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At least 19 recordsLinked to original sources

PubMed2026

Patient expectations assessed before randomisation and after the first treatment session, and their associations with pain outcome at 3 months in patients with tennis elbow: a secondary analysis of a randomised controlled feasibility trial in Norwegian secondary care.

OBJECTIVE: To evaluate patients' expectations of pain improvement before randomisation (T1) and after the first treatment (T2), and to examine how expectations at these two time points were associated with pain outcome measured at 3 months (T3). DESIGN: Exploratory secondary analyses of a three-arm, randomised controlled feasibility trial in patients with tennis elbow comparing heavy slow resistance training, shock wave therapy and advice (1:1:1). SETTING: Outpatient clinic at Oslo University Hospital. PARTICIPANTS: Adults with lateral epicondylalgia, commonly known as tennis elbow. MAIN OUTCOME MEASURES: Expected pain was rated on a Numeric Rating Scale (NRS, 0-10) at T1 and T2. Present pain (NRS, 0-10) was reported at 3 months (T3). Changes in expectations from T1 to T2 were summarised descriptively. Univariable linear regressions assessed associations between T3 pain and expectations at T1 and T2, treatment group and baseline factors. Explained variance was quantified by R2. Multivariable models including demographics and baseline pain were evaluated via adjusted R2. RESULTS: Fifty-four participants were included. In the shock wave group, nine (47%) came to expect greater improvement from T1 to T2; by contrast, in the advice group, seven (41%) expected less improvement. Expectations at T1 were not associated with T3 pain, whereas expectations at T2 were positively associated with T3 pain (b=0.61, 95% CI 0.33 to 0.89, p<0.01, R2=0.27), suggesting that higher expected pain at T2 was associated with higher reported pain at T3. Adding education and baseline pain increased explained variance modestly (R2 from 0.27 to 0.32). CONCLUSION: In this study, expectations measured after randomisation and one treatment session were associated with pain at 3 months for patients with tennis elbow. Larger, prospectively designed studies should investigate how postrandomisation expectations relate to clinical outcomes in non-blinded musculoskeletal trials. TRIAL REGISTRATION NUMBER: NCT04803825.

Humans↗

PubMed2026

Feasibility, Satisfaction, and Preliminary Efficacy Trial of text4FATHER for Engaging Expectant Fathers in Infant Care from Pregnancy to Early Infancy.

Engaging fathers perinatally improves infant outcomes and parent well-being, yet few strategies share evidence with fathers. We explored the feasibility, acceptability, and preliminary efficacy of text4FATHER-a texting intervention designed to improve fathers' infant care beliefs, self-efficacy, behaviors, and partner support from mid-pregnancy to 2 months post-birth. In this exploratory pilot randomized controlled trial, 97 adult expectant fathers with less than a college degree were randomized to receive text4FATHER or not. Self-reported outcomes by fathers and mothers were assessed at baseline (mid-pregnancy) and 2 months post-birth. We analyzed intent-to-treat effects using random coefficient regression models. We found recruiting expectant fathers feasible; of eligible father-mother dyads, 123/163 consented (recruitment feasibility = 68%). All intervention fathers (100%) reported being satisfied with text4FATHER; 100% of mothers of intervention fathers also reported satisfaction with the father getting texts. First-time fathers' antenatal attachment beliefs and coparenting support were higher in text4FATHER condition vs. control from baseline to 7-month follow-up; increases in first-time fathers' confidence in fathering and infant care were also observed-the latter finding was corroborated by partners of first-time fathers. text4FATHER is a promising intervention, particularly for first-time expectant fathers with lower educational levels who have no natural clinical or public health touchpoints. Its efficacy and effectiveness should be confirmed using larger and more diverse samples.

Confidence↗

PubMed2024

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Journal Article↗

PubMed2026

In C5-heterozygous intercrosses, the proportion of C5-homozygous-null female offspring exceeds the expected Mendelian ratio.

The complement system has functions beyond host defense, including roles in development and reproduction. However, the role of complement C5 in fertilization and early embryonic development remains unclear. Here, we investigated the reproductive phenotype of C5-deficient mice on a BALB/c background. C5-/- mice were fertile and showed no obvious reproductive abnormalities under standard laboratory housing conditions. However, offspring from C5+/- × C5+/- mating showed a significant deviation from the expected Mendelian distribution, with an increased proportion of female C5-/- offspring, whereas male offspring showed no comparable distortion. In vitro fertilization reproduced this skewed ratio which was detectable at the blastocyst stage, suggesting that the underlying mechanism operates during fertilization or preimplantation development. Parent-of-origin analysis further suggested a contribution of maternal C5. During preimplantation development, C5, C5a receptor 1 (C5ar1), and C5a receptor 2 (C5ar2) mRNA levels showed distinct dynamic expression profiles. These findings revealed an unexpected sex- and genotype-dependent reproductive phenotype associated with C5 deficiency and suggest that C5-dependent signaling may contribute to genotype-dependent selection during fertilization or preimplantation development. The dynamic expression of C5a receptors further supports a potential role for C5a signaling in early embryonic development and expands the biological role of complement beyond immune defense to include regulation of mammalian reproduction.

complement↗

PubMed2026

Genetic testing and reporting: What the endocrinologists should know and can expect (Joint position paper of the ENDO-ERN).

Over the last decade, next generation sequencing (NGS) has become an essential tool for diagnostic DNA testing in human genetics. To improve the understanding of available genetic testing strategies and to facilitate the request of genetic testing in daily endocrine practice, clinical and laboratory experts in the field have summarized the major issues which should be known and considered. In this joint position paper of the ENDO-ERN, the roles and responsibilities of the health care professionals involved in the diagnostic workflow are described, and the major issues concerning genetic testing workflows are overviewed. These issues encompass all relevant steps, including test request and pre-analytical procedures, laboratory and data processing workflows, quality assurance, and reporting. As NGS procedures result in an increasing number of variants of unknown significance and incidental findings, these aspects are addressed as well. Accompanied by illustrations of the genetic diagnostic workflow and of concise reports for a fast orientation about the major aspects of genetic testing, this joint paper should support the health care professionals during a request for genetic testing.

VUS↗

PubMed2025

[Achievements and Expectations of the Rare Disease Diagnostic Support Program in the Republic of Korea].

OBJECTIVES: The Rare Disease Diagnostic Support Program in the Republic of Korea aims to improve early diagnosis and diagnostic yield for patients with rare diseases, particularly for those residing in non-metropolitan areas, by providing whole genome sequencing (WGS) services through regional medical institutions. This study evaluated the performance of the program, focusing on its clinical utility, including early diagnosis and treatment linkage, and its policy impact related to patient benefits. METHODS: From August 2024, WGS was performed on 410 patients with suspected rare diseases at 23 institutions outside the metropolitan area. A one-stop diagnostic pathway was established to perform sample collection, test referral, report delivery, and genetic counseling within a single clinical flow based on the patient’s location of residence. Sequencing was performed by external laboratories. RESULTS: Among the 410 patients, pathogenic variants were identified in 129 (31.5%), with a turnaround time of 28 days. Of those diagnosed, 78.2% received treatment benefits via national programs such as co-payment exemption and medical expense support programs. Approximately 30% of the patients were eligible for therapeutic intervention, particularly medication or dietary therapy. Family genetic testing of three members identified potential carriers or high-risk groups in 28 households (65.1%). Consent for secondary findings was 99.0%, with clinically significant variants found in 3.9% of cases. CONCLUSIONS: The program demonstrated clinical value by improving diagnostic accessibility, reducing regional disparities, facilitating timely treatment, and supporting preventive care through family risk identification. These findings support the need for sustainable expansion of genome-based diagnostic services in the national health policy.

Diagnosis↗

PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗

PubMed2026

Redefining the real problem in psychedelic trials: Why fighting the Lessebo matters more than blinding integrity.

Imperfect blinding is not specific to psychedelic trials. In randomized trials, treatment allocation is frequently correctly guessed, yet blinding integrity is rarely assessed outside of psychedelic research and is generally not considered a barrier in regulatory evaluation. The intense debate in psychedelics may reflect a broader double standard affecting mental health research, when uncertainties arising from imperfect blinding are confounded by those linked to patient-reported outcome measures. Indeed, people living with mental disorders are often viewed as unreliable reporters, despite well-documented limitations of clinician-rated scales and the absence of robust biological markers of symptomatic change. Importantly, it is the maintenance of reasonable doubt of treatment allocation that sustains internal validity and ethical feasibility of placebo-controlled designs, rather than perfect blinding. Concerns about expectancy bias in psychedelic trials are closely tied to blinding debates. When allocation is inferred, expectations may cluster in the arm perceived as active or in stereotyped experiences and influence outcomes differently in active and control arms, leading to a risk of lessebo, a negative placebo effect due to the negative expectation related to receiving a placebo. However, we argue that an underrecognized mechanism of lessebo is disappointment. This risk may reflect insufficient clinical management of disappointment rather than pre-treatment expectation alone. We therefore propose shifting the emphasis from preserving inevitably imperfect blinding towards mitigating disappointment in both arms. Establishing non-stereotyped expectations prior to treatment through structured psychoeducation, strengthened therapeutic alliance, and realistic preparation would help avoid lessebo effects. Such strategies would enhance ethical rigor, interpretability, and the clinical usefulness of psychedelic trials.

Humans↗

PubMed2026

Dispositional optimism and open-label placebo responses in hair cortisol concentrations and psychological distress-A randomized controlled trial.

Open-label placebo (OLP) treatments show beneficial effects on various health-related outcomes, but studies investigating OLP effects on physiological measures remain scarce. This randomized controlled trial examined the effect of a 4-week OLP intervention on psychological distress and hair cortisol concentrations (HCC) in 202 healthy university students preparing for mandatory oral exams and whether dispositional optimism moderates the OLP effects. Participants were randomly assigned to an OLP or control group. Psychological distress was repeatedly assessed via negative affect, test anxiety, and subjective stress. HCC was measured before and within the intervention. Treatment expectations were additionally examined in interaction with optimism. Results show that OLPs significantly reduced psychological distress and HCC compared to the controls. Optimism moderated the OLP effect on HCC, with less optimistic individuals demonstrating the strongest reduction, independent of expectation. Optimism did not moderate OLP effects in psychological distress. However, the OLP effect on psychological distress depended on the three-way interaction of group, optimism, and expectation. The results suggest that OLPs alleviate the psychophysiological impact of a real-life stressor and indicate that optimism and expectation differently shape psychological and physiological OLP responses. These findings are discussed within the framework of the interactionist perspective.

Humans↗

PubMed2026

Financial incentives and social messaging for repeat SARS-CoV-2 antibody testing among the underserved: A randomized trial.

Financial incentives may influence health behavior beyond their expected monetary value, and their effectiveness may depend on how the behavior is framed. Behavioral theories of decision making suggest that individuals may value protection against small-stakes losses more than expected utility predicts, while theories of family-centered health behavior suggest that messages emphasizing benefits to family members may strengthen participation in preventive health activities. We tested these ideas in a 2×2 factorial randomized trial involving 625 households recruited from a Federally Qualified Health Center serving low-income Latino/Hispanic communities. Participants completed repeat SARS-CoV-2 antibody testing. The trial crossed two messaging strategies (Family vs. Personal) with two incentive structures (Loss Protection vs. Lottery) that offered equivalent expected monetary value. Family Messaging emphasized protecting one's family from COVID-19, whereas Personal Messaging emphasized protecting oneself. Loss Protection allowed participants to secure an at-risk reward through repeat testing, whereas the Lottery condition offered a chance of a large reward. Repeat testing was approximately 8 percentage points higher under Family Messaging and 7 percentage points higher under Loss Protection. Baseline trust in medical providers, financial barriers to vaccination, and risk aversion were associated with initial testing, whereas household characteristics were not associated with repeat testing. Incentive design may matter beyond expected monetary value and that framing health behaviors in terms of family welfare may increase participation in repeated healthy activities. Broadly, the results support behavioral theories emphasizing loss aversion, anticipated regret, and family-centered motivations, and suggest practical approaches for improving engagement in repeat health behaviors. CLINICALTRIALS.GOV REGISTRATION NUMBER:: NCT01901624.

Adult↗

PubMed2026

Expression dynamics of mCry3A and eCry3.1Ab transgenes in Bt corn hybrids across growth and environments.

In 2017 and 2018, studies were conducted in Iowa, US across three environments with a history of greater than expected corn rootworm injury i.e., greater than one node of injury to (US EPA 2009) and one environment without rootworm injury, and at different growth stages, to determine the expression levels of mCry3A and eCry3.1Ab transgenes in the roots of different Bt corn hybrids namely the molecular stack (MZIR098), breeding stack (MIR604 × 5307), 5307 and MIR604. ELISA results showed that expressions of both mCry3A and eCry3.1Ab transgenes, were higher in the MZIR098 molecular stack and breeding stack (MIR604 × 5307), than the MIR604 and 5307 at V3 and VT growth stages over both years. To protect the roots from feeding damage by the corn rootworm larvae, expression of the transgenes must be high at the V3 growth stage. The expression of the transgene was significantly impacted by the stage of plant growth while the environments with greater than expected corn rootworm injury did not impact expression of the transgenes. It was found that the expression of mCry3A and eCry3.1Ab transgenes were high at the V3 plant growth stage compared to the VT growth stage. Stacking two or more genes together in the same plant such as the molecular and breeding stacks have the potential to protect roots in environments with higher-than-expected damage and slow down the evolution of resistance in field populations of rootworms.

Zea mays↗

PubMed2026

Current Diagnostic Pathways for Rheumatoid Arthritis-Associated Interstitial Lung Disease Result in Substantial Underdiagnosis and Excess Mortality: A Multicenter Norwegian Quality Assurance Audit.

OBJECTIVE: Recent guidelines suggest risk-stratified screening for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the diagnostic gap between current routine care and this screening approach remains unquantified. We assessed currently detected RA-ILD in Norway, benchmarking findings against recent screening-based estimates of the true disease burden. METHODS: This 10-year quality assurance audit across six centers covered 43% of the Norwegian population. RA-ILD cases identified via ICD-10 codes were confirmed by manual chart review. Prevalence was calculated relative to a registry-derived total RA background population and benchmarked against a 10% expected target derived from recent prospective studies. Mortality was compared to a 3:1 frequency-matched RA control group using Cox proportional hazards regression. RESULTS: Among 17,305 RA patients, 188 (1.1%) had verified ILD; when benchmarked against an expected 10% prevalence, this indicates an 89% diagnostic gap in routine clinical care. Mean age at ILD detection was 67.5 years. Most cases (93.6%) possessed ≥2 established risk factors for RA-ILD: 93.6% were seropositive, 76.1% had smoking histories, while RA onset age ≥60 and persistently increased inflammatory laboratory markers were present in over half of patients. RA-ILD was associated with significantly increased mortality; 66 (4.1/100 person-years) deaths occurred in the RA-ILD group vs. 120 (2.3/100 person-years) among RA controls (HR 1.77; 95% CI: 1.31-2.39, p<0.001). CONCLUSION: When comparing to prevalence expectations, current routine care may leave a substantial proportion of cases undetected, primarily capturing a high-risk phenotype with excess mortality. Systematic, risk-stratified screening is needed to bridge this diagnostic gap, aiming to enable earlier intervention.

Interstitial lung disease↗

PubMed2026

A prospective crossover study comparing ICCS-recommended and Palmer-adjusted filling rates in children with spina bifida.

OBJECTIVE: This study aimed to investigate whether the maximal cystometric capacity (MCC) in children with spina bifida (SB) is indeed lower, as predicted by the Palmer formula, and to evaluate the impact of different bladder filling rates on urodynamic parameters. MATERIALS AND METHODS: This prospective, randomized, two-sequence crossover-controlled study included 70 children aged 3-18 years with spina bifida under regular follow-up. In Group 1, the first two bladder fillings were performed at the ICCS-recommended rate, and the third at 75% of that rate (Palmer formula). In Group 2, the sequence was reversed. Urodynamic parameters, including maximal cystometric capacity (MCC), bladder compliance, detrusor activity, filling pressures, and detrusor leak point pressure (DLPP), were analyzed across fillings. RESULTS: Cystometric bladder capacity was lower during fillings performed at the Palmer-adjusted rate compared with those at the ICCS-recommended rate. The proportion of reduced compliance significantly decreased in Group 1 (p = 0.046) but remained unchanged in Group 2. A significant positive correlation was observed between expected bladder capacity (EBC) and measured MCC in both groups (ρ ≈ 0.5-0.6). The highest correlation and agreement were found in Group 1 during the third filling at the Palmer rate (ICC = 0.606). No significant intra- or intergroup differences were observed in detrusor pressure, end-filling pressure, DLPP, or overactive bladder prevalence. CONCLUSION: Bladder filling rate was associated with differences in both cystometric capacity and bladder compliance in children with spina bifida. Fillings performed according to the Palmer formula (approximately 75% of the ICCS-recommended rate) were associated with capacities that more closely approximated age-expected values and with modest differences in bladder compliance. Conversely, faster filling rates did not produce similar benefits. These findings suggest that slower filling strategies may improve measurement consistency and agreement with expected bladder capacity estimates. However, the magnitude and direct clinical impact of these differences should be interpreted cautiously, particularly in light of the potential influence of sequence-related effects.

Humans↗

PubMed2025

Mindfulness and Sex Education for Sexual Dysfunction in Breast Cancer Survivors: Mediators and Moderators of Treatment Outcome.

Mindfulness-based cognitive therapy (MBCT) and supportive-expressive sex education therapy (STEP) are effective group treatments for sexual dysfunction after breast cancer (BrCa). We explored mediators and moderators of outcomes following the 8-week groups. BrCa survivors (n = 116, mean age = 49.9 ± 9.5) were randomized to group and completed measures before, immediately after, and 6 months after treatment. Mediators assessed were changes in depression, chronic pain acceptance, pain catastrophizing, and trait mindfulness. Potential moderators included age, treatment expectations, baseline mental health, cancer treatment duration, use of chemotherapy, and adjuvant endocrine therapy. Longitudinal mediation and moderation were assessed using linear mixed models. Increases in pain acceptance mediated improvements in sexual desire and reductions in both sexual distress and vaginal pain. Decreases in pain catastrophizing mediated improvements in sexual distress. Higher expectations for treatment led to greater reductions in sexual distress. Those with low baseline anxiety showed greater improvements in desire and distress. Low baseline depression predicted greater improvements in desire, but only in the STEP arm. Older STEP participants improved significantly more than younger STEP participants. Cancer-related treatment variables, and the impact of adjuvant endocrine therapy, had differential effects on outcomes based on the treatment arm of the study. In conclusion, treatments aimed at improving pain acceptance and pain catastrophizing are likely to promote improvements in sexual health among BrCa survivors, and factoring in patients' expectations about treatment improvements, depression and anxiety, age, duration of cancer treatment, chemotherapy, and adjuvant hormonal therapy may help to guide treatment recommendations for sexual dysfunction.

Humans↗

PubMed2026

Incorporating indel channels into average-case analysis of seed-chain-extend.

MOTIVATION: Given a sequence s1 of n letters drawn independently and identically (i.i.d.) from an alphabet of size σ and a mutated substring s2 of length m<n, we want to recover the mutation history that generated s2 from s1. Many modern sequence aligners for this task use seed-chain-extend with k-mer seeds. Previously, Shaw and Yu showed linear-gap cost chaining can produce a chain with 1-O(1m) recoverability, the proportion of the mutation history that is recovered, in O(mn2.43θ log n) expected time for seed-chain-extend (assuming pre-seeded reference), where θ<0.206 is the mutation rate under a substitution-only channel and s1 is uniformly random. A gap remains between theory and practice, as real genomes include insertions and deletions (indels). RESULTS: We introduce mathematical machinery to deal with the two new obstacles introduced by indel channels: the dependence of neighbouring anchors and the presence of anchors that are only partially correct. We prove that expected recoverability of an optimal chain is ≥1-O(1m) and expected runtime is O(mn3.15·θT log n), given the total mutation rate θT=θi+θd+θs (sum of substitution, insertion, and deletion rates) is θT≤0.159. We thus narrow (but not close) the gap between theory and practice. AVAILABILITY AND IMPLEMENTATION: https://github.com/Lazarus42/seed_chainer_indels.

INDEL Mutation↗

PubMed2025

Permutation tests to assess sex differences in omics data.

It is common to sex-stratify analyses of omics data and to report effects as 'sex-specific' when they are significant in only one sex. However, when analysing hundreds or thousands of molecules, this approach will yield many spurious 'sex-specific' effects if not supported by significant interactions. I illustrate this problem using an RNA sequencing dataset showing almost no significant sex by treatment interactions, but where sex-stratified analyses yield hundreds of 'sex-specific' effects of treatment. These 'sex-specific' effects could be spurious or could be real but not show interactions due to low statistical power. To distinguish these possibilities, I describe permutation tests, which provide an intuitive way to determine if a pattern of observations differs from what would be expected due to chance. For this dataset, assigning sex at random often generates more 'sex-specific' effects than the real data, demonstrating that there is little evidence of sex differences. Next, I simulate an RNA sequencing dataset that includes genes modelled to have sex-specific effects of a condition. As expected, analysis of this simulated dataset yields both significant interactions and sex-specific effects in sex-stratified analyses. While stratified analyses detect a higher number of sex-specific effects than the analysis of interactions, they erroneously identify genes not modelled to show sex-specific effects more often than interactions. A permutation test confirms that the number of sex-specific effects observed in the simulated dataset is greater than expected due to chance. Permutation tests can be applied to omics studies of sex differences, simultaneously providing (i) a clear and simple demonstration of the problems of sex-stratified analyses, and (ii) additional evidence of sex-specific effects where these are present. R code is provided for permutations, simulations, and plots to visualize potential sex-specific effects, which can be adapted to other types of data.

Female↗

PubMed2025

Estimands for Clinical Effectiveness of Risk-Reducing Early Salpingectomy in Women With High Risk of Ovarian Cancer.

IMPORTANCE: Risk-reducing early-salpingectomy (RRES) and delayed oophorectomy (DO) is a novel 2-stage alternative prevention strategy to risk-reducing salpingo-oophorectomy (RRSO) that avoids detrimental consequences of premature menopause. However, direct data on the clinical effectiveness for ovarian cancer (OC) risk reduction are lacking. OBJECTIVE: To explore how to define clinical effectiveness from prospective cohort studies using the estimand framework and sample size requirements. DESIGN, SETTING, AND PARTICIPANTS: In this comparative effectiveness research study, estimand and analysis options were considered to evaluate the clinical effectiveness of RRES with DO by extending the UK PROTECTOR cohort study, a multicenter, prospective, observational, national cohort study (N = 1250 recruited from January 1, 2019, to December 31, 2024) evaluating RRES and DO for OC surgical prevention. Participants were premenopausal women 30 years or older at increased OC risk due to BRCA1/BRCA2 pathogenic variants. Participants could choose RRES, RRSO, or no surgery at entry. Sample size requirements used initial data (eg, age and BRCA1/2 distribution) from PROTECTOR (analysis undertaken from January 1, 2024, to December 31, 2025). MAIN OUTCOMES AND MEASURES: Incidence of OC after (not at) RRES and before or at DO in women with normal histologic analysis findings at surgery. The proportion of cancers prevented was estimated as the completement of the observed (O) to expected (E; assuming no preventive effect of surgery) number of cancers detected (1 - O/E). RESULTS: Initial data were obtained from 889 women in PROTECTOR (overall mean [SD] age, 39 [5] years), with 255 (28.7%) choosing RRSO (mean [SD] age, 42 [4] years), 405 (45.5%) choosing RRES (mean [SD] age, 38 [4] years), and 229 (25.7%) choosing no surgery (mean [SD], 38 [5] years). The preferred estimand outcome was OC incidence after surgery (RRES or RRSO) with a "while on intervention" strategy to account for intercurrent events. The primary target measure was the proportion of cancers prevented for RRES vs no surgery with superiority testing. The secondary target measure was noninferiority of RRES vs RRSO. An estimated 1150 RRES participants with 8 to 10 years of follow-up would provide approximately 92% power to show that 20% or more of cancers are prevented using a 1-sample binomial test of the O:E risk (external reference) at the 5% level under a range of assumptions and at least the same power for a noninferiority margin for the proportion of cancers prevented by RRES of those prevented by RRSO. Estimands based on incidence ratios had an infeasible sample size. CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study of UK BRCA carriers, the estimand differed from other ongoing clinical effectiveness studies of RRES and DO. Advantages include direct use of expected risk at baseline (unknown at design stage), easier interpretation across cohorts than absolute risk differences, and providing a feasible recruitment target for PROTECTOR to evaluate clinical effectiveness.

Humans↗

PubMed2026

GWAS of Tau-Neurodegeneration Mismatch Identifies New Risk Loci for Susceptibility to Tau.

BACKGROUND: In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau-neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. METHODS: Here, I perform a genome-wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. RESULTS: A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome-wide significance threshold (p ≤ 5 × 10-8). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10-8; rs9784993, MAF = 0.197, p = 4.92 × 10-8) was associated with lower Tau/Neurodegeneration residuals, indicating higher-than-expected neurodegeneration given tau levels. CONCLUSION: GWAS of tau-related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau-neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.

Humans↗