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Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study
Get PDFThe use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings.
Methods
Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction.
Results
Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility.
Conclusions
This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care
Fibrinogen and Bleeding in Adult Cardiac Surgery: A Review of the Literature
Get PDFBackground: Fibrinogen is a substrate for blood clots formation. In cardiac surgery, a number of different mechanisms lead to a decrease in fibrinogen levels and consequent impaired haemostasis. Patients undergoing cardiac surgery are therefore frequently exposed to blood loss and allogeneic blood transfusion, which are risk factors associated with morbidity and mortality. Thus, particular efforts in fibrinogen management should be made to decrease bleeding and the need for blood transfusion. Therefore, fibrinogen remains an active focus of investigations from basic science to clinical practice. This review aims to summarise the latest evidence regarding the role of fibrinogen and current practices in fibrinogen management in adult cardiac surgery. Methods: The PubMed database was systematically searched for literature investigating the role and disorders of fibrinogen in cardiac surgery and diagnostic and therapeutic procedures related to fibrinogen deficiency aimed at reducing blood loss and transfusion requirements. Clinical trials and reviews from the last 10 years were included. Results: In total, 146 articles were analysed. Conclusion: The early diagnosis and treatment of fibrinogen deficiency is crucial in maintaining haemostasis in bleeding patients. Further studies are needed to better understand the association between fibrinogen levels, bleeding, and fibrinogen supplementation and their impacts on patient outcomes in different clinical settings
Compression Neuropathies of the Upper Extremity: A Review
Get PDFCompressive neuropathies of the forearm are common and involve structures innervated by the median, ulnar, and radial nerves. A thorough patient history, occupational history, and physical examination can aid diagnosis. Electromyography, X-ray, and Magnetic Resonance Imaging may prove useful in select syndromes. Generally, first line therapy of all compressive neuropathies consists of activity modification, rest, splinting, and non-steroidal anti-inflammatory drugs. Many patients experience improvement with conservative measures. For those lacking adequate response, steroid injections may improve symptoms. Surgical release is the last line therapy and has varied outcomes depending on the compression. Carpal Tunnel syndrome (CTS) is the most common, followed by ulnar tunnel syndrome. Open and endoscopic CTS release appear to have similar outcomes. Endoscopic release appears to incur decreased cost baring a low rate of complications, although this is debated in the literature. Additional syndromes of median nerve compression include pronator syndrome (PS), anterior interosseous syndrome, and ligament of Struthers syndrome. Ulnar nerve compressive neuropathies include cubital tunnel syndrome and Guyon’s canal. Radial nerve compressive neuropathies include radial tunnel syndrome and Wartenberg’s syndrome. The goal of this review is to provide all clinicians with guidance on diagnosis and treatment of commonly encountered compressive neuropathies of the forearm
Empagliflozin Use and Fournier’s Gangrene: Case Report and Systematic Literature Review
Get PDFBackground: Fournier’s gangrene (FG) is a rare necrotising soft tissue infection localised in the genital areas with possible dramatic outcomes. Recently, sodium glucose co-transporter-2 (SGLT2) inhibitors were identified as a risk factor. Methods: We present a case report of a 57-year-old female patient with type 2 diabetes mellitus (T2DM) in treatment with empagliflozin which led to the development of FG. Moreover, we performed a systematic review assessing the association between empagliflozin use and FG. Results: The female patient with 15-years treated diabetes presented a massive FG after 6 months from starting empagliflozin. Over the period of two months, she was successfully treated in a low-income setting. The systematic review included two studies with a total of 9915 participants. Although no participant had FG, there was an increased rate of urinary and genital infection in patients treated with empagliflozin compared to those treated with other antidiabetics or placebo. Conclusions: FG should be considered as a possible complication in patients using SGLT2. Patients should be educated to report early signs of genital infection and healthy behaviours as well as a balanced diet should be promoted to aid in the prevention of FG
Chyloperitoneum as the Initial Manifestation of Gastrointestinal Neoplasia
Get PDFhyloperitoneum is defined as the presence of lymph within the peritoneal cavity, resulting from obstruction or injury of lymph ducts, mostly at the level of the gastrointestinal tract. This can occur in the context of congenital diseases, traumas, infections, neoplasms, hepatic disease, heart disease, and postoperative complications. The most common symptoms described are abdominal distention and mild pain in a course of weeks to months, with dyspnea, peritonitis, and in a few cases weight gain is observed due to the high intra-abdominal pressure. We present a case of a 56-year-old male with no significant personal history, who has a clinical picture of approximately three months of evolution, consisting in sensation of an abdominal mass predominantly in the left hemiabdomen, associated with progressive abdominal distension, changes in intestinal habit, lower limb edema, dyspepsia, occasional postprandial emesis, and unintentional weight loss of 20 kg. In non-traumatic conditions, the most frequent cause of chylous ascites is a malignancy disease followed by cirrhosis and mycobacterial infections. Taking into consideration that adenocarcinoma is the most frequently reported histologic subtype of jejunum neoplasm, and that not all cases of lymphoma debut with chylous ascites, it can be concluded that the proportion of patients that present with this condition is exceptionally low. Chyloperitoneum is an infrequent finding, having the higher detection rate in lymphatic alterations and malignancies of gastrointestinal location, in which some of the most commonly neoplasms associated with this complication are lymphoma, neuroendocrine tumors, sarcomas, and leukemia
MSF Hospital in Tabarre, Haiti: Why a Field General Surgery Fellowship Is Necessary
Get PDFRecently, the Hospital at Tabarre in Port-au-Prince Haiti was reopened by the Operational Center of Paris—Médecins Sans Frontières (MSF). This hospital is now purely a Trauma Center staffed by five national general surgeons and five orthopedic surgeons. MSF hopes that the new trauma focus of Tabarre Hospital and the presence of a full complement of experienced national surgeons can enable this site to become one of the training sites for exptriate surgeons on their first humanitarian mission with MSF. The general surgical case charts from the first 3 months after the reopening of the hospital were retrospectively reviewed. All procedures done by the general surgical department in the operating room theatre were registered and short and long-term results analyzed. The Hospital at Tabarre has a very high rate of penetrating traumas compared to other MSF hospitals, and seems ideally suited to train expatriate surgeons during their first missions in the field with MSF because of the experience of the National surgical staff. Additionally, it is felt that a longer Field General Surgery fellowship can and should be developed within MSF to ensure that the next generation of general surgeons can continue to provide the type of surgical care that is still needed in the field
Extracellular Vesicles in Autologous Cell Salvaged Blood in Orthopedic Surgery
Get PDF(1) Background: Cell salvage is highly recommended in orthopedic surgery to avoid allogeneic transfusions. Preparational steps during cell salvage may induce extracellular vesicle (EV) formation with potential thrombogenic activity. The purpose of our study was to assess the appearance of EVs at retransfusion. (2) Methods: After ethics committee approval and informed consent, blood was withdrawn from the autotransfusion system (Xtra, Sorin, Germany) of 23 patients undergoing joint arthroplasty. EVs were assessed by flow cytometry in two times centrifugated samples. EVs were stained with specific antibodies against cellular origins from platelets (CD41), myeloid cells (CD15), monocytes (CD14), and erythrocytes (CD235a). The measured events/µL in the flow cytometer were corrected to the number of EVs in the retransfusate. (3) Results: We measured low event rates of EVs from platelets and myeloid origin (<1 event/µL) and from monocytic origin (<2 events/µL). Mean event rates of 17,042 events/µL (range 12–81,164 events/µL) were found for EVs from red blood cells. (4) Conclusion: Retransfusate contains negligible amounts of potentially thrombogenic EVs from platelet and monocytic origin. Frequent EVs from erythrocytes may indicate red blood cell destruction and/or activation during autologous cell salvage. Further research is needed to investigate the clinical relevance of EVs from salvaged red blood cells
Differential effect of pre-pregnancy low BMI on fetal macrosomia: a population-based cohort study
Get PDFThe differential effect of pre-pregnancy low BMI on macrosomia has not been fully addressed. Herein, we conducted a city-wide population-based cohort study to illuminate the association between pre-pregnancy low BMI and macrosomia, stratifying by maternal age, parity, and GDM status.
Methods
All pregnant women who paid their first prenatal visit to the hospital in Qingdao during August 1, 2018, to June 30, 2020, were recruited to this study. The interactive effect of maternal age and pre-pregnancy low BMI on macrosomia was evaluated using logistic regression models, followed by strata-specific analyses.
Results
A total of 105,768 mother-child pairs were included, and the proportion of fetal macrosomia was 11.66%. The interactive effect of maternal pre-pregnancy BMI and age was statistically significant on macrosomia irrespective of parity (nullipara: Padjusted=0.0265; multipara: Padjusted=0.0356). The protective effect of low BMI on macrosomia was most prominent among nullipara aged 35 years and above (aOR=0.16, 95% CI 0.05–0.49) and multipara aged 25 years and below (aOR=0.17, 95% CI 0.05–0.55). In nullipara without GDM, the risk estimates gradually declined with increasing conception age (20-to-24 years: aOR=0.64, 95% CI 0.51–0.80; 25-to-29 years: aOR=0.43 95% CI 0.36–0.52; 30-to-34 years: aOR=0.40 95% CI 0.29–0.53; and ≥35 years: aOR=0.19, 95% CI 0.06–0.60). A similar pattern could also be observed in nullipara with GDM, where the aOR for low BMI on macrosomia decreased from 0.54 (95% CI 0.32–0.93) in pregnant women aged 25–29 years to 0.30 (95% CI 0.12–0.75) among those aged 30–34 years. However, younger multiparous mothers, especially those aged 25 years and below without GDM (aOR=0.21, 95% CI 0.06–0.68), were more benefited from a lower BMI against the development of macrosomia
Glucocorticoids and breast cancer risk
Get PDFGlucocorticoids are essential endogenous steroid hormones secreted in response to stress, and treatment with synthetic forms is widespread for numerous inflammatory conditions including asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, and arthritis [1]. Emerging evidence suggests that glucocorticoids can exert both anti- and pro-inflammatory effects, modulated through suppressing or augmenting immune response [1]. Given these divergent biologic properties, glucocorticoids could theoretically reduce breast cancer risk via anti-inflammatory effects or could increase breast cancer risk and progression by inducing insulin resistance and promoting immunosuppression [2]. Yet, despite biological plausibility, epidemiologic studies of glucocorticoid use and breast cancer are limited.
New data
As such, the recent prospective cohort study by Cairat et al. [3] is an important contribution to the literature as an investigation into the potential role of glucocorticoids in breast cancer etiology. In this study, authors evaluated associations between glucocorticoid use and breast cancer risk among over 65,000 postmenopausal French women in the E3N cohort. Using linkage to outpatient health expenditures, authors observed that receipt of at least two reimbursements of systemic glucocorticoids was associated with a reduced risk of invasive breast cancer, which appeared to follow a dose-response trend with increasing number of reimbursements. The observed associations did not differ substantially by type of glucocorticoid, or by timing or duration of use. However, inverse associations were significant only among women older than 60 years at first use. In stratified analyses, the inverse associations were restricted to estrogen receptor (ER)-positive tumors, and stage I and II disease. Interestingly, authors also observed positive associations between glucocorticoids and risk of in situ breast cancer and stage III/IV breast cancer, although confidence intervals for these measures of association were wide given smaller numbers of cases. In sensitivity analysis, only recurrent users (not occasional users) were at higher risk of in situ or stage III or IV disease and only recurrent users were at lower risk of stage I or II breast cancer. The authors conclude that the association between systemic glucocorticoid use and breast cancer risk may differ by tumor subtypes and stage of disease.
Unlike prior studies, Cairat et al. were able assess whether the associations of glucocorticoids and breast cancer differed according to hormone receptor status, histological subtype, tumor grade, and stage at diagnosis. This is particularly important given the various pharmacological properties of glucocorticoids and evidence for cross-talk between estrogen receptors and glucocorticoid receptors in mammary epithelial cells [4], which suggests that glucocorticoids could differentially impact breast cancer subtypes. An additional strength of this study was the inclusion of comprehensive information on potential confounders including body mass index, alcohol consumption, family history of breast cancer, and use of nonsteroidal anti-inflammatory medication; factors which were not considered in prior population registry-based studies in Denmark [5, 6] where no associations between receipt of glucocorticoid prescription and breast cancer risk were observed.
This study is informative in teasing apart heterogeneity in glucocorticoid-breast cance
A phenome-wide association study of genetically mimicked statins
Get PDFBeyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c).
Methods
We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c.
Results
As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition.
Conclusions
Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice