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PubMed1996

Contribution of lung and chest wall mechanics following emphysema resection.

OBJECTIVE: To determine the contributions of (1) chest wall (Pcw) and (2) lung elastic recoil pressure (PL) to (3) total elastic recoil pressure exerted by the respiratory system (Prs) in 18 patients (12 men) aged 66 +/- 6 years (mean +/- 1 SD) with severe emphysema who underwent video-assisted thoracoscopic bilateral lung volume reduction surgery under paralyzed (vecuronium) general anesthesia (isoflurane). DESIGN: We measured preoperative and 6-week postoperative lung function studies, and intraoperative inspiratory lung conductance (GL), PL, Pcw, and Prs (cm H2O) at end-expiratory lung volume (EELV), EELV plus 0.60 +/- 0.0 L, and EELV plus 1.15 +/- 0.0 L. All values are mean +/- SEM. RESULTS: Preoperative vs postoperative FVC was 1.9 +/- 0.1 L vs 2.3 +/- 0.1 L (p = 0.03); FEV1 was 0.6 +/- 0.1 L vs 0.9 +/- 0.1 L (p < 0.02); total lung capacity was 7.4 +/- 0.4 L vs 5.9 +/- 0.3 L (p < 0.001); functional residual capacity was 5.7 +/- 0.4 L vs 4.4 +/- 0.2 L (p = 0.001). At EELV preoperative vs postoperative, PL was 0.0 +/- 0.3 vs 1.1 +/- 0.05 (p = 0.04), Pcw was 5.0 +/- 0.7 vs 2.4 +/- 0.9 (p = 0.02), and Prs was 5.0 +/- 0.8 vs 3.5 +/- 0.7 (p = 0.08). AT EELV plus 0.60 L, PL was 3.2 +/- 0.6 vs 6.1 +/- 0.9 (p < 0.001), Pcw was 8.8 +/- 0.8 vs 7.0 +/- 0.9 (p = 0.12), and Prs was 12.0 +/- 0.8 vs 13.1 +/- 0.7 (p = 0.80). At EELV plus 1.15 L, PL was 6.8 +/- 0.9 vs 10.3 +/- 1.1 (p < 0.001), Pcw was 13.5 +/- 1.0 vs 11.2 +/- 1.2 (p = 0.12), and Prs was 20 +/- 1.2 vs 21.5 +/- 1.0 p = 0.93). AT EELV plus 0.06 L, GL was 0.09 +/- 0.00 L/S/cm H2O vs 0.16 +/- 0.01 (p < 0.01). At EELV plus 1.15 L, GL was 0.12 +/- 0.01 vs 0.21 +/- 0.03 (p < 0.05) with similar preoperative vs postoperative GL/PL slopes. CONCLUSION: The increase in PL and decrease in Pcw following LVRS for emphysema may be responsible for the increase in spirometry and airway conductance.

Aged↗

PubMed2026

Characterizing the Uncertainty, Misclassification and Inconsistency of Polygenic Prediction.

Polygenic risk scores (PRSs) hold promise for precision medicine, yet their clinical translation is hindered by substantial uncertainty in individual risk estimates and often limited agreement in risk stratification across multiple PRSs for the same disease. We develop a unified inferential framework to calibrate PRS point estimates and uncertainties for both quantitative traits and binary phenotypes, and to characterize how PRS accuracy, uncertainty, pairwise correlation jointly determine misclassification and classification inconsistency. We show, both theoretically and empirically, that individual- and population-level misclassification and inconsistency rates are highly predictable in independent datasets. We further evaluate PRS integration and uncertainty-aware probabilistic thresholding strategies that reduce misclassification and improve concordance in risk stratification. Together, these results demonstrate that instability in PRS-based classification is a predictable statistical consequence of uncertainty and establish a principled foundation for incorporating uncertainty into PRS-based risk interpretation, communication, and clinical decision-making.

Journal Article↗

PubMed2026

Polygenic risk scores associate with asthma phenotypes and proteomic analyses implicate IL1R1 in two family-based studies.

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p = 10-24 [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.

Journal Article↗

PubMed2001

Postradiation prostatic sarcoma: de novo carcinogenesis or dedifferentiation of prostatic adenocarcinoma?

Postradiation sarcoma (PRS) of the prostate is rare. We describe the second case associated with brachytherapy for adenocarcinoma and review the literature on prior cases of PRS as well as carcinosarcoma, a dedifferentiated form ofadenocarcinoma that may be confused with true prostate sarcoma. It is clear that radiation to the prostate confers a significantly increased risk for subsequent sarcoma, although not within the prostate. Because many of the reported cases of PRS were admixed with adenocarcinoma and had relatively short latency periods, we conclude that these cases of PRS ofthe prostate are, in fact, carcinosarcoma. Therefore, with only one case reported following therapeutic irradiation, PRS of the prostate is extremely rare.

Adenocarcinoma↗

PubMed2002

Parsonnet's risk score predicts late survival but not late functional results after aortic valve replacement in octogenarians.

BACKGROUND AND AIM OF THE STUDY: The study aim was to assess whether outcome after aortic valve replacement (AVR) in octogenarians can be anticipated by their preoperative clinical status. METHODS: Early and late results of 101 consecutive patients operated on for AVR between 1988 and 1998 in the authors' department were reviewed. Data were compared for two patient groups determined by Parsonnet's risk score (PRS) values: group A (n = 42), PRS <30, and group B (n = 59), PRS > or =30. RESULTS: Hospital mortality was 7.1% in group A and 16.9% in group B (p = NS). Follow up was complete (total 268 patient-years; mean 2.7 years per patient). Five- and eight-year survival rates were 76% and 39% in group A, and 57% and 16% in group B (p <0.05). Late mortality was mainly related to non-cardiac causes. Among 61 survivors on completion of follow up, functional results (mean NYHA class and mean Karnofsky score) were 1.5+/-0.8 versus 1.5+/-0.7 and 61+/-18 versus 61+/-17 in groups A and B, respectively. Among survivors, 24/31 from group A versus 22/30 from group B were still living in their own home. CONCLUSION: These results indicated that the PRS overestimated the operative risk of AVR in octogenarians. PRS also appeared to be related to late survival in these patients, but did not predict any postoperative functional benefits.

Age Factors↗

PubMed2005

Latex-vegetable syndrome due to custard apple and aubergine: new variations of the hevein symphony.

An increasing number of vegetables with crossreactions to latex are being described in patients with latex-vegetable syndrome. We present two of these vegetables, custard apple linked in two previous cases with latex sensitisation, and aubergine, that had not been described up to now in patients with latex sensitisation. The diagnosis of both cases was based on the clinical history, positive skin prick test (SPT) and specific IgE to the offending vegetables, as well as to positive SPT and specific IgE levels to latex and the major fruits involved in the latex-fruit syndrome (avocado, banana, and chestnut). Further, crude extracts from latex, custard apple and aubergine, as well as the purified allergens Hev b 6.02 and Prs a 1 were used in in vitro and in vivo assays: IgE immunodetection, histamine release (HRT) and basophil activation (BAT) tests and skin prick tests. In case 1, both purified Hev b 6.02 and Prs a 1 induced positive responses in skin prick tests, high levels of basophil activation and histamine release. Specific IgE immunodetection uncovered a reactive band of 45 kd in the crude custard apple extract, which was also recognized by anti-chitinase monospecific antibodies. The serum from patient 1 also detected Prs a 1 in immunodetection. Hev b 6.02 produced positive skin responses and showed high biological activity in HRT and BAT in the case of patient 2. However, Prs a 1 was reactive neither in SPT nor in IgE immunodetection. In fact, no band was detected using the serum of patient 2 in avocado or aubergine extracts. By contrast, Prs a 1 reached high values of basophil activation and over 10% of histamine release in case 2.

Adult↗

PubMed2006

[Construction of recombinant yellow fever virus 17D containing 2A fragment as a vaccine vector].

The Yellow Fever (YF) vaccine, an attenuated yellow fever 17D (YF-17D) live vaccine, is one of the most effective and safest vaccines in the world and is regarded as one of the best candidates for viral expression vector. We here first reported in China the construction and characterization of the recombinant expression vector of yellow fever 17D which contained the proteinase 2A fragment of foot-and-mouth disease virus (FMDV). Three cDNA fragments representing the full-length YF-17D genome, named 5'-end cDNA (A), 3'-end cDNA (B) and middle cDNA (C), were obtained by reverse transcription polymerase chain reaction (RT-PCR), together with the introduction of SP6 enhancer, necessary restriction sites and overlaps for homologous recombination in yeast. Fragment A and B were then introduced into pRS424 in turn by DNA recombination, followed by transfection of fragment C and the recombinant pRS424 containing A and B (pRS-A-B) into yeast. A recombinant vector containing full length cDNA of YF-17D (pRS-YF) was obtained by screening on medium lack of tryptophan and uracil. A recombinant YF-17D expression vector containing FMDV-2A gene fragment (pRS-YF-2A1) was then constructed by methods of DNA recombination and homologous recombination in yeast described above. In vitro transcription of the recombinant vector pRS-YF-2A1 was then carried out and introduced into BHK-21 cells by electroporation. Results of indirect immunofluorescence assay (IFA) and titer determination showed a stable infectious recombinant virus was gotten, whose features such as growth curve were similar to those of the parental YF-17D. The results suggest that the recombinant vector pRS-YF-2A1, by introduction of heterogenous genes via 2A region, is potential to be an effective live vaccine expression vector.

Animals↗

PubMed2006

Receptor modifications in vulvar dystrophies before and after treatment with topical hormones: comparison between the dextran-charcoal technique and immunohistochemical evaluation.

PURPOSE OF INVESTIGATION: The objective of the study was first to quantify estrogen receptors (ERs) and progesterone receptors (PRs) in dystrophic vulvar tissue before and after topical hormone treatment in an attempt to evaluate whether receptor modifications occurred. Second we compared quantitative analysis with immunohistochemical staining of the vulvar specimens. METHODS: We studied 115 vulvar specimens obtained from 75 consenting women ranging from 21 to 78 years of age. Of the patients, 12 had histologically normal vulvar skin, 45 had vulvar dystrophies that were not treated by topical steroid therapy, 28 patients had vulvar dystrophies that were treated by testosterone propionate (TP) 2%, 12 patients had vulvar dystrophies that were treated by progesterone in hydroalcoholic gel and 18 patients had vulvar malignant tumors. For immunohistochemical analysis we considered 25 cases of vulvar dystrophies: 11 cases of squamous hyperplasia (SH) and 14 cases of lichen sclerosus (LS). Among these 25 cases, 15 (5 SH and 10 LS) were treated with TP 2%. RESULTS: After treatment of the vulvar dystrophies with progesterone, the positivity of ERs decreased (58.3% vs 77.8%). After treatment of the vulvar dystrophies with TP 2%, the positivity of PRs significantly decreased (14.3% vs 68.9%) whereas after treatment with progesterone the positivity of PRs increased (83.3%). The immunohistochemical study showed some differences in comparison to the quantitative study. In fact we found low basal positivity especially for PRs (16% vs 68.9% of the quantitative study). This finding was due to the use of a cutoff of at least ++ in order to increase the specificity. After treatment with TP 2%, we observed an increase of immunohistochemical positivity for ERs even in cases that were negative before treatment and a lack of PRs even in cases that were positive before treatment. CONCLUSIONS: These data demonstrate the efficacy of androgen therapy with TP 2% in vulvar dystrophies with increased trophism due to the increase of ERs.

Administration, Topical↗

PubMed1995

High progesterone levels adversely affect embryo quality and pregnancy rates in in vitro fertilization and oocyte donation programs.

OBJECTIVE: To assess the effect of P levels on oocyte and embryo quality and pregnancy rates (PRs) in IVF and oocyte donation. DESIGN: Retrospective analysis of PRs in ovum donors and their recipients with regard to P levels on day of hCG administration. SETTING: In Vitro Fertilization Units, oocyte donation programs. PATIENTS: In vitro fertilization patients who agreed to donate oocytes were treated by hMG alone (53 cycles) or in combination with a GnRH analog (122 cycles). INTERVENTIONS: Uterine preparation in oocyte recipients consisted of 6 mg/d E2 valerate. Progesterone (100 mg/d) was added when oocytes became available. Hormonal treatment was continued until 12 weeks of gestation. RESULTS: Using a series of Fisher's Exact Tests, a critical threshold for P was identified at 1.9 ng/mL (conversion factor to SI units, 3.185). With elevated P levels (> 1.9 ng/mL), lower PRs were noted for the donors (7.1% versus 17%), as well for the recipients (8.3% versus 26.7%). CONCLUSIONS: Exposure to elevated P levels resulted in lower PRs for the donors and significantly lower PRs in the recipients. Because the endometria in the recipients were prepared uniformly, we conclude that this is the result of detrimental effects of P on oocyte or embryo quality.

Adult↗

PubMed1993

Human X-linked phosphoribosylpyrophosphate synthetase superactivity is associated with distinct point mutations in the PRPS1 gene.

Superactivity of phosphoribosylpyrophosphate synthetase (PRS) is an X chromosome-linked disorder of purine metabolism, characterized by gout with uric acid overproduction and, in some families, neurodevelopmental impairment. Two highly homologous isoforms of PRS (PRS1 and PRS2), each encoded by a distinct X chromosome-linked locus, have been identified, and PRS1 and 2 cDNAs have been cloned. The entire 954-base pair translated regions of PRS1 and 2 cDNAs derived from cultured lymphoblasts and fibroblasts from two patients in whom purine nucleotide feedback resistance of PRS is associated with enzyme superactivity and neurodevelopmental defects were examined by direct sequencing after polymerase chain reaction amplification of PRS transcripts. Nucleotide sequences of PRS2 cDNAs from the patients and normal individuals were identical. In contrast, PRS1 cDNAs from the patients differ from normal PRS1 cDNA, each by a single base substitution. PRS1 cDNA from patient N. B. showed an A to G transition at nucleotide 341, corresponding to an asparagine to serine change at amino acid residue 113 of mature PRS1. A G to C transversion at nucleotide 547, indicating an aspartic acid to histidine change at amino acid 182, was found for PRS1 cDNA from patient S. M. Point mutations at the sites identified in the PRS1 cDNAs of the two patients were confirmed by the results of RNase mapping analysis. Normal, N. B., and S. M. PRS1 cDNAs were introduced into Escherichia coli BL21 (DE3)/pLyS, and recombinant N. B. and S. M. PRS1s showed the purine nucleotide feedback resistance phenotypes characteristic of PRS from patients' cells.

Base Sequence↗

PubMed1993

Laparoscopic endometriosis treatment: is it better?

OBJECTIVE: To assess the hypothesis that pregnancy rates (PRs) after operative laparoscopy (Laparoscopy Group) for endometriosis treatment would be equal to or greater than diagnostic laparoscopy only (No Treatment Group), diagnostic laparoscopy with medical treatment (Medical Treatment Group), and laparotomy (Laparotomy Group). DESIGN: Prospectively recorded data were analyzed to identify significant variables affecting PRs. These variables were statistically controlled for using survival analysis with multiple fixed covariates to compare operative laparoscopy PRs versus other treatment PRs. SETTING: Treatment was performed by the senior author in a referral reproductive endocrinology and surgery private practice. PATIENTS: Five hundred seventy-nine infertile women were diagnosed with endometriosis. A subset (n = 258) considered to have endometriosis only was evaluated separately (Endometriosis-Only Subset). INTERVENTIONS: Treatment groups included: No Treatment Group, Medical Treatment Group, Laparoscopy Group, and Laparotomy Group. MAIN OUTCOME MEASURE(S): Pregnancy was used as the indicator of treatment success. RESULTS: Laparoscopy Group PRs were at least equal to all other treatment groups and were significantly higher than some other treatment groups in some comparisons. CONCLUSIONS: Operative laparoscopy is the treatment of choice for infertile women with endometriosis unless they have severe tubal and/or fimbrial disease.

Cohort Studies↗

PubMed1995

Teaching information mastery: evaluating information provided by pharmaceutical representatives.

BACKGROUND: The pharmaceutical industry plays a large role in the lifelong learning of family physicians. Controversy exists over how to integrate this potential information source into residency curricula. METHODS: Based on a a faculty and resident needs assessment, a curriculum was designed to teach the evaluation of pharmaceutical representatives' (PRs) presentations. The Pharmaceutical Representative Evaluation Form is the keystone of the curriculum. This evaluation form guides discussion of pharmaceutical presentation to facilitate understanding of the sales process and help residents confirm or dispute the presentation's content, based on the sales methods used. A second goal of the evaluation program is to improve the content of the PRs' presentations. RESULTS: Residents rapidly acquire the ability to identify potential fallacies of logic and other misleading sales techniques in representatives' presentations. Compared with pretest results, residents' posttest scores demonstrate an understanding that PRs and the acceptance of promotional items can affect their prescribing behavior. Most PRs are pleased that their role is seen as educational. CONCLUSIONS: Physicians must function more as information managers than as information repositories, and it is important that residents be able to obtain useful information from PRs. Our curriculum has been effective in increasing residents' abilities to evaluate the pharmaceutical sales process and allowing them to separate the ¿wheat from the chaff¿ contained in this ubiquitous source of information.

Advertising↗

PubMed1996

[PRPP synthetase superactivity].

Phosphoribosylpyrophosphate(PRPP) synthetase(PRS) catalyzes the formation of PRPP from ATP and ribose-5-phosphate. PRPP is an important substrate for the synthesis of purine, pyrimidine, and pyridine dinucleotides. Human PRS exists as complex aggregates composed of the 34 kDa catalytic subunits(PRS1 and PRS2) and other 39 kDa component designated PRPP synthetase-associated protein (PAP39). PRS superactivity is an X-chromosome linked disorder, characterized by gout and uric acid overproduction resulting from accelerated synthesis of PRPP and purine nucleotides. Among the nearly 30 affected families identified to date, there are several families in which PRS superactivity with purine nucleotide feedback resistance are associated with neurodevelopmental abnormalities in addition to hyperuricemia and gout. Different nucleotide substitutions in the PRPS1 gene encoding PRS1 have identified in six unrelated affected families with purine nucleotide feedback-resistant PRS superactivity.

Gout↗

PubMed1998

Immunocytochemical localization of nuclear estrogen receptors and progestin receptors within the rat dorsal raphe nucleus.

Estradiol and progesterone modulate central serotonergic activity; however, the mechanism(s) of action remain unclear. Recently, estradiol-induced progestin receptors (PRs) have been localized within the majority of serotonin (5-HT) neurons in the female macaque dorsal raphe nucleus (DRN; Bethea [1994] Neuroendocrinology 60:50-61). In the present study, we investigated whether estrogen receptors (ERs) and/or PRs exist within 5-HT and/or non-5-HT cells in the female and male rat DRN and whether estradiol treatment alters the expression of these receptors. Young adult female and male Sprague-Dawley rats were gonadectomized, and 1 week later, half of the animals received a subcutaneous Silastic implant of estradiol-17beta. Animals were transcardially perfused 2 days later with acrolein and paraformaldehyde, and sequential dual-label immunocytochemistry was performed on adjacent sections by using either a PR antibody or an ERalpha antibody. This was followed by an antibody to either the 5-HT-synthesizing enzyme, tryptophan hydroxylase (TPH), or to the astrocytic marker, glial fibrillary acidic protein (GFAP). Cells containing immunoreactivity (ir) for nuclear ERs or PRs were identified within the rat DRN in a region-specific distribution in both sexes. No colocalization of nuclear ER-ir or PR-ir with cytoplasmic TPH-ir or GFAP-ir was observed in either sex or treatment, indicating that the steroid target cells are neither 5-HT neurons nor astrocytes. Females were found to have approximately 30% more PR-labeled cells compared with males throughout the DRN (P < 0.05), but no sex difference was detected in the number of neurons demonstrating ER-ir. In both sexes, 2 days of estradiol exposure decreased the number of cells with ER-ir, whereas it greatly increased the number of cells containing PR-ir in several DRN regions (P < 0.005). Collectively, these findings demonstrate the existence of nonserotonergic cells that contain nuclear ERs or PRs within the female and male rat DRN, including estradiol-inducible PRs. These findings point to a species difference in ovarian steroid regulation of 5-HT activity between the macaque and the rat, perhaps transsynaptically via local neurons in the rat brain.

Animals↗

PubMed1998

Use of antibodies against estrogen and progesterone receptors to identify metastatic breast and ovarian carcinomas by conventional immunohistochemical and tyramide signal amplification methods.

The immunohistochemical detection of estrogen receptors (ERs) and progesterone receptors (PRs) is useful for the differentiation of cytostatically treatable breast and ovarian carcinomas from other metastatic adenocarcinomas of unknown primary sites. We retrospectively studied metastases of 68 breast, 24 ovarian, 15 bronchogenic, 35 gastric, 22 pancreatic, 23 colonic, 27 renal cell, and 26 primary bronchogenic carcinomas by using a panel of 3 antibodies against ERs and 4 antibodies against PRs and applying both a conventional immunohistochemical detection method and the highly sensitive tyramide signal amplification (TSA) technique. Antibody 6F11 against ERs was slightly more sensitive than clone 1D5 with both detection methods, staining 5% more breast carcinomas and 4% more ovarian carcinomas with TSA, compared with conventional immunohistochemical analysis. Furthermore, clone 6F11 detected ERs in 4 of 26 primary bronchogenic carcinomas and 1 of 35 metastases of gastric carcinomas with conventional immunohistochemical techniques; an additional 9 primary and 6 metastatic bronchogenic carcinomas and 2 metastatic gastric carcinomas were positive with TSA. The resulting specificities for breast and ovarian carcinomas versus all other carcinomas were 0.97 with conventional immunohistochemical techniques and 0.85 with TSA. Antibody 1A6 against PRs was slightly more sensitive but least specific for breast and ovarian carcinomas (specificity was 0.96 with conventional immunohistochemical methods and 0.91 with TSA), compared with antibody hPRa3 and a polyclonal antibody (specificity was 1.00 with both detection methods). Antibodies TE111 against ERs and 10A9 against PRs were significantly less sensitive than the other antibodies. We conclude that TSA cannot be recommended for the detection of ERs and PRs to differentiate breast and ovarian carcinomas from other metastatic adenocarcinomas of unknown primary sites.

Antibodies, Monoclonal↗

PubMed2024

Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models.

PURPOSE: The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results. We performed multiple modeling experiments integrating clinical and demographic data from electronic health records with genetic data to understand which decisions may affect performance. METHODS: Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from 2 large independent health systems, and polygenic risk scores (PRS) were generated across all patients of European ancestry with genetic data in the corresponding biobanks. Crohn's disease was studied based on its substantial genetic component, established electronic health records-based definition, and sufficient prevalence for training and testing. We investigated the impact of choices regarding the PRS integration method, training sample, model complexity, and performance metrics. RESULTS: Overall, our results showed that including PRS resulted in higher performance, but this gain was only robust in situations with limited clinical information. We found consistent performance increases from more compute-intensive models, such as random forest, but the impact of other decisions varied by site. CONCLUSION: This work highlights the importance of considering methodological decision points in interpreting the impact of PRS on prediction performance in clinical models.

Humans↗

PubMed2025

Predicting Weight Loss After Vertical Sleeve Gastrectomy Using a Whole-genome Sequencing-derived Polygenic Risk Score in the All of Us Cohort.

OBJECTIVE: To create a genome-wide polygenic risk score (PRS) to improve prediction of a 12-month percentage weight loss (WL) after vertical sleeve gastrectomy (VSG). BACKGROUND: Variability in post-VSG WL is not well explained by clinical factors. The All of Us program provides access to a 414,830 short-read whole-genome sequencing resource, enabling unbiased discovery of genetic predictors after VSG. METHODS: VSG counts, demographic, anthropomorphic and vital sign information were obtained from the linked electronic health record. The discovery cohort (DC) included participants from version 7 carried into version 8 while the validation cohort (VC) included those newly added to v8. We defined good responders and nonresponders as having WL±1SD from the mean. Following quality filtering, we applied a 2-stage penalized-regression, followed by elastic-net logistic regression, to identify 1583 stable variants and derive β-weights. We then tested this PRS on the DC into a prediction model. RESULTS: We identified 395 participants in the DC and 336 participants in the VC, respectively. Of these, VSG, 44 were classified as good responders (≥37% WL) and 55 as nonresponders (≤19% WL). In the VC, 55 were classified as good responders and 48 as nonresponders. Adding the PRS to models to clinical predictors increased the area under the curve following logistic regression by 0.03; P <4.3 × 10 -14 , random forest by 0.03; P <9.1 × 10 -7 , decision tree by 0.05; P = 1.2 × 10 -3 , and gradient boosting by 0.08; P <8.3 × 10 -10 . CONCLUSIONS: Use of short-read whole-genome sequencing from All of Us (AoU) can be effectively used to generate PRS to enhance predictive WL accuracy. This work has implications for outcomes of both bariatric surgery and other surgical procedures.

Humans↗

PubMed1993

Oestrogen and progesterone receptors in colorectal cancer and human colonic cancer cell lines.

Receptors for oestrogen (ER) and progesterone (PR) were assayed in tissue from 17 patients with colorectal cancer and five colonic cancer cell lines using enzyme immunoassays. ERs and PRs were detected in 15 and 17 cancers respectively, although the levels detected were low: median (range) ER 1.3 (0-11.3) and PR 3.9 (0.3-10.2) fmol per mg protein. These values were not significantly different from median (range) levels of ER (1.1 (0.6-3.0) fmol/mg) and PR (1.9 (0.5-3.2) fmol/mg) detected in normal mucosa. There were significant positive correlations between the levels of ER and PR for cancer tissue (tau = 0.56, P < 0.005; r(log transform) = 0.68, P < 0.003; n = 17) but not for mucosa, and between levels of ER in cancer tissue and mucosa (tau = 0.55, P < 0.05; r(log transform) = 0.70, P < 0.025; n = 10) but not between the corresponding PR values. In maintenance media, which contained phenol red and unstripped fetal calf serum, the median (range) concentration of ER was 1.9 (1.2-10.4) fmol/mg and that for PR 24.3 (9.1-63.2) fmol/mg in the five cell lines studied (HT-29, LS174T, SW620, LoVo, COLO 320DM). The addition of oestradiol (10 nmol/l) to phenol red-free medium containing 5 per cent dextran-coated charcoal-treated fetal calf serum had little effect on the concentration of ERs or PRs in SW620, LoVo and COLO 320DM cells after 7 days' culture. It is concluded that ERs and PRs are expressed in malignant and normal colonic mucosa. ERs appear to be a feature of the colonic mucosa rather than the malignant process, but in carcinoma may regulate synthesis of PRs, suggesting a degree of oestrogen responsiveness.

Aged↗