AimTo evaluate the efficacy and safety of a fully self-administered, app-based biofeedback intervention for the prevention of episodic migraineMethodsThis open-label, randomized, waitlist-controlled multicenter trial included adults with episodic migraine assigned to 12 weeks of daily biofeedback or a waitlist control. The primary outcome was change in monthly migraine days (MMDs) from baseline to weeks 9-12. Secondary outcomes included migraine intensity, acute medication use, and migraine-specific quality of life (MSQ v2.1). Statistical analyses were performed according to the intention-to-treat principle by a statistician masked to treatment assignment.ResultsOf 1113 individuals screened, 279 participants (mean [SD] age, 41 [10] years; 92% women) were randomized to the intervention (n = 140) or waitlist control (n = 139). Baseline MMDs were 4.8 (2.4) and 4.6 (2.3) in the intervention and control groups, respectively. During weeks 9-12, the estimated reduction in MMDs was 0.9 days (95% CI, -1.4 to -0.5) in the intervention group and 0.0 days (95% CI, -0.5 to 0.4) in the control group (between-group difference, 0.9 days; 95% CI, 0.3 to 1.5; P = 0.002). Participants receiving biofeedback also showed greater improvements in MSQ v2.1 total scores (mean difference, 5.3 points; 95% CI, 2.1 to 8.6; P = 0.001). Nine device-related adverse events occurred, all with mild severity.ConclusionApp-based self-administered biofeedback was associated with a statistically significant reduction in migraine frequency and improved quality of life, with a favorable safety profile.

Abstract Background Women with polycystic ovary syndrome (PCOS) face breastfeeding challenges. We aimed to compare exclusive breastfeeding rates in women with PCOS to those in a population-based cohort, and to explore the effect of metformin and metabolic factors on exclusive breastfeeding in women with PCOS. Methods This cohort study included 653 women from the pilot, PregMet, and PregMet2 randomized trials on metformin in pregnant women with PCOS (2000–2017), and 63,927 women from the Norwegian Mother, Father and Child Cohort Study (MoBa) (1999–2008) as the reference group. Logistic regression estimated odds ratios for exclusive breastfeeding one month postpartum in women with PCOS versus MoBa women, and in women with PCOS randomized to metformin or placebo. Results Women with PCOS reported less exclusive breastfeeding than MoBa women one month postpartum (adjusted OR (aOR) 0.52 (0.42–0.63)). Among women of normal weight, those with PCOS breastfed to the same extent as MoBa women (aOR 0.98 (0.63–1.54)), but less in the overweight or obesity categories (aOR 0.56 (0.39–0.82) and aOR 0.55 (0.40–0.76), respectively). However, differences across weight categories were not statistically significant (p-value for interaction = 0.088). We found no difference in exclusive breastfeeding between metformin and placebo-treated women with PCOS. Hypertensive disorders and gestational diabetes did not affect exclusive breastfeeding rate in PCOS. Conclusions Exclusive breastfeeding did not differ between normal weight women with PCOS and women from the MoBa study. Among women with high BMI, women with PCOS breastfed less exclusively than MoBa women. In PCOS, neither metformin treatment, hypertension nor gestational diabetes affected exclusive breastfeeding.

Background:Biofeedback is an established treatment principle for migraine, but home-based therapy with proven efficacy is not available. Objective:This study aims to assess the feasibility, usability, and safety of 12 weeks of daily use of a novel medical device (Cerebri; Nordic Brain Tech AS) for therapist-independent multimodal biofeedback preventative treatment in adults with episodic migraine. Methods:In this open-label, one-armed trial, 20 adult participants with episodic migraine used Cerebri for 12 weeks. The primary outcome was the feasibility of the Cerebri system, measured by the level of adherence to daily biofeedback and electronic headache diary (eDiary) entries. Secondary outcomes were safety, usability, and efficacy. Results:Initial adherence to biofeedback was high (16/20, 80% in weeks 1-4), declining to 20% (4/20) by weeks 9-12. eDiary adherence remained high (15/20, 75% in weeks 9-12). Reduction in migraine days was not significant (-0.6, 95% CI -2.4 to 1.1 days; P=.47). App usability was impacted by software issues. No safety concerns were reported. Conclusions:Cerebri demonstrates potential in self-managed migraine treatment, with strong initial engagement and high safety. Usability issues, including technical bugs, were identified as the most important modifiable cause for the decline in adherence. This highlights the need for further app refinement to sustain user engagement.

Streptococcal species are human commensals known to colonize multiple body sites. Despite being early gut colonizers, we lack strain-level information about their origin and persistence in the gut. To gain more insight into the habitats of the streptococci present in the infant gut, we did a systematic study where mother-infant pairs were sampled from multiple body sites (stool, oral cavity, vagina, breast milk). We performed whole metagenome sequencing and isolated streptococci from 100 infant stool samples (collected at 10 days of age). To trace the streptococci at the strain level, we designed selective qPCR primers for seven streptococcal strains, and these were later utilized to screen corresponding samples from multiple body sites of the infants and their mothers. We found that two of the strains (one Streptococcus parasanguinis and one Streptococcus vestibularis) were highly prevalent in stool samples, both from infants during their first 2 years of life and from their mothers, indicating that these strains are adapted to the gut environment. Interestingly, another S. parasanguinis strain, closely related to the gut-prevalent strain, showed a completely different prevalence pattern, and was mainly detected in vaginal swabs, breast milk and oral swabs. Comparisons of their genomes revealed major differences in genes encoding adhesins, suggesting that host surface attachment could be a key factor for the observed differences in body site specificity. Together, our extensive tracing of streptococci across body sites of 100 infants and their mothers, provide strain-level information of prevalence patterns and reveal the presence of gut-specific streptococci. ### Competing Interest Statement The authors have declared no competing interest.

IntroductionDelirium is an acute alteration in attention, awareness, arousal, and cognition, precipitated by a sudden illness and highly prevalent in older, frail and acutely hospitalized patients. It is associated with poor outcomes, and few effective treatment alternatives. Non-pharmacological interventions and music show promising effects, warranting further research. This pilot randomized repeated measures trial aims to test feasibility of the trial methodology, acceptability, fidelity and safety of the music interventions, suitability of the effect-outcomes. and preliminary effectiveness.MethodAcute geriatric patients with delirium or subsyndromal delirium will be randomized to Preferred Recorded Music (n = 30) or Preferred Live Music (n = 30), delivered for 30 minutes, over three consecutive days. Planned feasibility outcomes will comprise recruitment rate, retention and attrition rates, percentage of adherence, deviations rates, and success of treatment fidelity. Clinical outcomes will include: (a) trajectory of delirium symptoms: level of arousal as assessed by Observational Scale of Level of Arousal (OSLA) and modified Richmond Agitation Sedation Scale (mRASS); attention, assessed using backwards tests and digit span tests; orientation and short-term memory, assessed using recall tasks and orientation questions from Memorial Delirium Assessment Scale, (b) duration of delirium, (c) length of hospital stay, and (d) use of PRN medication (benzodiazepines and antipsychotics).DiscussionThe trial will provide results needed to design a subsequent sufficiently powered RCT, informing on the expected recruitment, feasibility and acceptability of the interventions and assessments and preliminary effectiveness

Abstract Background To examine whether weekday-to-weekend sleep duration (WWD) difference and specific WWD patterns are associated with mental and somatic health and academic performance in a student population. Methods This study utilized cross-sectional data from the SHoT-2018 survey which includes responses from 50,054 full-time university/college students in Norway. Participants completed online questionnaires and reported sleep duration separately for weekdays and weekends. Medium sleep duration was defined as 7 to 9 h, short sleep duration as < 7 h and long sleep duration as > 9 h. Regression analyses were used to examine whether the degree and patterns of WWD was associated with health-related outcomes and academic performance. Results The mean age of the sample was 23.2 years and comprised of 68.8% women. Most students (81.7%) slept longer on weekends compared to weekdays and 30.0% of the students reported a mean sleep duration shorter than 7 h. WWD difference was positively associated with higher odds of overweight/obesity, dissatisfaction with life, psychological distress, somatic burden and failed study exam. Concerning WWD patterns, the odds of students reporting unfavorably on the outcomes were particularly high for those who slept short on both weekdays and weekends, while those who slept short on weekdays seemed to benefit from sleeping longer (“catching up”) on weekends. Conclusions Overall, WWD was associated with adverse health outcomes for students. Short sleep duration both on weekday and weekend was associated with the most detrimental outcomes in terms of health and academic performance, while sleeping in on weekends may alleviate some of the detriments.

Background The use of molecular methods has led to increased detection of Enteroaggregative Escherichia coli (EAEC) in faecal samples. Studies have yielded conflicting results regarding the clinical relevance of this finding. The objective of this study was to investigate the prevalence of EAEC in faecal samples from patients with diarrhoea and healthy controls and describe characteristics of EAEC positive persons. Methods From March 1st, 2017 to February 28th, 2019, we investigated all consecutive faecal samples from patients with diarrhoea received at the laboratory and collected faecal samples from randomly invited healthy controls from mid-Norway. Real-time multiplex PCR was used for detection of bacterial, viral, and parasitic pathogens. We registered sex, age, urban versus non-urban residency, and travel history for all participants. Statistical analyses were performed with Pearson chi-squared test, Kruskal-Wallis test, and Mann-Whitney U test. Results We identified EAEC in 440 of 9487 (4.6%) patients with diarrhoea and 8 of 375 (2.2%) healthy controls. The EAEC prevalence was 19.1% among those with diarrhoea and recent foreign travel and 2.2% in those without travel history independent of diarrhoea. Concomitant pathogens were detected in 64.3% of EAEC-positive patients with diarrhoea. The median age was 28.5 in those with EAEC-positive diarrhoea and 38 in those with EAEC-negative diarrhoea (p <0.01). In patients with diarrhoea, travel was reported in 72% of those with EAEC and concomitant pathogens, and 54% and 12% in those with only EAEC and no EAEC, respectively (p <0.01). Conclusions EAEC was a common detection, particularly in patients with diarrhoea and recent international travel, and was found together with other intestinal pathogens in the majority of cases. Our results suggest that domestically acquired EAEC is not associated with diarrhoea. Patients with EAEC-positive diarrhoea and concomitant pathogens were young and often reported recent travel history compared to other patients with diarrhoea.

LBA12007 Background: Cancer cachexia arises from the interaction between the host and the tumour, triggering an inflammatory response that leads to weight and appetite loss, diminished physical activity, reduced treatment efficacy and survival. Combining interventions to address inflammation, weight loss, and physical activity is proposed as an effective strategy. Building on a promising pilot study, we conducted the MENAC (Multimodal Exercise Nutrition Anti-inflammatory Cachexia) trial to comprehensively evaluate this approach in patients with lung and pancreatic cancer undergoing systemic anti-cancer treatment (SACT). Methods: MENAC was an investigator-initiated, multicentre, open label, randomised phase 3 trial conducted at 17 sites in 4 countries. Patients with stage III or IV lung or pancreatic cancer receiving SACT with non-curative intent were randomly assigned (1:1) to a multimodal intervention consisting of nutritional counselling plus fish oil containing oral nutritional supplements, physical exercise [endurance and strength] and non-steroidal anti-inflammatory drugs [NSAIDs]) versus standard care. Randomisation was stratified by country, cancer type and stage. Primary Objective: To assess differences between arms in change in body weight. Secondary Objectives: To assess differences in muscle mass (measured by CT L3 technique) and physical activity (assessed through step counts using ActivPAL activity meter) between arms. Assessments were conducted at basline (pre-randomisation) and at endpoint (after 6 weeks). Results: From May 2015 to February 2022, 212 patients were enrolled (105 to multimodal treatment, 107 standard care). Over 6 weeks, weight stabilised in patients assigned to multimodal treatment compared with those assigned to standard care (mean weight change [SD] 0.05 kg [3.8] vs – 0.99 kg [3.2], respectively) with a mean difference in weight change of -1.04, 95 % CI -2.02 to -0.06, p=0.04. There was no conclusive difference in muscle mass (mean change [SD] -6.5cm 2 [ 10.1] vs -6.3cm 2 [11.9], p=0.93) or in mean step counts [SD] (-377.7 [2075] vs -458 [1858], p=0.89). There were 28 and 24 reported SAEs in the intervention and control arm respectively, no SUSARs were reported. Conclusions: A multimodal cachexia intervention stabilised weight compared to standard care at six weeks. There was no difference in physical activity or muscle mass between trial arms. Clinical trial information: NCT02330926 .

Background and aimsThis study explored the associations between symptoms of the Suicide Crisis Syndrome (SCS) at admission and self-harm and death by suicide post-discharge. The association between clinicians' emotional responses toward inpatients at admission and post-discharge self-harm and suicide death was also explored.MethodsWithin the first 24-h of admission, patients completed a self-report measure of symptoms of SCS, and clinicians reported their emotional responses toward the patients. Follow-up data were obtained from the Norwegian Patient Registry and the Norwegian Cause of Death Registry.ResultsWithin 18 months post-discharge, 44 (12.7%) out of 347 patients had self-harmed, and five patients (1.4%) had died by suicide. At admission, patients who later self-harmed reported higher symptoms of SCS compared to the other patients. Clinicians reported more negative emotional responses toward the self-harm group. In a regression analysis, previous suicidal behavior and a diagnosis of "emotionally unstable personality disorder" (EUPD; F60.3) were associated with increased risk of self-harm post-discharge.ConclusionThe results indicated that patients with post-discharge episodes of self-harm are significantly different from patients who do not self-harm in terms of more intense symptoms of SCS during admission. Clinicians' negative emotional responses may be relevant in the assessment of the risk of post-discharge self-harm.

Women with polycystic ovary syndrome (PCOS) have more pregnancy complications like gestational diabetes, hypertension, and preterm labor than other women. Metformin has been used in an attempt to improve pregnancy outcomes. Our study aims to explore childbirth experiences in women with PCOS compared with a reference population. It also explores the potential influence of metformin, obesity, pregnancy complications, and the duration and mode of birth on childbirth experiences. This study is a cohort study combining data from two randomized trials conducted in Norway, Sweden and Iceland. The PregMet2 study ( ClinicalTrials.gov , NCT01587378) investigated the use of metformin vs. placebo in pregnant women with PCOS. The Labour Progression Study ( ClinicalTrials.gov , NCT02221427) compared the WHO partograph to Zhang's guidelines for progression of labor and were used as the reference population. A total of 365 women with PCOS and 3604 reference women were included. Both studies used the Childbirth Experience Questionnaire (CEQ). Main outcome measures were total CEQ score and four domain scores. The CEQ scores were compared using Mann–Whitney U test for women in Robson group 1 with PCOS ( n  = 131) and reference women ( n  = 3604). CEQ scores were also compared between metformin-treated ( n  = 180) and placebo-treated ( n  = 185) women with PCOS, and for different subgroups of women with PCOS. There was no difference in total CEQ score between women with PCOS and reference women—Wilcoxon–Mann–Whitney (WMW)-odds 0.96 (95% confidence interval [CI] 0.78–1.17). We detected no difference in CEQ scores between the metformin- and placebo-treated women with PCOS (WMW-odds 1.13, 95% CI 0.89–1.43). Complications in pregnancy did not affect CEQ (WMW-odds 1, 95% CI 0.76–1.31). Higher body mass index (WMW-odds 0.75, 95% CI 0.58–0.96), longer duration of labor (WMW-odds 0.69, 95% CI 0.49–0.96), and cesarean section (WMW-odds 0.29, 95% CI 0.2–0.42) were associated with lower CEQ scores in women with PCOS. Women with PCOS experience childbirth similarly to the reference women. Metformin did not influence childbirth experience in women with PCOS, neither did pregnancy complications. Obesity, long duration of labor or cesarean section had a negative impact on childbirth experience.

INTRODUCTION:Women with polycystic ovary syndrome (PCOS) have more pregnancy complications like gestational diabetes, hypertension, and preterm labor than other women. Metformin has been used in an attempt to improve pregnancy outcomes. Our study aims to explore childbirth experiences in women with PCOS compared with a reference population. It also explores the potential influence of metformin, obesity, pregnancy complications, and the duration and mode of birth on childbirth experiences. MATERIAL AND METHODS:This study is a cohort study combining data from two randomized trials conducted in Norway, Sweden and Iceland. The PregMet2 study (ClinicalTrials.gov, NCT01587378) investigated the use of metformin vs. placebo in pregnant women with PCOS. The Labour Progression Study (ClinicalTrials.gov, NCT02221427) compared the WHO partograph to Zhang's guidelines for progression of labor and were used as the reference population. A total of 365 women with PCOS and 3604 reference women were included. Both studies used the Childbirth Experience Questionnaire (CEQ). Main outcome measures were total CEQ score and four domain scores. The CEQ scores were compared using Mann-Whitney U test for women in Robson group 1 with PCOS (n = 131) and reference women (n = 3604). CEQ scores were also compared between metformin-treated (n = 180) and placebo-treated (n = 185) women with PCOS, and for different subgroups of women with PCOS. RESULTS:There was no difference in total CEQ score between women with PCOS and reference women-Wilcoxon-Mann-Whitney (WMW)-odds 0.96 (95% confidence interval [CI] 0.78-1.17). We detected no difference in CEQ scores between the metformin- and placebo-treated women with PCOS (WMW-odds 1.13, 95% CI 0.89-1.43). Complications in pregnancy did not affect CEQ (WMW-odds 1, 95% CI 0.76-1.31). Higher body mass index (WMW-odds 0.75, 95% CI 0.58-0.96), longer duration of labor (WMW-odds 0.69, 95% CI 0.49-0.96), and cesarean section (WMW-odds 0.29, 95% CI 0.2-0.42) were associated with lower CEQ scores in women with PCOS. CONCLUSIONS:Women with PCOS experience childbirth similarly to the reference women. Metformin did not influence childbirth experience in women with PCOS, neither did pregnancy complications. Obesity, long duration of labor or cesarean section had a negative impact on childbirth experience.

AbstractRegulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety‐nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C‐reactive protein (n = 22, 42.3%), interleukin‐6 (n = 16, 30.8%) and tumour necrosis factor‐α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin‐like growth factor binding protein 3 (IGFBP‐3) and insulin‐like growth factor 1 (IGF‐1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP‐3, IGF‐1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

BACKGROUND:The impact of light exposure on mental health is increasingly recognised. Modifying inpatient evening light exposure may be a low-intensity intervention for mental disorders, but few randomised controlled trials (RCTs) exist. We report a large-scale pragmatic effectiveness RCT exploring whether individuals with acute psychiatric illnesses experience additional benefits from admission to an inpatient ward where changes in the evening light exposure are integrated into the therapeutic environment. METHODS AND FINDINGS:From 10/25/2018 to 03/29/2019, and 10/01/2019 to 11/15/2019, all adults (≥18 years of age) admitted for acute inpatient psychiatric care in Trondheim, Norway, were randomly allocated to a ward with a blue-depleted evening light environment or a ward with a standard light environment. Baseline and outcome data for individuals who provided deferred informed consent were used. The primary outcome measure was the mean duration of admission in days per individual. Secondary outcomes were estimated mean differences in key clinical outcomes: Improvement during admission (The Clinical Global Impressions Scale-Improvement, CGI-I) and illness severity at discharge (CGI-S), aggressive behaviour during admission (Broset Violence Checklist, BVC), violent incidents (Staff Observation Aggression Scale-Revised, SOAS-R), side effects and patient satisfaction, probabilities of suicidality, need for supervision due to suicidality, and change from involuntary to voluntary admission. The Intent to Treat sample comprised 476 individuals (mean age 37 (standard deviation (SD) 13.3); 193 (41%) were male, 283 (59%) were female). There were no differences in the mean duration of admission (7.1 days for inpatients exposed to the blue-depleted evening light environment versus 6.7 days for patients exposed to the standard evening light environment; estimated mean difference: 0.4 days (95% confidence interval (CI) [-0.9, 1.9]; p = 0.523). Inpatients exposed to the blue-depleted evening light showed higher improvement during admission (CGI-I difference 0.28 (95% CI [0.02, 0.54]; p = 0.035), Number Needed to Treat for clinically meaningful improvement (NNT): 12); lower illness severity at discharge (CGI-S difference -0.18 (95% CI [-0.34, -0.02]; p = 0.029), NNT for mild severity at discharge: 7); and lower levels of aggressive behaviour (difference in BVC predicted serious events per 100 days: -2.98 (95% CI [-4.98, -0.99]; p = 0.003), NNT: 9). There were no differences in other secondary outcomes. The nature of this study meant it was impossible to blind patients or clinical staff to the lighting condition. CONCLUSIONS:Modifying the evening light environment in acute psychiatric hospitals according to chronobiological principles does not change duration of admissions but can have clinically significant benefits without increasing side effects, reducing patient satisfaction or requiring additional clinical staff. TRIAL REGISTRATION:Clinicaltrials.gov NCT03788993; 2018 (CRISTIN ID 602154).

ImportancePolycystic ovary syndrome (PCOS) is a common endocrine disorder, characterized by subfertility, increased risk of metabolic diseases, and pregnancy complications. Previous studies diverge regarding the association between maternal PCOS and newborn anthropometrics.ObjectiveTo explore the association between maternal PCOS and newborn anthropometrics and the modifying effects of maternal body mass index, PCOS phenotype, and gestational diabetes.Design, Setting, and ParticipantsThis cohort study followed up women from the first half of pregnancy to birth and combined data from 3 clinical trials of pregnant women with PCOS and a reference population consisting of participants in the Norwegian Mother, Father, and Child Cohort (MoBa) Study, with data from the Medical Birth Registry of Norway. The recruitment period for the clinical trials was between October 1, 2000, and August 31, 2017, and for MoBa, between July 1, 1999, and December 31, 2008. Participants included women with singleton pregnancies and live-born children. Data were analyzed from January 1 to June 15, 2023.ExposureMaternal PCOS status.Main Outcomes and MeasuresNewborn birth weight, birth length, and head circumference as continuous variables and z scores, and ponderal index (calculated as the birth weight in grams × 100 divided by the birth length in centimeters cubed), placenta weight, and ratio of birth weight to placenta weight (BWPW).ResultsThe cohort included 390 pregnant women with PCOS (mean [SD] age, 29.6 [4.2] years) and 68 708 women in the reference group (mean [SD] age, 30.4 [4.5] years). Offspring in the PCOS group had lower birth weight, birth length, and head circumference than in the reference group offspring. The estimated mean differences in z scores were −0.26 (95% CI, −0.38 to −0.14) for birth weight, −0.19 (95% CI, −0.33 to −0.05) for birth length, and −0.13 (95% CI, −0.26 to −0.01) for head circumference. The PCOS group also had a lower ponderal index (−0.04 [95% CI, −0.07 to −0.004] g × 100/cm3) and placenta weight (−24 [95% CI, −43 to −5)] g), and higher BWPW ratio (0.4 [95% CI, 0.3 to 0.5]). The association between growth restriction and PCOS was more apparent when additionally adjusting for body mass index. Neither PCOS phenotype nor gestational diabetes diagnosis was associated with neonatal anthropometry in women with PCOS.Conclusions and RelevanceIn this cohort of mother-infant pairs, maternal PCOS status was associated with lower birth weight, shorter birth length, and smaller head circumference in the offspring. This growth restriction was more pronounced when adjusting for BMI, providing insight into the association between PCOS and body mass index. The study contributed to the understanding of how PCOS affects the offspring.

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

Abstract There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40–628). Forty‐nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24‐h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

AbstractThe use of patient‐reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self‐report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990–2023). Seven thousand four hundred thirty‐five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full‐text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty‐four (48%) were double‐blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty‐nine trials (78%) included multiple cancer types. Twenty‐seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4–96). The most frequent QOL measure was the EORTC QLQ‐C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well‐validated QOL measures, including cachexia‐specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co‐primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific‐based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.

The World Allergy Organization recommends probiotics in the prevention of atopic dermatitis in high-risk populations. Mutations in the filaggrin gene (FLG) result in an increased risk of atopic dermatitis through disruption of the skin keratin layer. This exploratory study investigated whether the preventive effect of maternal probiotics was evident in children with and without FLG mutations. DNA was collected from children (n = 228) from the Probiotic in the Prevention of Allergy among Children in Trondheim (ProPACT) study. Samples were analysed for 3 common FLG mutations (R501X, R2447X, and 2282del4). Overall, 7% of children had heterozygous FLG mutations; each child had only one of the 3 mutations. Mutation status had no association with atopic dermatitis (RR = 1.1; 95% CI 0.5 to 2.3). The risk ratio (RR) for having atopic dermatitis following maternal probiotics was 0.6 (95% CI 0.4 to 0.9) and RR was similar if the child expressed an FLG mutation (RR = 0.6; 95% CI 0.1 to 4.1) or wildtype FLG (RR = 0.6; 95% CI 0.4 to 0.9). The preventive effect of probiotics for atopic dermatitis was also evident in children without FLG mutation. Larger confirmatory studies are needed.