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PubMed1996

National survey on the attitudes of Canadian physicians towards drug-detailing by pharmaceutical representatives.

OBJECTIVE: Our objective was to study the attitudes of Canadian physicians toward product presentations by pharmaceutical representatives (PRs), the use of inducements by the pharmaceutical industry, and methods to improve the quality of prescribing information provided to physicians. DESIGN: We used a mailed survey. PARTICIPANTS: A random sample of 550 Canadian physicians in all settings was chosen. OUTCOME MEASURES: The main outcome measure was the proportion of respondents agreeing with a series of statements. RESULTS: The response rate was 262 of 525 deliverable surveys (50 per cent). Respondents had a mean of 4.2 interactions per week with PRs. Of the 262 respondents (5.8 per cent of data were incomplete), 193 (80 per cent) believed that PRs overemphasize their products' effectiveness, 108 (45 per cent) thought PRs do not present fairly the drugs' negative aspects, and 223 (92 per cent) felt that PRs have production promotion as a goal. Most, 175 (70 per cent), believe that drug-detailing affects physicians' prescribing behavior. Most, 210 (86 per cent), considered drug samples acceptable, but fewer agreed that other inducements were acceptable. Of the respondents, 183 (74 per cent) agreed that PRs should be required to use guidelines for standardized, comprehensive drug-detailing, and 165 (65 per cent) agreed that face-to-face drug-detailing by PRs using standardized guidelines would be an effective way to receive information. CONCLUSIONS: There is dissatisfaction among Canadian physicians about the quality of information provided by the pharmaceutical industry. Standardized, comprehensive guidelines would be accepted by physicians as one improvement.

Advertising↗

PubMed2001

Pierre Robin sequence and interstitial deletion 2q32.3-q33.2.

Pierre Robin sequence (PRS) consists of the nonrandom association of micrognathia, cleft palate (CP), and glossoptosis. It also includes respiratory and feeding difficulties that appear to be neurogenic rather than mechanical in causation. Genetic determinants are thought to underlie this functional and morphological entity, based on the existence of Mendelian syndromes with PRS, and the rare observations of familial nonsyndromic PRS, in which some of the affected individuals have isolated CP. We report the association of PRS with deletion 2q32.3-q33.2 due to an unbalanced reciprocal translocation 46,XX, t(2;21), del 2(q32.3q33.2), and we refine the deletion interval with regard to YAC probes and polymorphic DNA markers. The deletion was shown to be flanked by D2S369 (telomeric) and D2S315 (centromeric), thus it maps to a recently determined chromosomal region known to be nonrandomly associated with CP. This observation supports the hypothesis for the genetic bases of nonsyndromic PRS, strengthens its possible genetic association with isolated CP, and provides a candidate PRS locus, in chromosomal region 2q32.3-q33.2.

Chromosome Banding↗

PubMed2002

Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999.

BACKGROUND: Despite improved therapies, 30-40% of patients with Ewing tumors (ET) experience recurrence and have a poor prognosis. The authors analyzed factors prognostic of survival in patients with recurrent ET. METHODS: The authors assessed the relation between postrecurrence survival (PRS) and demographic, disease, and treatment factors in 71 patients who experienced recurrent ET after treatment on one of three consecutive institutional protocols. RESULTS: Thirty-four patients (47.9%) had distant recurrence, 25 patients (35.2%) had local recurrence, and 12 patients (16.9%) had both distant and local recurrence at a median of 1.7 years after diagnosis. The probability of 5-year PRS (+/- 1 standard error) was 17.7%+/-4.5%. Recurrence > or = 2 years after diagnosis predicted a significantly better outcome (5-year PRS, 34.9%+/-8.5%) compared with earlier recurrence (5.0%+/-2.8%; P < 0.001). Patients who had both local and distant recurrence fared worse (5-year PRS, 12.5%+/-8.3%) compared with patients who had local recurrence alone (21.7%+/-7.8%) or distant recurrence alone (17.6+/-6.1%). Among patients with local recurrence alone, those who underwent salvage with radical surgery had significantly higher 5-year PRS estimates (31.4%+/-11.6%) compared with the other patients (9.1%+/-6.1%; P = 0.023). Pulmonary irradiation significantly improved the outcomes of patients with isolated pulmonary recurrence (5-year PRS estimate, 30.3%+/-12.5% vs. 16.7%+/-10.8%, respectively; P = 0.018). CONCLUSIONS: Although outcomes are generally poor after patients experience recurrence of ET, certain patient groups differ appreciably in their likelihood of survival. Patients who experience recurrence > or = 2 years after diagnosis and patients who have local recurrence that can be treated with radical surgery and intensive chemotherapy have the most favorable outcomes.

Adolescent↗

PubMed2007

Placebo response in binge eating disorder.

OBJECTIVE: Placebo response in studies of binge eating disorder (BED) has raised concern about its diagnostic stability. The aims of this study were (1) to compare placebo responders (PRs) with nonresponders (NRs); (2) to investigate the course of BED following placebo response; and (3) to examine attributions regarding placebo response. METHOD: The baseline placebo run-in phase (BL) was part of a RCT investigating sibutramine hydrochloride for BED; it included 451 participants, ages 19-63, diagnosed with BED. Follow-up (FU) included 33 PRs. RESULTS: : In this study, 32.6% of participants responded to placebo (PRs = 147; NRs = 304). PRs exhibited significantly less symptom severity. At FU (n = 33), many PRs reported continued symptoms. CONCLUSION: PRs exhibited significantly less severe pathology than NRs. Placebo response in BED may transitory or incomplete. The results of this study suggest variable stability in the BED diagnosis.

Adolescent↗

PubMed1975

Changes of plasma renin, angiotensin II and renin substrate during reversal of malignant renovascular hypertension.

The relationship between plasma renin activity (PRA), angiotensin II (AT II) and renin substrate concentration (PRS) were studied in a patient with left renal artery occlusion and malignant hypertension before and after left-side nephrectomy. Initially, PRA and AT II were grossly elevated, while PRS was low. Treatment with alpha-methyl-DOPA and saline led to a fall in PRA and AT II and a large rise in PRS. The correlation between PRA and AT II (r=0.937; n=9, p less than 0.001) was highly significant. PRA and PRS were negatively correlated before operation (r=-0.78; n=6; p less than 0.05). A comparison of changes in PRS before and after nephrectomy suggests that renin substrate formation was increased when the ischemic kidney was still in situ. Following nephrectomy, PRA and blood pressure fell to normal within 5 hours, while PRS remained unchanged for this period of time. A two-compartmental analysis of the renin disappearance curve after nephrectomy revealed the presence of a fast and slow component with half-lives of 10 and 95 min, respectively.

Angiotensin II↗

PubMed2003

Mutation detection in rice waxy mutants by PCR-RF-SSCP.

PCR-RF-SSCP (PRS), which combines cleaved amplified polymorphic sequence (CAPS) and single-strand conformation polymorphism (SSCP), is expected to be a useful technique for DNA polymorphism analysis. We evaluated the ability of PRS to detect single nucleotide polymorphism (SNP) using the Waxy gene, Wx, of rice, and subsequently were able to identify point mutations in wx mutant lines. The approximately 6-kb Wx gene was divided into five regions for PCR amplification. Two regions, in which most of the point mutations of the wx mutants have been identified, were amplified by PCR and cloned into a vector, and those clones containing SNPs produced as a result of the inherent inaccuracy of PCR were used for the evaluation of PRS. The efficiency of PRS in the detection of SNPs of these clones was over 70%. PRS analysis of the wx genes in 18 waxy mutants was carried out in the five regions using two different restriction endonucleases and two gel conditions, with and without glycerol. Of the 18 lines tested, 17 showed band patterns different from that of the wild type. Most of the mutations identified in this study were nucleotide changes in exons, which result in amino acid changes. One mutation generated an in-frame stop codon, and another was a frame shift mutation by one-base deletion. Two mutations found at a splice site were considered to inhibit normal splicing of mRNA. These results show that PRS is a useful technique for detecting point mutations in large plant genes.

Chromosome Mapping↗

PubMed1989

Actions of RU 38486 on progesterone facilitation and sequential inhibition of rat estrous behavior: correlation with neural progestin receptor levels.

The present study examined the actions of the antiprogestin RU 38486 on progesterone (P)-induced facilitation and sequential inhibition of estrous behavior and on brain cytosol progestin receptor (PR) levels in ovariectomized, estrogen-primed (0.5 micrograms of estradiol benzoate for 3 days) female rats. RU 38486 suppressed P-facilitated receptive and proceptive responses in a dose-dependent fashion when administered 1 hr prior to P. RU 38486 did not, however, block the sequential inhibitory effect of P. Indeed, when it was administered alone at a dose of 1 mg, animals were rendered behaviorally unresponsive to a P treatment 25 hr later. It is unclear whether RU 38486 is an agonist for P sequential inhibition of estrous behavior or if the apparent agonist action of RU 38486 actually results from a long-term antagonist effect. Estrogen-induced PRs remain elevated (35-55% above basal) in the hypothalamus (HYP) and preoptic area (POA) at 24 and 48 hr following the last estrogen injection. Thus P facilitation of estrous behavior is correlated with increased levels of cytosol PRs. RU 38486 reduced cytosol PRs in both brain regions to basal levels within 2 hr, and the levels remained suppressed 25 hr following the treatment. Hence there is a strong correlation between behavioral inhibition and suppressed cytosol PRs at both short (5 hr) and long (25 hr) intervals after RU 38486 administration. A P treatment which produced sequential inhibition of estrous responsiveness 24 hr later did not reduce the estrogen-induced level of cytosol PRs in either brain region. These results suggest that mechanisms in addition to induction of PRs may be necessary to ensure successful mating.

Animals↗

PubMed1982

Respiratory mechanics of Pekin ducks under four conditions: pressure breathing, anesthesia, paralysis or breathing CO2-enriched gas.

Impedance magnitude (Z) of the lower respiratory system was studied in Pekin ducks, using forced oscillations of a small volume at the airways opening in the range 1.6-16 Hz. The experiments were performed on 5 awake ducks enclosed in a body plethysmograph and spontaneously breathing ambient air at a transrespiratory pressure (Prs, the pressure difference between the lung and the body surface) which was varied in steps from -10 cm H2O (compression) to +10 cm H2O (distension). In 3 anesthetized birds, the effects of CO2 breathing and muscular paralysis were also studied. Analysis of end-expiratory Z data yielded estimates of respiratory resistance (R), inertance (I) and compliance (C). During positive or negative pressure breathing in conscious ducks, minute volume (V) and end-tidal CO2 (PETCO2) remained unchanged from normal (Prs = zero) while tidal volume (VT) and ventilatory period (Ttot) decreased. The respiratory system in late expiration can be modelled well with a simple series R-I-C mechanical model at Prs values of zero, +10 and -10 cm H2O. The value of Z increased at all frequencies studied during compression of the respiratory system (Prs = -10 cm H2O) and did not change much from normal (Prs = zero) during distension (Prs = +10 cm H2O). Both resistance and inertance increased during compression. During distension contradictory changes in resistance and inertance suggest that complex changes in flow profile and/or in flow pathways occurred with positive pressure breathing. Anesthesia or paralysis did not noticeably change the oscillatory resistance or inertance, but increased oscillatory compliance. CO2-breathing did not affect the respiratory impedance in late expiration, but reduced its flow dependence along the ventilatory cycle.

Airway Resistance↗

PubMed1976

Dose-dependent dual effect of morphine on electrophysiologic correlates of positive reinforcement (reward contingent positive variation: RCPV) in the cat.

In cats trained to press a lever for milk reward, the postreinforcement EEG synchronization (PRS) and the associated epicortical steady potential shift, known as "Reward Contingent Positive Variation (RCPV) restricted to the occipital cortex, were studied prior to and after administration of morphine sulfate. Contrary to what has ordinarily been described as a typical feline response to morphine, such as restlessness, aggressiveness, rage, and exaggerated startle reaction to environmental stimuli, associated with an increased tonus of the brainstem-hypothalamic arousal system and desynchronized EEG patterns, doses of 0.1-0.4 mg/kg, IM, caused a strong monophasic enhancement of the PRS-RCPV phenomenon. Doses of 0.6-1.0 mg/kg, IM, had clearly a biphasic action: the initial enhancement of the PRS-RCPV responses was followed by their strong suppression. Chlorpromazine (0.1-1.6 mg/kg, i.e.) promptly restored the EEG responses. During the peak effect of the enhancing doses of morphine, the reward-related EEG phenomena also occurred prior to or after the nonrewarded bar press when the animals licked the empty cup. This dissociation of the PRS-RCPV from consumption was much more conspicuous in animals whose control frequency of the PRS oscillations was higher, and after morphine showed more significant slowing. Despite the strong facilitation of the PRS-RCPV in the presence of light, morphine, in contrast to LSD-25, was not able to restore the reward-induced phenomena in the dark.

Animals↗

PubMed2024

Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening.

PURPOSE: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

Humans↗

PubMed2026

Polygenic risk scores in major depressive disorder: A systematic review across diagnostic, treatment, course/severity, and subtype domains.

BACKGROUND: Major depressive disorder (MDD) is heterogeneous across diagnostic, treatment-related, course/severity, and subtype domains. Polygenic risk score (PRS) studies have examined these domains, but differences in PRS sources, samples, methods, and endpoint definitions have fragmented the evidence. We synthesised findings and examined potential contributors to heterogeneity. METHODS: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science were searched for studies published from January 2016 through 25 November 2025. Result records were synthesised using SWiM, and certainty was assessed with an adapted GRADE framework. RESULTS: Sixty studies contributed 493 retained records; 450 were descriptively classified as positive, null, or reverse, although records were not independent. Positive findings accounted for 44/56 diagnostic, 61/273 treatment-related, 64/100 course/severity, and 14/21 subtype records. For MDD/depression-derived PRSs and case-control MDD status, all 10 contributing studies showed higher liability in cases (exploratory exact sign test p = 0.002; FDR q = 0.004). The same PRS group showed positive findings for overall depressive symptom severity (14/18), although the study-level test was imprecise (5/5 studies; p = 0.063). Pharmacological response/remission findings for these PRSs were mostly null or directionally mixed (10 positive, 18 null, and 9 reverse). Treatment-resistant depression (TRD) findings differed by operational definition. Atypical and psychotic subtype signals arose mainly from single-study PRS and endpoint contrasts. CONCLUSIONS: PRS evidence was clearest for MDD diagnostic status and showed a tentative pattern for overall symptom burden. Treatment and subtype findings were less consistent or less replicated. Larger, ancestrally diverse studies with standardised endpoints and transparent PRS methods are needed.

Humans↗

PubMed2004

Stroke in women of reproductive age: comparison between stroke related and unrelated to pregnancy.

Pregnancy may increase the risk of stroke. However, few studies have compared strokes in women of reproductive age that occur in pregnancy or the puerperium (pregnancy-related stroke, PRS) with those unrelated to pregnancy. This study assesses risk factors and etiologies of stroke in these women based on relationship to pregnancy. From 1984 to 2002, all female patients 15 through 40 years of age with a first-ever stroke at National Taiwan University Hospital were included in this study. PRS was defined as patients who had stroke occurrence during pregnancy or within 6 weeks postpartum. Stroke was categorized as cerebral infarction (CI), cerebral hemorrhage (CH), or subarachnoid hemorrhage (SAH) and divided into subtype according to etiology. Risk factors and etiologies were compared for patients with PRS and stroke unrelated to pregnancy. We identified 49 patients with PRS, and 353 patients with stroke unrelated to pregnancy. There was no statistically significant difference in distribution of CI subtypes. Cerebral venous thrombosis (CVT) was more common in PRS than stroke unrelated to pregnancy (39% vs. 7%, P<0.001), and 73% of these cases occurred postpartum. Preeclampsia-eclampsia was an important cause of peripartum CH (37%), but not CI (4%). Among PRS cases, postpartum cerebral venous thrombosis and preeclampsia-eclampsia were the major causes of CI and CH, respectively.

Adolescent↗

PubMed1994

Sperm recovery and survival: two tests that predict in vitro fertilization outcome.

OBJECTIVES: To determine if human sperm recovery during swim-up and sperm survival after 24 hours, as obtained from a screening semen specimen, are predictive of subsequent IVF and clinical pregnancy rates (PRs) and to determine if these techniques can identify men with normal semen analysis parameters and poor IVF success. DESIGN: Historical prospective study. SETTING: All semen evaluations and IVF cycles were performed at the University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania. PATIENTS, PARTICIPANTS: Couples undergoing IVF at Magee-Womens Hospital from August 1988 through June 1993. INTERVENTIONS: A screening semen analysis and swim-up procedure were performed on all couples undergoing IVF. The number of spermatozoa recovered after swim-up and the percentage of motile spermatozoa present after a 24-hour incubation were recorded. MAIN OUTCOME MEASURES: Fertilization and PRs were compared according to the parameters obtained from routine semen analysis, the number of spermatozoa obtained with swim-up, and the percentage of motile spermatozoa at 24 hours. RESULTS: Using chi2 or Fisher's exact test, fertilization rates were significantly different according to the number of spermatozoa recovered after swim-up (< or = 2.0 and > 2.0 x 10(6) spermatozoa recovered, 48.3% versus 71.4%) as were PRs (16.9% versus 29.8%). Similarly, the percentage of motile spermatozoa present at 24 hours (< or = 20% and > 20%) discriminated between fertilization rates (45.9% versus 65.8%) and PRs (16.4% versus 36.5%). Among a subset of men with normal semen analyses and total motile sperm counts > or = 40 x 10(6), the results from swim-up and survival discriminated between men with high and low fertilization and PRs. Receiver operating characteristic analysis revealed that swim-up results better discriminated between pregnant and nonpregnant IVF patients than sperm motility, but that the percentage of motile spermatozoa present at 24 hours was no better in this regard than sperm motility. CONCLUSIONS: The number of spermatozoa recovered after swim-up and the percentage of spermatozoa that maintain their motility after 24 hours were both helpful in assessing IVF and PRs and may be helpful in altering physicians to a subset of men having normal semen analysis parameters yet poor IVF success.

Cell Survival↗

PubMed1997

Expression of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: an immunohistochemical and in situ hybridization study.

OBJECTIVE: To clarify the role of ovarian steroids in the development and progression of endometriosis, estrogen receptors (ERs) and progesterone receptors (PRs) were localized by immunohistochemistry, and ER messenger RNA (mRNA) was detected by in situ hybridization in the uterine endometrium and in normal and altered pelvic peritoneum. DESIGN: Retrospective and prospective study. SETTING: Nagasaki University School of Medicine, Nagasaki, Japan. PATIENT(S): A retrospective study of 61 formalin-fixed uterine endometria and normal and altered pelvic peritonea from patients suffering from various gynecologic diseases was conducted. In addition, in 22 fresh frozen tissue specimens, ER mRNA expression was evaluated prospectively. MAIN OUTCOME MEASURE(S): In formalin-fixed tissues, ER and PR were localized immunohistochemically. The results of immunohistochemical staining were scored from 0 to 4, depending on the signal intensity and frequency of positive cells. In fresh frozen specimens, ER mRNA expression was assessed by nonradioactive in situ hybridization using thymine-thymine dimerized oligonucleotide probes. RESULTS: The highest score of ERs and PRs was observed in the epithelial and stromal cells of the normal uterine endometrium at the early proliferative phase of the menstrual cycle. The ER and PR scores declined throughout the secretory phase. In typical endometriotic lesions, the ER and PR scores were constantly high independent of the menstrual cycle. The expression pattern of ER mRNA was mostly in parallel with that of ERs. In typical endometriosis, ERs and PRs were found in both glandular epithelial cells and their surrounding stromal cells. Expression of ER mRNA was found in typical endometriotic peritonea and in pelvic peritoneum with columnar epithelial cells, but not in normal pelvic peritoneum (mesothelium). Estrogen receptors and PRs were negative in mesothelium, but were positive in the nuclei of fibroblasts in the connective tissue. CONCLUSION(S): We demonstrated the expression of ERs, ER mRNA, and PRs in the columnar cells in pelvic peritonea and typical endometriosis, but not in normal mesothelium. These results suggest that endometriosis may originate from the columnar cells with ERs and PRs in the pelvic peritoneal lining.

Endometriosis↗

PubMed2000

Liver transplantation for hepatocellular carcinoma: a proposal of a prognostic scoring system.

BACKGROUND: The current staging system of hepatocellular carcinoma established by the International Union Against Cancer and the American Joint Committee on Cancer does not necessarily predict the outcomes after hepatic resection or transplantation. STUDY DESIGN: Various clinical and pathologic risk factors for tumor recurrence were examined on 344 consecutive patients who received hepatic transplantation in the presence of nonfibrolamellar hepatocellular carcinoma to establish a reliable risk scoring system. RESULTS: Multivariate analysis identified three factors as independently significant poor prognosticators: 1) bilobarly distributed tumors, 2) size of the greatest tumor (2 to 5 cm and > 5 cm), and 3) vascular invasion (microscopic and macroscopic). Prognostic risk score (PRS) of each patient was calculated from the relative risks of multivariate analysis. The patients were grouped into five grades of tumor recurrence risk: grade 1: PRS = 0 to < 7.5; grade 2: PRS = 7.5 to < or = 11.0; grade 3: PRS > 11.0 to 15.0; grade 4: PRS > or = 15.0; and grade 5: positive node, metastasis, or margin. The proposed PRS system correlated extremely well with tumor-free survival after liver transplantation (100%, 61%, 40%, 5%, and 0%, from grades 1 to 5, respectively, at 5 years), but current pTNM staging did not. CONCLUSIONS: 1) Patients with grades 1 and 2 are effectively treated with liver transplantation, 2) patients with grades 4 and 5 are poor candidates for liver transplantation, and 3) patients with grade 1 do not benefit from adjuvant chemotherapy.

Adolescent↗

PubMed1996

Pierre Robin syndrome: characteristics of hearing loss, effect of age on hearing level and possibilities in therapy planning.

Hearing loss was studied in 22 patients with Pierre Robin syndrome (PRS) aged three to 12 years (median 5.0 years). The results were compared to those obtained in 62 patients with isolated cleft palate (ICP) aged one to 27 years (median 5.5 years). Hearing loss was more frequently found in PRS (73.3 per cent) than in ICP (58.1 per cent) patients (p = 0.02). PRS patients had more ears with moderate (21-40 dB) and severe (> 40 dB) hearing loss, disturbing their social contact, with no tendency to normalization with age (Spearman r = 0.065). In contrast to PRS, ICP patients showed a significant tendency to hearing level normalization with ageing (Spearman r = -0.453; p = 0.001). Planigraphs of temporal bones showed inadequately developed pneumatization of the mastoid bone in all PRS patients and in most ICP patients. No malformation of the inner or middle ear was found in either group. PRS patients have a significantly higher risk of conductive hearing loss than those with ICP. Use of tympanostomy (ventilation) tubes is therapy of choice in patients with Pierre Robin syndrome, and it should be introduced as early as possible, even at the same time as palatoplasty.

Acoustic Impedance Tests↗

PubMed2022

Polygenic heterogeneity in antidepressant treatment and placebo response.

The genetic architecture of antidepressant response is poorly understood. Polygenic risk scores (PRS), exploration of placebo response and the use of sub-scales might provide insights. Here, we investigate the association between PRSs for relevant complex traits and response to vortioxetine treatment and placebo using clinical scales, including sub-scales and self-reported assessments. We collected a clinical test sample of Major Depressive Disorder (MDD) patients treated with vortioxetine (N = 907) or placebo (N = 455) from seven randomized, double-blind, clinical trials. In parallel, we obtained data from an observational web-based study of vortioxetine-treated patients (N = 642) with self-reported response. PRSs for antidepressant response, psychiatric disorders, and symptom traits were derived using summary statistics from well-powered genome-wide association studies (GWAS). Association tests were performed between the PRSs and treatment response in each of the two test samples and empirical p-values were evaluated. In the clinical test sample, no PRSs were significantly associated with response to vortioxetine treatment or placebo following Bonferroni correction. However, clinically assessed treatment response PRS was nominally associated with vortioxetine treatment and placebo response given by several secondary outcome scales (improvement on HAM-A, HAM-A Psychic Anxiety sub-scale, CPFQ & PDQ), (P ≤ 0.026). Further, higher subjective well-being PRS (P ≤ 0.033) and lower depression PRS (P = 0.01) were nominally associated with higher placebo response. In the self-reported test sample, higher schizophrenia PRS was significantly associated with poorer self-reported response (P = 0.0001). The identified PRSs explain a low proportion of the variance (1.2-5.3%) in placebo and treatment response. Although the results were limited, we believe that PRS associations bear unredeemed potential as a predictor for treatment response, as more well-powered and phenotypically similar GWAS bases become available.

Humans↗

PubMed2026

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.

Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21-1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks.

Aged↗