc4 phenotype, which was composed of patients with hypoxic respiratory failure requiring IMV with sepsis and/or neurologic dysfunction at ICU admission.

Health Care Costs Associated With Hospice Use For People With Dementia In The US.

Policy makers in the US are increasingly concerned that greater use of the Medicare hospice benefit by people with dementia is driving up costs. Yet this perspective fails to incorporate potential cost savings associated with hospice. We estimated the association between hospice use by people with dementia and health care costs, using Medicare Current Beneficiary Survey data from the period 2002-19. For community-dwelling people with dementia, Medicare costs were lower for those who used hospice than for those who did not, whether hospice enrollment was in the last three days ($2,200) or last three months ($7,200) of life, primarily through lower inpatient care costs in the last days of life. In nursing homes, total and Medicare costs were lower for hospice users with dementia who enrolled within a month of death than for those who did not use hospice. Total costs for the entire last year of life for those who used any days of hospice in the last year compared with no hospice did not differ, although Medicare costs were higher and Medicaid costs lower for those in nursing homes. Medicare policies that reduce hospice access and incentivize hospice disenrollment may actually increase Medicare costs, given that hospice cost savings generally derive from a person's last days or weeks of life.

Recurrent photic zone euxinia limited ocean oxygenation and animal evolution during the Ediacaran.

The Ediacaran Period (~635-539 Ma) is marked by the emergence and diversification of complex metazoans linked to ocean redox changes, but the processes and mechanism of the redox evolution in the Ediacaran ocean are intensely debated. Here we use mercury isotope compositions from multiple black shale sections of the Doushantuo Formation in South China to reconstruct Ediacaran oceanic redox conditions. Mercury isotopes show compelling evidence for recurrent and spatially dynamic photic zone euxinia (PZE) on the continental margin of South China during time intervals coincident with previously identified ocean oxygenation events. We suggest that PZE was driven by increased availability of sulfate and nutrients from a transiently oxygenated ocean, but PZE may have also initiated negative feedbacks that inhibited oxygen production by promoting anoxygenic photosynthesis and limiting the habitable space for eukaryotes, hence abating the long-term rise of oxygen and restricting the Ediacaran expansion of macroscopic oxygen-demanding animals.

Using Functional Status at the Time of Palliative Care Consult to Identify Opportunities for Earlier Referral.

Background: In order to improve early access to palliative care, strategies for monitoring referral practices in real-time are needed. Objective: To evaluate how Australia-Modified Karnofsky Performance Status (AKPS) at the time of initial palliative care consult differs between serious illnesses and could be used to identify opportunities for earlier referral. Methods: We retrospectively evaluated data from an inpatient palliative care consult registry. Serious illnesses were classified using ICD-10 codes. AKPS was assessed by palliative care clinicians during consult. Results: The AKPS distribution varied substantially between the different serious illnesses (p < 0.001). While patients with cancer and heart disease often had preserved functional status, the majority of patients with dementia, neurological, lung, liver, and renal disease were already completely bedbound at the time of initial palliative care consult. Conclusion: Measuring functional status at the time of palliative care referral could be helpful for monitoring referral practices and identifying opportunities for earlier referral.

Paid Care for People with Functional Impairment and Serious Illness: Results from the Health and Retirement Study.

BACKGROUND: Paid caregivers (e.g., home health aides) care for individuals living at home with functional impairment and serious illnesses (health conditions with high risk of mortality that impact function and quality of life). OBJECTIVE: To characterize those who receive paid care and identify factors associated with receipt of paid care in the context of serious illness and socioeconomic status. DESIGN: Retrospective cohort study. PARTICIPANTS: Community-dwelling participants ≥ 65 years enrolled in the Health and Retirement Study (HRS) between 1998 and 2018 with new-onset functional impairment (e.g., bathing, dressing) and linked fee-for-service Medicare claims (n = 2521). MAIN MEASURES: Dementia was identified using HRS responses and non-dementia serious illness (e.g., advanced cancer, end-stage renal disease) was identified using Medicare claims. Paid care support was identified using HRS survey report of paid help with functional tasks. KEY RESULTS: While about 27% of the sample received paid care, those with both dementia and non-dementia serious illnesses in addition to functional impairment received the most paid care (41.7% received ≥ 40 h of paid care per week). In multivariable models, those with Medicaid were more likely to receive any paid care (p < 0.001), but those in the highest income quartile received more hours of paid care (p = 0.05) when paid care was present. Those with non-dementia serious illness were more likely to receive any paid care (p < 0.001), but those with dementia received more hours of care (p < 0.001) when paid care was present. CONCLUSIONS: Paid caregivers play a significant role in meeting the care needs of those with functional impairment and serious illness and high paid care hours are common among those with dementia in particular. Future work should explore how paid caregivers can collaborate with families and healthcare teams to improve the health and well-being of the seriously ill throughout the income spectrum.

Is the middle Cambrian Brooksella a hexactinellid sponge, trace fossil or pseudofossil?

First described as a medusoid jellyfish, the "star-shaped" Brooksella from the Conasauga shale Lagerstätten, Southeastern USA, was variously reconsidered as algae, feeding traces, gas bubbles, and most recently hexactinellid sponges. In this work, we present new morphological, chemical, and structural data to evaluate its hexactinellid affinities, as well as whether it could be a trace fossil or pseudofossil. External and cross-sectional surfaces, thin sections, X-ray computed tomography (CT) and micro-CT imaging, revealed no evidence that Brooksella is a hexactinellid sponge or a trace fossil. Although internally Brooksella contains abundant voids and variously orientated tubes consistent with multiple burrowing or bioeroding organisms, these structures have no relation to Brooksella's external lobe-like morphology. Furthermore, Brooksella has no pattern of growth comparable to the linear growth of early Paleozoic hexactinellids; rather, its growth is similar to syndepositional concretions. Lastly, Brooksella, except for its lobes and occasional central depression, is no different in microstructure to the silica concretions of the Conasauga Formation, strongly indicating it is a morphologically unusual endmember of the silica concretions of the formation. These findings highlight the need for thorough and accurate descriptions in Cambrian paleontology; wherein care must be taken to examine the full range of biotic and abiotic hypotheses for these compelling and unique fossils.

An Update: National Institutes of Health Research Funding for Palliative Medicine 2016-2020.

Background: The evidence base to support palliative care clinical practice is inadequate and opportunities to improve the evidence base remain despite the field's rapid growth. Objective: The aim of this study was to examine current National Institutes of Health (NIH) funding of palliative medicine research and trends over time. Design: We sought to identify NIH funding of palliative medicine (2016-2020) in two stages: (1) we searched the NIH grant database, RePORTER, for grants with the keywords, "palliative care," "end-of-life care," "hospice," and "end of life," and (2) identified palliative care researchers likely to have secured NIH funding using three strategies. Methods: We abstracted (1) the first and last authors' names from original investigations published in major palliative medicine journals from 2016 to 2018; (2) names from a PubMed-generated list of original articles published in major medicine, nursing, and subspecialty journals using the above keywords; and (3) palliative medicine journal editorial board members and members of key palliative medicine initiatives. We cross-matched the pooled names against NIH grants funded from 2016 to 2021. Results: A crosswalk analysis of the author search and NIH RePORTER search identified 1658 grants. Of those, 541 were categorized as relevant to palliative medicine, which represented 419 unique principal investigators (mean of 1.34 grants per investigator). Compared with 2011-2015, the number of NIH-funded grants increased by 25%, NIH dollars increased by 35%, and the distribution of grant types remained stable. Conclusions: Despite the challenging NIH funding climate, the number of NIH grants and funding to palliative care have increased. Given the increased funding allocation toward Alzheimer's dementia and related dementia research at the congressional level, this increase in funding reflects this funding allocation and does not represent overall growth. Dedicated federal funding for palliative care research remains critical to grow the evidence base for persons living with serious illnesses and their families.

Improving the Approach to Defining, Classifying, Reporting and Monitoring Adverse Events in Seriously Ill Older Adults: Recommendations from a Multi-stakeholder Convening.

BACKGROUND: Clinical trials are needed to study topics relevant to older adults with serious illness. Investigators conducting clinical trials with this population are challenged by how to appropriately define, classify, report, and monitor serious and non-serious adverse events (SAEs/AEs), given that some traditionally reported AEs (pressure ulcers, delirium) and SAEs (death, hospitalization) are common in persons with serious illness, and may be consistent with their goals of care. OBJECTIVES: A multi-stakeholder group convened to establish greater clarity on and new approaches to address this critical issue. PARTICIPANTS: Thirty-two study investigators, members of regulatory and sponsor agencies, and patient stakeholders took part. APPROACH: The group met virtually four times and, using a collaborative approach, conducted a survey, select interviews, and reviewed regulatory guidance to collectively define the problem and identify a new approach. RESULTS: SAE/AE challenges fell into two areas: (1) definitions and classifications, including (a) implausible relationships, (b) misalignment with patient-centered care goals, and (c) well-known associations, and (2) reporting and monitoring, including (a) limited guidance, (b) inconsistent standards across regulators, and (c) Data Safety Monitoring Board (DSMB) member knowledge gaps. Problems largely reflected practice norms rather than regulatory requirements that already support context-specific and aggregate reporting. Approaches can be improved by adopting principles that better align strategies for addressing adverse events with the type of intervention being tested, favoring routine and aggregate over expedited reporting, and prioritizing how SAE/AEs relate to patient-centered care goals. Reporting plans and decisions should follow an algorithm underpinned by these principles. CONCLUSIONS: Adoption of the proposed approach-and supporting it with education and better alignment with regulatory guidance and procedures-could improve the quality and efficiency of clinical trials' safety involving older adults with serious illness and other vulnerable populations.

Assessment of minority frequency pretreatment HIV drug-resistant variants in pregnant women and associations with virologic non-suppression at term.

OBJECTIVE: To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term. DESIGN: A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls. METHODS: HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared. RESULTS: PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases' median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085). CONCLUSIONS: We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.