Uncertainty in serious illness: A national interdisciplinary consensus exercise to identify clinical research priorities.

BACKGROUND: Serious illness is characterised by uncertainty, particularly in older age groups. Uncertainty may be experienced by patients, family carers, and health professionals about a broad variety of issues. There are many evidence gaps regarding the experience and management of uncertainty. AIM: We aimed to identify priority research areas concerning uncertainty in serious illness, to ensure that future research better meets the needs of those affected by uncertainty and reduce research inefficiencies. METHODS: Rapid prioritisation workshop comprising five focus groups to identify research areas, followed by a ranking exercise to prioritise them. Participants were healthcare professionals caring for those with serious illnesses including geriatrics, palliative care, intensive care; researchers; patient/carer representatives, and policymakers. Descriptive analysis of ranking data and qualitative framework analysis of focus group transcripts was undertaken. RESULTS: Thirty-four participants took part; 67% female, mean age 47 (range 33-67). The highest priority was communication of uncertainty, ranked first by 15 participants (overall ranking score 1.59/3). Subsequent priorities were: 2) How to cope with uncertainty; 3) healthcare professional education/training; 4) Optimising clinical approaches to uncertainty; and 5) exploring in-depth experiences of uncertainty. Research questions regarding optimal management of uncertainty were given higher priority than questions about experiences of uncertainty and its impact. CONCLUSIONS: These co-produced, clinically-focused research priorities map out key evidence gaps concerning uncertainty in serious illness. Managing uncertainty is the most pressing issue, and researchers should prioritise how to optimally manage uncertainty in order to reduce distress, unlock decision paralysis and improve illness and care experience.

Anticipatory prescribing in community end-of-life care: systematic review and narrative synthesis of the evidence since 2017.

BACKGROUND: The anticipatory prescribing of injectable medications is recommended practice in controlling distressing symptoms in the last days of life. A 2017 systematic review found practice and guidance was based on inadequate evidence. Since then, there has been considerable additional research, warranting a new review. AIM: To review the evidence published since 2017 concerning anticipatory prescribing of injectable medications for adults at the end-of-life in the community, to inform practice and guidance. DESIGN: Systematic review and narrative synthesis. METHODS: Nine literature databases were searched from May 2017 to March 2022, alongside reference, citation and journal hand-searches. Gough's Weight of Evidence framework was used to appraise included studies. RESULTS: Twenty-eight papers were included in the synthesis. Evidence published since 2017 shows that standardised prescribing of four medications for anticipated symptoms is commonplace in the UK; evidence of practices in other countries is limited. There is limited data on how often medications are administered in the community. Prescriptions are 'accepted' by family caregivers despite inadequate explanations and they generally appreciate having access to medications. Robust evidence of the clinical and cost-effectiveness of anticipatory prescribing remains absent. CONCLUSION: The evidence underpinning anticipatory prescribing practice and policy remains based primarily on healthcare professionals' perceptions that the intervention is reassuring, provides effective, timely symptom relief in the community and prevents crisis hospital admissions. There is still inadequate evidence regarding optimal medications and dose ranges, and the effectiveness of these prescriptions. Patient and family caregiver experiences of anticipatory prescriptions warrant urgent investigation. PROSPERO REGISTRATION: CRD42016052108.

Total uncertainty: a systematic review and thematic synthesis of experiences of uncertainty in older people with advanced multimorbidity, their informal carers and health professionals.

OBJECTIVES: uncertainty pervades the complex illness trajectories experienced by older adults with multimorbidity. Uncertainty is experienced by older people, their informal carers and professionals providing care, yet is incompletely understood. We aimed to identify and synthesise systematically the experience of uncertainty in advanced multimorbidity from patient, carer and professional perspectives. DESIGN: systematic literature review of published and grey qualitative literature from 9 databases (Prospero CRD 42021227480). PARTICIPANTS: older people with advanced multimorbidity, and informal carers/professionals providing care to this group. Exclusion criteria: early multimorbidity, insufficient focus on uncertainty. ANALYSIS: weight-of-evidence assessment was used to appraise included articles. We undertook thematic synthesis of multi-perspective experiences and response to uncertainty. RESULTS: from 4,738 unique search results, we included 44 articles relating to 40 studies. 22 focused on patient experiences of uncertainty (n = 460), 15 on carer experiences (n = 197), and 19 on health professional experiences (n = 490), with 10 exploring multiple perspectives. We identified a shared experience of 'Total Uncertainty' across five domains: 'appraising and managing multiple illnesses'; 'fragmented care and communication'; 'feeling overwhelmed'; 'uncertainty of others' and 'continual change'. Participants responded to uncertainty by either active (addressing, avoiding) or passive (accepting) means. CONCLUSIONS: the novel concept of 'Total Uncertainty' represents a step change in our understanding of illness experience in advanced multimorbidity. Patients, carers and health professionals experienced uncertainty in similar domains, suggesting a shared understanding is feasible. The domains of total uncertainty form a useful organising framework for health professionals caring for older adults with multimorbidity.

The associations between maternal BMI and gestational weight gain and health outcomes in offspring at age 1 and 7 years.

In secondary analyses of a randomised controlled trial of exercise during pregnancy, we examined associations between mid-pregnancy maternal body mass index (BMI) and excessive gestational weight gain (GWG) with offspring health. Follow-up data were available on 57 mother-child pairs at 1-year and 52 pairs at 7-year follow-ups. Clinical assessments included body composition and fasting blood tests. At age 1 year, increased maternal BMI in mid-gestation was associated with greater weight standard deviation scores (SDS) in the offspring (p = 0.035), with no observed associations for excessive GWG. At age 7 years, greater maternal BMI was associated with increased weight SDS (p < 0.001), BMI SDS (p = 0.005), and total body fat percentage (p = 0.037) in their children. Irrespective of maternal BMI, children born to mothers with excessive GWG had greater abdominal adiposity (p = 0.043) and less favourable lipid profile (lower HDL-C and higher triglycerides). At 7 years, maternal BMI and excessive GWG had compounded adverse associations with offspring adiposity. Compared to offspring of mothers with overweight/obesity plus excessive GWG, children of normal-weight mothers with adequate and excessive GWG were 0.97 and 0.64 SDS lighter (p = 0.002 and p = 0.014, respectively), and 0.98 and 0.63 SDS leaner (p = 0.001 and p = 0.014, respectively). Both greater maternal BMI in mid-pregnancy and excessive GWG were independently associated with increased adiposity in offspring at 7 years.

Gamifying Parenting Education Using an App Developed for Pacific and Other New Zealand Families (Play Kindly): Qualitative Study.

BACKGROUND: Play Kindly is a gamified animated app designed to address common behavioral problems in childhood. The interface is designed to appeal to Pacific people, a population group with a higher risk of developing clinically significant behavioral problems than most other ethnic groups in New Zealand. OBJECTIVE: The aim of this study is to explore the opinions of parents and professionals about the acceptability, usability, and content of Play Kindly. METHODS: We used qualitative and Pacific and Maori research methodologies. A total of five focus groups with 45 parents and 12 individual interviews with professionals were conducted. The five focus groups consisted of 2 pan-Pacific groups, 1 Maori group, 1 open group, and 1 group of young Pacific adults or prospective parents. The professionals were from a range of disciplines, and the majority had expertise in early childhood, parenting interventions, or research in this field. RESULTS: Play Kindly appealed to both parents and professionals. Participants related to the scenarios, which were created in collaboration with a playwright and animator. Although most participants liked the Pacific feel, there was some disagreement about how culturally specific the app should be. A range of issues with usability and gamification techniques were highlighted, likely attributed to the low budget and lack of initial co-design with parents as well as professionals with specific expertise in parenting. A number of parents and professionals felt that the parenting strategies were overly simplified and did not take into account the context in which the behavior occurred. Professionals suggested narrowing the focus of the app to deliver two important parenting messages: playing with your child and positively reinforcing desired behaviors. CONCLUSIONS: Play Kindly is the first culturally adapted parenting app of its kind designed for Pacific parents and other New Zealanders with children 2-5 years of age. This app has potential in Pacific communities where there are limited culturally specific parenting resources. The results of this study will guide improvements of the app prior to testing it in an open trial.

Advance care plans and hospitalized frail older adults: a systematic review.

INTRODUCTION: Frail older people are known to have low rates of advance care planning (ACP). Many frail patients prefer less aggressive treatment, but these preferences are often not known or respected. Frail patients often have multiple hospital admissions, potentially providing opportunities for ACP. OBJECTIVE: To systematically review the literature concerning ACP with frail older people in the acute hospital, with particular reference to: (1) Does ACP improve outcomes? (2) What are the views of patients, relatives and healthcare professionals regarding ACP? (3) Does ACP currently occur? (4) What are the facilitators and barriers to ACP? DESIGN: Systematic literature review and narrative synthesis. Electronic search of MEDLINE, CINAHL, ASSIA, PsycINFO and Embase databases from January 1990 to May 2019 inclusive. Studies in the acute setting of populations with a mean age >75 years, not focused on a disease-specific terminal condition were included. RESULTS: 16 133 articles were retrieved, 14 met inclusion criteria. No studies used an objective measure of frailty. One randomised controlled trial (RCT) found that ACP improves outcomes for older patients. Although 74%-84% of capacitous older inpatients are receptive to ACP, rates of ACP are 0%-5%; the reasons for this discrepancy have been little studied. The nature of ACP in clinical practice is unknown thus the extent to which it reflects the RCT intervention cannot be assessed. The outcomes that are important to patients are poorly understood and family and physician experiences have not been explored. CONCLUSIONS: A better understanding of this area could help to improve end-of-life care for frail older people. PROSPERO REGISTRATION NUMBER: CRD42017080246.

Exercise in pregnancy: 1-year and 7-year follow-ups of mothers and offspring after a randomized controlled trial.

There are limited data on long-term outcomes of mothers or their offspring following exercise interventions during pregnancy. We assessed long-term effects of an exercise intervention (home-based stationary cycling) between 20-36 weeks of gestation on anthropometry and body composition in mothers and offspring after 1 and 7 years. 84 women were randomised to intervention or usual activity, with follow-up data available for 61 mother-child pairs (38 exercisers) at 1 year and 57 (33 exercisers) at 7 years. At 1 year, there were no observed differences in measured outcomes between mothers and offspring in the two groups. At the 7-year follow-up, mothers were mostly similar, except that exercisers had lower systolic blood pressure (-6.2 mmHg; p = 0.049). However, offspring of mothers who exercised during pregnancy had increased total body fat (+3.2%; p = 0.034) and greater abdominal (+4.1% android fat; p = 0.040) and gynoid (+3.5% gynoid fat; p = 0.042) adiposity compared with controls. Exercise interventions beginning during pregnancy may be beneficial to long-term maternal health. However, the initiation of exercise during pregnancy amongst sedentary mothers may be associated with adverse effects in the offspring during childhood. Larger follow-up studies are required to investigate long-term effects of exercise in pregnancy.

Characteristics of Recurrent Large-for-Gestational-Age Infants in Obese Women.

Objective The objective of this study was to identify characteristics associated with recurrent large-for-gestational-age (LGA) infants in obese women and to explore the relationship between interpregnancy weight change and gestational weight gain (GWG) on risk of recurrence. Study Design We conducted a population-based historical cohort study of 1,190 obese women in Missouri who delivered LGA infants in their first pregnancy with two consecutive pregnancies resulting in singleton live births during 1998 to 2005. Adjusted odds ratios (aORs) for recurrent LGA infants were calculated with multiple logistic regression. Population-attributable risk assessed the relative importance of specific characteristics. Results A second LGA infant was delivered by 501 women (42%). Recurrence of LGA infants was associated with GWG (aOR, 1.03 [per pound]; 95% confidence interval [CI], 1.02-1.04), maternal age (aOR, 1.05 [per year]; 95% CI, 1.02-1.08), birth weight of the first LGA infant (aOR, 1.001 [per gram]; 95% CI, 1.000-1.001), being married (aOR, 1.71; 95% CI, 1.02-2.49), diabetes (aOR, 1.79; 95% CI, 1.24-2.59), and pre-pregnancy body mass index (BMI) (aOR, 1.04 [per unit BMI]; 95% CI, 1.02-1.06). Excessive GWG contributed the most to LGA infant recurrence (13%). Interpregnancy weight change was not significantly associated with LGA infant recurrence. Conclusion Lower pre-pregnancy BMI and reduced GWG may mitigate the risk of recurrent LGA infants in obese women.

Key emerging issues in frontotemporal dementia.

Frontotemporal dementia (FTD) encompasses the syndromes of behavioural variant FTD (bvFTD) and primary progressive aphasia (PPA) and refers to those neurodegenerative diseases characterised by predominant pathological involvement of the frontal and temporal lobes. Recent years have witnessed major advances in the clinical characterisation of FTD, reflected in the publication of updated diagnostic criteria for bvFTD and PPA, and the discovery of new pathogenic mutations has added to the understanding of genotype-phenotype interactions and of disease mechanisms. Emerging results from longitudinal studies of familial FTD show that imaging and cognitive changes occur years before symptom onset and such studies may yield biomarkers of early disease that in turn will facilitate earlier diagnosis. The hope and (guarded) expectation is that these advances may together herald the beginning of the end of the chapter in which FTD is considered an inexorably progressive and untreatable condition.

Fifty Percent Prevalence of Extracampine Hallucinations in Parkinson's Disease Patients.

Extracampine hallucinations (EH), the sense of a presence or fleeting movement in the absence of an associated visual percept, have been reported in Parkinson's disease (PD) patients but their prevalence, characteristics, and temporal relationship to visual hallucinations (VH) remain unclear. Given that, VH are predictive of cognitive impairment in PD, improved understanding of EH may have significant prognostic implications. The objective of this study is to evaluate the prevalence and characteristics of EH in a large unselected population with PD and to assess the temporal relationship between EH, VH, and memory decline. Cross-sectional data were collected from 414 PD patients using a questionnaire circulated via an online patient community. Data were obtained regarding the occurrence, timing, and characteristics of VH and EH and symptoms of PD, disease duration, disease severity, and medication history. About 50.4% of respondents reported EH and 15.5% reported VH. EH were typically experienced alongside, rather than behind, the individual (p < 0.001) without clear lateralization (p = 0.438) and were more likely to be of unfamiliar presences (p < 0.001). The occurrence of EH was associated with Hoehn and Yahr score (p = 0.002) but not disease duration (p = 0.158). EH onset was associated with VH onset (p = 0.046) and occurred after the onset of anosmia (p < 0.001), cognitive decline (p = 0.002), and sleep disturbance (p = 0.002). The reported prevalence of EH in PD patients was threefold greater than that of VH, with similar timings of onset, suggesting that EH are under-recognized and under-reported. Further work is needed to determine whether EH are predictive of cognitive decline.

The role of exercise in reducing the risks of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and is particularly prevalent among obese women. Both GDM and obesity confer significant comorbidities for the mother and her offspring, including perinatal complications, excessive fetal growth and long-term risks for maternal and offspring obesity and diabetes. Exercise has well-documented health benefits and reduces peripheral insulin resistance in nonpregnant individuals, a major risk factor for the development of diabetes. Observational studies conducted in large population-based cohorts suggest that women who are the most active before pregnancy are less insulin-resistant in late pregnancy and have lower rates of GDM. This article will review the evidence supporting a role for exercise in the prevention of GDM, the management of glycemic control in women with established GDM, and the reduction of GDM-associated maternal and offspring health consequences. Wherever possible, the discussion will focus on studies carried out on obese women. However, there are many areas where strong evidence is lacking in obese populations, and it may be inferred from similar studies performed in normal weight pregnant women.

Autoimmune limbic encephalitis presenting as relapsing psychosis.

A 34-year-old woman with a history of relapsing psychosis presented with a 15-month history of impassivity and social withdrawal associated with cognitive impairment. The subsequent recurrence of psychomotor agitation, auditory hallucinations and delusional thinking resulted in an emergency admission under psychiatric services. Initial investigations, including MRI of the brain and cerebrospinal fluid studies were unremarkable and she was treated for a primary psychiatric disorder. The diagnosis of autoimmune limbic encephalitis was established after further investigations revealed the presence of antibodies to the NR1 subunit of the N-Methyl-d-aspartate receptor (NMDAR). Immunotherapy resulted in rapid resolution of psychosis and marked improvement in cognitive and social function. This case underlines the importance of considering anti-NMDAR encephalitis within the differential diagnosis of psychosis associated with cognitive impairment even in those with an apparent previous psychiatric history and response to antipsychotics.

Phenotypic differences in children conceived from fresh and thawed embryos in in vitro fertilization compared with naturally conceived children.

OBJECTIVE: To determine whether anthropometric and biochemical features differ in in vitro fertilization (IVF) children conceived via fresh (IVFF) or thawed (IVFT) embryo transfer compared with naturally conceived controls. DESIGN: A cross-sectional controlled study. SETTING: University clinical research unit. PATIENT(S): Healthy prepubertal children (3.5-11.0 years), singletons, born at term (>37 weeks), who were either naturally conceived (controls; n = 94) or IVF children conceived via the transfer of a fresh (IVFF; n = 72) or thawed (IVFT; n = 43) embryo. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assessments of anthropometry (adjusted for parental variables), dual-energy X-ray absorptiometry-derived body composition, fasting plasma growth factors, lipids, and parameters of glucose regulation. RESULT(S): The IVFF but not the IVFT children weighed less at birth than the control children. The IVFF children were taller than both the controls and IVFT children. Sex-specific analyses showed height differences among girls, with IVFF girls being taller than their control and IVFT counterparts. Taller stature in IVFF children was associated with increased insulin-like growth factor I (IGF-I) concentrations compared with controls, whereas the IVFT children displayed increased IGF-II and decreased insulin-like growth factor binding protein 3 (IGFBP-3) concentrations compared with the controls. More favorable lipid profiles were also evident in IVFF but not IVFT children compared with the control children. CONCLUSION(S): These preliminary findings highlight that the transfer of a fresh versus a thawed IVF embryo affects height, plasma growth factor, and lipid profiles in childhood. Therefore, embryo derivation should be considered when assessing physical and biochemical phenotype of IVF children.

The impact of interpregnancy weight change on birthweight in obese women.

OBJECTIVE: The purpose of this study was to estimate the impact of interpregnancy weight change from first to second pregnancies in obese women on the risk of large-for-gestational-age (LGA) and small-for-gestational-age (SGA) infants. STUDY DESIGN: A population-based historical cohort analysis of 10,444 obese women in Missouri who delivered their first 2 singleton live infants from 1998-2005. Interpregnancy weight change was calculated as the difference between prepregnancy body mass index (BMI) of the first and second pregnancies. LGA and SGA births were compared among 3 interpregnancy weight change groups: (1) weight loss (≥2 BMI units), (2) weight gain (≥2 BMI units), and (3) reference group (BMI maintained within 2 units). Adjusted odds ratios (aOR) were calculated for LGA and SGA births with the use of multiple logistic regression. A dose-response relationship was assessed with a linear-by-linear χ(2) test. RESULTS: Compared with the reference group, interpregnancy weight loss was associated with lower risk of an LGA infant (aOR, 0.61; 95% confidence interval, 0.52-0.73), whereas interpregnancy weight gain was associated with increased risk of an LGA infant (aOR, 1.37; 95% confidence interval, 1.21-1.54). Interpregnancy BMI change was not related to SGA infant risk, except for weight loss of >8 BMI units. A significant dose-response relationship was observed for LGA infant risk (P < .001), but not SGA infant risk (P = .840). CONCLUSION: Mild-to-moderate interpregnancy weight loss in obese women reduced the risk of subsequent birth of LGA infants without increasing the risk of SGA infants. The interpregnancy interval may be a crucial period for targeting weight loss in obese women.

Exercise in pregnancy: weighing up the long-term impact on the next generation.

There is now a large body of evidence demonstrating the influence of the in utero environment on postnatal growth. Regular aerobic exercise during pregnancy elicits maternal and fetal adaptations that seem specific to the period of gestation in which training is initiated and maintained. This review considers the evidence for both positive and negative long-term health outcomes for offspring.

Effects of exercise training on maternal hormonal changes in pregnancy.

CONTEXT & OBJECTIVE: A recent paper by our group reported that regular aerobic exercise during pregnancy led to lower foetal IGF-I and IGF-II concentrations and a modest reduction in offspring birth weight when compared with the offspring of nontraining control participants. Maternal hormonal alterations in response to exercise training may be associated with the regulation of nutrient availability for foetal growth through placental regulation of maternal metabolism. OBJECTIVE: To determine whether the reduction in offspring size was associated with changes in the maternal IGF axis [including placental growth hormone (PGH)], leptin and/or free fatty acids (FFA) in response to aerobic exercise training in the second half of pregnancy. DESIGN AND SETTING: A randomized, controlled trial of exercise in pregnancy. PATIENTS: Eighty-four healthy nulliparous women (mean±SD age 30±4 year, BMI 25·5±4 kg/m(2) ). MEASUREMENTS: Serum samples were drawn at 19 and 35 weeks gestation to determine serum IGF-I, IGF-II, IGF-binding protein-1, IGF-binding protein-3, PGH, leptin and FFA. RESULTS: Exercise training in pregnancy had no impact on the pregnancy-related changes in the maternal IGF axis. Women in the exercise group experienced a 29% increase in leptin in late gestation (P=0·026 vs control) and a trend towards lower FFA (P=0·07 vs control). Late pregnancy changes in maternal leptin were inversely related to offspring birth weight (r= -0·24, P<0·05) and BMI (r= -0·25, P<0·05). CONCLUSIONS: An increase in leptin in exercising pregnant women may reflect subtle changes within the placenta in response to regular exercise and may contribute to the reduction in offspring size previously reported in this cohort.

Exercise training in pregnancy reduces offspring size without changes in maternal insulin sensitivity.

CONTEXT: Epidemiological studies have identified the importance of the in utero environment in providing a healthy start to life. Previous studies have suggested that the maternal environment, in particular a reduction in maternal insulin sensitivity, contributes significantly to fetal growth. Regular aerobic exercise, through an effect on maternal insulin sensitivity, may influence offspring size by regulating nutrient supply to the fetus. OBJECTIVE: The aim of the study was to determine the effects of aerobic exercise training in the second half of pregnancy on maternal insulin sensitivity and neonatal outcomes. DESIGN AND SETTING: We conducted a community-based, randomized, controlled trial of exercise in pregnancy. PARTICIPANTS: Eighty-four healthy nulliparous women (mean +/- sd, age, 30 +/- 4 yr; body mass index, 25.5 +/- 4 kg/m(2)) participated in the study. INTERVENTION: Subjects participated in a home-based stationary cycling program from 20 wk gestation to delivery. MAIN OUTCOME MEASURES: Maternal insulin sensitivity, neonatal auxology, body composition, and growth-related peptides in cord blood were measured. RESULTS: Offspring of exercisers had lower birth weight (sd score, control, 0.23 +/- 0.8; exercise, -0.19 +/- 0.9; P = 0.03) and body mass index at birth (sd score, control, 0.40 +/- 0.9; exercise, -0.01 +/- 0.09; P = 0.04). The reduction in maternal insulin sensitivity in late gestation was not affected by exercise (P = 0.45) and was unrelated to offspring size. Exercise offspring had lower cord serum IGF-I (P = 0.03) and IGF-II (P = 0.04). CONCLUSIONS: Regular exercise was associated with lower birth weights and reduced cord concentrations of growth-related peptides, suggesting an influence of exercise on endocrine regulation of fetal growth. These effects on offspring growth were not associated with an exercise training effect on maternal insulin sensitivity.