PANGEN: an online platform for the comparison and creation of diagnostic gene panels.

Targeted gene panel sequencing is used to limit the search for causative genetic variants solely to genes with an established association with the phenotype. The design of gene panels is challenging due to the lack of consensus regarding phenotypic associations for some genes, which results in high variation in gene composition for the same panel offered by different laboratories. We developed PANGEN, a platform that provides a centralized resource for gene panel information, with the ability to compare and generate new intelligent diagnostic panels. Gene-phenotype associations were collected from 12 public and commercial sources (Blueprint, Cegat, Centogene, ClinGen, Fulgent, GeneDx, Health in Code, Human Phenotype Ontology, Invitae, PanelApp, Prevention genetics, and Pronto diagnostics). Gene-phenotype associations are categorized into tiers according to categories derived from the original source panel. Pairwise panel similarity was calculated by dividing the number of common genes by the total number of genes in both panels. Regions with extreme guanine-cytosine (GC) content were collected from the Genome in a Bottle stratifications dataset, and putative genomic duplications were retrieved from the University of Santa Cruz database. Overall, 1533 panels, 9759 phenotypes, and 6979 genes were collected. The platform provides an interface to (i) explore and compare collected panels, (ii) find similar panels, (iii) identify genes with high GC content or duplication levels, (iv) generate gene panels by combining panels from various sources, and (v) stratify a generated panel into genes with a strong phenotype association ('core') and those with a weaker association ('extended'). The presented platform represents a unique resource for gene panel exploration and comparison that facilitates the generation of tailored diagnostic panels through a public online web server. Database URL: https://c-gc.shinyapps.io/PANGEN/.

Development and Validation of a Colorectal Cancer Prediction Model: A Nationwide Cohort-Based Study.

BACKGROUND: Early diagnosis of colorectal cancer (CRC) is critical to increasing survival rates. Computerized risk prediction models hold great promise for identifying individuals at high risk for CRC. In order to utilize such models effectively in a population-wide screening setting, development and validation should be based on cohorts that are similar to the target population. AIM: Establish a risk prediction model for CRC diagnosis based on electronic health records (EHR) from subjects eligible for CRC screening. METHODS: A retrospective cohort study utilizing the EHR data of Clalit Health Services (CHS). The study includes CHS members aged 50-74 who were eligible for CRC screening from January 2013 to January 2019. The model was trained to predict receiving a CRC diagnosis within 2 years of the index date. Approximately 20,000 EHR demographic and clinical features were considered. RESULTS: The study includes 2935 subjects with CRC diagnosis, and 1,133,457 subjects without CRC diagnosis. Incidence values of CRC among subjects in the top 1% risk scores were higher than baseline (2.3% vs 0.3%; lift 8.38; P value < 0.001). Cumulative event probabilities increased with higher model scores. Model-based risk stratification among subjects with a positive FOBT, identified subjects with more than twice the risk for CRC compared to FOBT alone. CONCLUSIONS: We developed an individualized risk prediction model for CRC that can be utilized as a complementary decision support tool for healthcare providers to precisely identify subjects at high risk for CRC and refer them for confirmatory testing.

Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4.

Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole-exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2-causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/ß-catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/ß-catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain-of-function effect.

[CHARACTERIZATION OF THE INDICATIONS FOR PERFORMING GENE PANEL SEQUENCING TESTS IN A GENOMIC CENTER].

INTRODUCTION: Following the recent human genome revolution, novel technologies have been developed in the last decade enabling advanced sequencing tests, including genetic panel tests that focus on groups of specific genes associated with a certain medical condition (phenotype). Since the process of assembling a genetic panel may be complex and requires significant manpower and time, it is important to define the most common and requested panels, for gradual construction and introduction of panel tests starting with the most common. AIMS: Since no information was found in the literature defining the common panels, the aim of the study was to define the indications for performing a gene panel within the framework of the provided services, and to estimate their frequency. METHODS: Prospective data acquisition was performed by a party responsible for approval of panel tests within Clalit Health Services Organization. The indications for all approved panel tests were registered since the launch of Clalit's Genomic Center. The total number of indications was counted, and according to the Pareto principle, 20% of the most frequent indications were chosen. In addition, the indications were divided into main medical disciplines. RESULTS: Overall, 132 indications were recorded for approved gene panel tests; 20% of these indications, i.e. the first 26 indications in terms of frequency, covered 79.6% of the cases. The most frequent approved panels were epilepsy (10.4%, confidence interval (CI) 8.5-12.6%), Maturity-onset diabetes of the young (MODY) (9.6%, CI 7.8-11.7%), cardiomyopathy (8.3%, CI 6.6-10.3%) and hearing impairment (7.6%, CI 6.0-9.6%). The most common disciplines in descending order were neurological diseases (23.0%, CI 20.3-25.9%), endocrinology (13.1%, CI 11.1-15.6%), heart diseases (9.0%, CI 7.3-11.1%) and eye diseases (7.8%, CI 6.2-9.8%). CONCLUSIONS: A review of panel approvals at the Genomic Center of Clalit showed a number of frequent indications. DISCUSSION: We believe this information can be useful for the establishment of genomic laboratories, as well as for the improvement of the service to the patients, by enabling the referral for specific panel tests by medical experts who are not geneticists or genetic counselors, after appropriate training (such as the "Genetics First" program of Clalit).

Data From a One-Stop-Shop Comprehensive Cancer Screening Center.

PURPOSE: Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit. METHODS: Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate. RESULTS: Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10). CONCLUSION: We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].

Impact of Post-Transplantation Hypomagnesemia on Long-Term Graft and Patient Survival after Transplantation.

BACKGROUND: Post-transplant hypomagnesemia is commonly observed among patients prescribed calcineurin inhibitor (CNIs). METHODS: We conducted a retrospective single-center analysis (2000-2013, N = 726) to examine the association of hypomagnesemia with long-term patient and allograft outcomes in kidney transplant recipients. A median serum magnesium (Mg) level of all measured Mg levels from 1 month to 1 year posttransplant was calculated. RESULTS: For every increase in Mg of 0.1 mg/dL, the risk for either graft loss or death, overall mortality, and death with a functioning graft increased by 11%, 14%, and 12%, respectively (p < 0.01). In a multivariate model, patients with median Mg level ≥1.7 mg/dL had a reduced overall survival rate (HR 1.57, 95% CI: 1.04-2.38, p = 0.033) compared to those with median Mg level <1.7 mg/dL. This association was observed in subgroups of patients above 60 years old, in those who had a slow graft function (SGF) and in females. CONCLUSIONS: Posttransplant hypomagnesemia is associated with better patient and allograft survival up to 10 years posttransplant. This relationship remained significant after accounting for baseline allograft function, presence of SGF and CNI trough levels.

Rapid 8-Zone Lung Ultrasound Protocol is Comparable to a Full 12-Zone Protocol for Outcome Prediction in Hospitalized COVID-19 Patients.

OBJECTIVES: Safety precautions limit the clinical assessment of hospitalized Coronavirus disease 2019 (COVID-19) patients. The minimal exposure required to perform lung ultrasound (LUS) paired with its high accuracy, reproducibility, and availability make it an attractive solution for initial assessment of COVID-19 patients. We aim to evaluate whether the association between sonographic findings and clinical outcomes among COVID 19 patients is comparable between the validated 12-zone protocol and a shorter, 8-zone protocol, in which the posterior lung regions are omitted. METHODS: One hundred and one COVID-19 patients hospitalized in a dedicated COVID-19 ward in a tertiary referral hospital were examined upon admission and scored by 2 LUS protocols. The association between the scores and a composite outcome consisting of death, transfer to the intensive care unit (ICU) or initiation of invasive or noninvasive mechanical ventilation was estimated and compared. RESULTS: LUS scores in both the 8- and the 12-zone protocols were associated with the composite outcome during hospitalization (hazard ratio [HR] 1.21 [1.03-1.42, P = .022] and HR 1.13 [1.01-1.27, P = .037], respectively). The observed difference in the discriminatory ROC-AUC values for the 8- and 12-zone scores was not significant (0.767 and 0.754 [P = .647], respectively). CONCLUSION: A short 8-zone LUS protocol is as accurate as the previously validated, 12-zone protocol for prognostication of clinical deterioration in nonventilated COVID-19 patients.

Treatment with Ixekizumab Following Secukinumab Failure in Patients with Psoriatic Arthritis: Real-Life Experience from a Resistant Population.

OBJECTIVE: To assess the clinical response to ixekizumab following secukinumab failure in patients with psoriatic arthritis. METHODS: A retrospective multi-center observational study included psoriatic arthritis (PsA) patients with a history of treatment with secukinumab, further treated with ixekizumab. Primary endpoint was primary response to treatment (drug survival > 6 months); secondary endpoints were changes in disease activity indices from initiation of ixekizumab to 6 and 12 months later and overall drug survival. RESULTS: Of 23 PsA patients, 86% (n = 20) received more than two TNF inhibitors (TNFi). Median secukinumab treatment time was 15 months (IQR 10-21.5 months). Subsequently, 19 patients (83%) had a primary response to ixekizumab. Overall treatment duration during follow-up period for primary responders was 14 months (IQR 10-20.5). Reasons for ixekizumab cessation were worsening psoriasis (27%), peripheral arthritis (27%), both (47%), worsening of axial disease (13%), and adverse events (6%). Articular disease indices including Disease Activity Index for Psoriatic Arthritis (DAPSA), tender joints count (TJC) and Simplified Disease Activity Index (SDAI) were significantly lower at 6 and 12 months (DAPSA 1.5-2 levels reduction; p = 0.018 and 1-1.5 levels reduction; p = 0.031, respectively; TJC -2.16 [-4.0, -0.3]; p = 0.025 and -1.69 [-3.09, -0.28]; p = 0.022, respectively; SDAI -10.13 [-16.4, -3.8], p = 0.003 and -12.2 [-17.1, -7.2], p = 0.0002, respectively). PASI75 at 6 and 12 months was achieved by 63% and 57%, respectively, and PASI100 at 6 and 12 months by 31% and 21%, respectively. CONCLUSION: Patients with resistant PsA, including inadequate response to secukinumab, demonstrated a good response to ixekizumab, albeit limited on time. Within class switch from secukinumab to ixekizumab may be a plausible therapeutic option in PsA patients following secukinumab failure.

Targeted therapies for immune thrombocytopenic purpura: a meta-analysis of randomized controlled trials.

Several targeted therapies have been approved in recent years for second-line treatment of immune thrombocytopenic purpura (ITP), providing an alternative to rituximab and splenectomy. The extent to which these drugs reduce bleeding risk has not been well defined. Targeted therapies recently approved for the treatment of ITP in adults were identified through a search of recently published professional guidelines. Randomized controlled trials (RCTs) supporting regulatory approval were identified through a search of drug labels on FDA@gov. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were computed for pre-specified efficacy outcomes including platelet recovery to ≥ 50,000/µL, major and minor bleeding events, and survival. ORs for all adverse events were also computed. Four targeted therapies were identified, including three thrombopoietin receptor agonists and one tyrosine kinase inhibitor. Six RCTs, comprising 752 patients, were included in the meta-analysis. More patients treated with targeted therapies for ITP as compared to placebo achieved platelet counts over ≥ 50,000/µL (OR 8.29, 95% CI 5.59-12.29). Compared to placebo, targeted therapies for ITP were associated with significantly lower odds for major bleeding (OR 0.43, 95% CI 0.21-0.91), minor bleeding (OR 0.66, 95% CI 0.45-0.97), and with numerically lower mortality rates (OR 0.24, 95% CI 0.05-1.07). The odds for adverse events were comparable between the two arms (OR 1.43 95% CI 0.76-2.67). Compared to placebo, targeted therapies for ITP increase platelet counts, decrease bleeding events, and show a trend towards lower mortality, without increased toxicity. These findings support their use as a second-line ITP treatment.

Can uric acid blood levels in renal transplant recipients predict allograft outcome?

BACKGROUND: Hyperuricemia is common after renal transplantation, especially in those receiving calcineurin inhibitors. Little, however, is known about the relationship between uric acid (UA) levels and allograft outcome. METHODS: We conducted a retrospective single-center analysis (N = 368) in order to assess UA blood levels post-transplant association with allograft outcome. For this study, a median serum UA level of all measured UA levels from 1 month to 1 year post renal transplantation was calculated. RESULTS: Patients were divided into 2 groups based on the median UA level measured between 1 and 12 months post-transplant. Those with median UA level ≥ 7 and ≥ 6 mg/dL (N = 164) versus median UA level < 7 and < 6 mg/dL for men and women respectively (N = 204) had lower GFR values at 1, 3 and 5 years posttransplant (mean GFR ± SD of 43.4 ± 20.6 and 58 ± 19.9 at 3 years post-transplant, p < 0.001). In multivariate models, UA levels were no longer significantly associated with renal allograft function. In a multivariate cox proportional hazard model, UA level was found to be independently associated with increased risk for death-censored graft loss (HR of 1.3, 95% CI 1.0-1.7, p < 0.05 for every increase of 1 mg/dL in UA level). CONCLUSION: Hyperuricemia was found to be associated with increased death- censored graft loss but not with allograft function. Increased UA levels were not found to be an independent predictor of long-term allograft function despite the known association of hyperuricemia with the progression of cardiovascular and renal disease.

Assessing the involvement of the placental microbiome and virome in preeclampsia using non coding RNA sequencing.

OBJECTIVES: Preeclampsia is a dangerous pregnancy complication. The source of preeclampsia is unknown, though the placenta is believed to have a central role in its pathogenesis. An association between maternal infection and preeclampsia has been demonstrated, yet the involvement of the placental microbiome in the etiology of preeclampsia has not been determined. In this study, we examined whether preeclampsia is associated with an imbalanced microorganism composition in the placenta. METHODS: To this end, we developed a novel method for the identification of bacteria/viruses based on sequencing of small non-coding RNA, which increases the microorganism-to-host ratio, this being a major challenge in microbiome methods. We validated the method on various infected tissues and demonstrated its efficiency in detecting microorganisms in samples with extremely low bacterial/viral biomass. We then applied the method to placenta specimens from preeclamptic and healthy pregnancies. Since the placenta is a remarkably large and heterogeneous organ, we explored the bacterial and viral RNA at each of 15 distinct locations. RESULTS: Bacterial RNA was detected at all locations and was consistent with previous studies of the placental microbiome, though without significant differences between the preeclampsia and control groups. Nevertheless, the bacterial RNA composition differed significantly between various areas of the placenta. Viral RNA was detected in extremely low quantities, below the threshold of significance, thus viral abundance could not be determined. CONCLUSIONS: Our results suggest that the bacterial and viral abundance in the placenta may have only limited involvement in the pathogenesis of preeclampsia. The evidence of a heterogenic bacterial RNA composition in the various placental locations warrants further investigation to capture the true nature of the placental microbiome.

Efficacy of a second external cephalic version (ECV) after a successful first external cephalic version with subsequent spontaneous reinversion to breech presentation: a retrospective cohort study.

OBJECTIVE: Determining the efficacy of performance of a second external cephalic version (ECV) following successful first ECV with subsequent spontaneous reinversion to breech presentation in reducing the rate of cesarean delivery (CD). METHODS: Data were reviewed on healthy women with fetuses in breech presentation who underwent a first ECV after 36 weeks. Routine ultrasound study was performed at 39-week gestation, and a repeat ECV procedure was performed if the fetus had reverted to non-cephalic presentation. Obstetrical outcome measures were compared between women who underwent one successful ECV between 36- and 41-week gestation in which the fetus remained in cephalic presentation until labor and those who underwent a successful first ECV after which the fetus returned to breech and a second ECV was performed. The primary outcome was the rate of secondary CD during vaginal delivery in cephalic presentation; rate of successful second ECV was the secondary outcome. RESULTS: Overall 250 women underwent one ECV attempt of which 169 (67%) were successful. Of them 28 reverted to breech presentation, all women underwent two attempts of which 21 (76%) were successful. A second successful ECV attempt was associated with a 33% incidence of a CD vs. 2.8% after one successful ECV in which the fetus remained in cephalic presentation. CONCLUSION: A second ECV after a successful first ECV with subsequent spontaneous reversion to breech presentation can be expected to be successful in 76% of cases but lead to CD in 33% of cases. Our findings can be used to support patient counseling and decision-making before second ECV attempt.

Effect of liver fibrosis on survival in patients with intrahepatic cholangiocarcinoma: a SEER population-based study.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a biliary tract malignancy with rising incidence in recent decades. While the causative role of cirrhosis in the development of iCCA is well established, the role of cirrhosis as a prognostic factor in iCCA is debatable. MATERIALS AND METHODS: The study population consisted of 512 patients diagnosed with iCCA between 2004-2016 collected from the Surveillance, Epidemiology and End Results (SEER) database. The impact of fibrosis on overall and cancer-specific survival 12, 36 and 60 months following diagnosis, was evaluated in the entire cohort and in sub-groups stratified according to treatment approach and the American Joint Committee on Cancer (AJCC) tumor stage using a Cox proportional-hazards model. RESULTS: After adjusting for age, sex, race, year of diagnosis, AJCC stage, and surgical treatment strategy, advanced fibrosis was associated with worse cancer-specific survival across follow up periods (HR 1.49 (1.13-1.96, p = 0.005); HR 1.44 (1.14-1.83, p = 0.002) and HR 1.45 (1.15-1.83, p = 0.002) for 12, 36 and 60 months, respectively). Similar effects were observed for overall survival. Among patients that underwent surgical resection, advanced fibrosis was associated with worse overall survival and cancer-specific survival across follow up periods. Fibrosis was associated with worse overall and cancer-specific survival in patients with a later stage (III-IV) at diagnosis but this effect was not demonstrated in early stages. CONCLUSIONS: Patients with iCCA and advanced liver fibrosis have an increased risk of both overall and cancer-specific mortality compared to patients with earlier stages of fibrosis.

Posttransplantation Hypomagnesemia as a Predictor of Better Graft Function after Transplantation.

BACKGROUND: Hypomagnesemia is frequently seen after transplantation and is particularly associated with the use of calcineurin inhibitors (CNIs). METHODS: We conducted a retrospective, single-center analysis (2000-2013, N = 726) to explore the relationship between hypomagnesemia and long-term allograft outcome in kidney transplant recipients. For this study, a median serum magnesium (Mg) level of all measured Mg levels from 1 month to 1 year after renal transplantation was calculated. RESULTS: For every increase in Mg by 0.1 mg/dL, the GFR decreased by 1.1 mL/min at 3 years posttransplant (p < 0.01) and by 1.5 mL/min at 5 years posttransplant. A median blood Mg level of ≥1.7 was found to be an independent predictor of a GFR <60 mL/min at 3 years posttransplant. The odds of having a GFR <60 mL/min 3 years posttransplant was almost 2-fold higher in the high Mg group than in the low Mg group. CONCLUSIONS: Hypomagnesemia from 1 to 12 months after renal transplantation is associated with a better allograft function up to 5 years posttransplant. This relationship was found to hold true after accounting for baseline allograft function and the presence of slow graft function.

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

Early persistent hyperparathyroidism post-renal transplantation as a predictor of worse graft function and mortality after transplantation.

BACKGROUND: Persistent hyperparathyroidism (pHPT) is frequently seen after transplantation contributing to post-transplant complications. METHODS: We conducted a retrospective single center analysis to explore the relationship of early pHPT and long-term allograft outcome. Patients were divided into high (N = 153) and low (N = 252) PTH groups based on serum parathyroid hormone (PTH) level 3 months post-transplant (PTH ≥ 150 and < 150 pg/mL, respectively). RESULTS: High PTH was found to be an independent predictor for reduced kidney allograft function up to 3 years post-transplant. eGFR decreased by 11.4 mL/min (P < .001) and the odds of having an eGFR < 60 mL/min 3 years post-transplant were sixfold higher (P < .01) in the high compared to the low PTH group. Subgroup analysis based on eGFR 1 year post-transplant, presence of slow graft function (SGF), and transplant type revealed similar results. High PTH three months post-transplant was also independently associated with an increased risk for overall mortality and for death with a functioning graft (P < .05). CONCLUSIONS: pHPT three months post-renal transplantation is an independent predictor for a worse allograft function up to 3 years post-transplant and a risk factor for mortality. This relationship remains statistically significant after accounting for baseline allograft function, presence of SGF and serum mineral levels abnormalities.

The effects of a postmiscarriage menstrual period prior to reconceiving.

BACKGROUND: The optimal interpregnancy interval after a single pregnancy loss is controversial. It is common obstetrical practice to recommend that women who have had a miscarriage in the first trimester of pregnancy should wait for 1 or more menstrual cycles before attempting to conceive again. OBJECTIVE: This study aimed to assess whether conception before the first menstrual period after a spontaneous pregnancy loss is associated with a risk of repeat miscarriage or adverse perinatal outcomes. STUDY DESIGN: This retrospective cohort study included 107 women who had a spontaneous miscarriage in the first trimester of pregnancy followed by a subsequent pregnancy with an interpregnancy interval of <12 weeks. All miscarriages had ended in either spontaneous expulsion of the products of conception or medical or surgical evacuation of the uterus. The perinatal outcome measures of 57 women who conceived after the first menstrual period following a spontaneous miscarriage were compared with perinatal outcome measures of 50 women who conceived before the first menstrual period following a spontaneous miscarriage. The primary outcome was rate of pregnancy loss, and the secondary outcomes were gestational age at delivery and birthweight. RESULTS: The rate of recurrent miscarriage was 10.4% for women who conceived before the first menstrual period following a spontaneous miscarriage and 15.8% for those who conceived after (P=.604). There were no differences in the gestational age at delivery (38.9 vs 38.7 weeks; P=.66) or the birthweight (3347±173 vs 3412±156 g; P=.5) between the 2 groups. Other outcomes, such as mode of delivery and 5-minute Apgar score, were also similar for both groups. A multiple logistic regression analysis confirmed that conception before the first menstrual period following a spontaneous miscarriage was not associated with a higher incidence of subsequent miscarriage (odds ratio, 1.74; P=.46) or any other untoward outcome. CONCLUSION: Conception shortly after a spontaneous miscarriage without waiting for at least the first postmiscarriage menstrual period is not associated with adverse maternal or neonatal outcomes compared with those of women with similar interpregnancy intervals who conceived after their next menstrual period.

Effect of Ticagrelor on Reducing the Risk of Gram-Positive Infections in Patients With Acute Coronary Syndrome.

In light of recent studies describing the antibacterial properties of ticagrelor, the association between treatment with ticagrelor and subsequent risk for infection following acute coronary syndrome (ACS) is taking on increased importance. A single center, retrospective, matched cohort analysis was performed. All patients older than 30 years of age admitted between January 1, 2013 and November 1, 2019 for an ACS and discharged with dual antiplatelet therapy (DAPT) were included. The primary outcome was defined as hospital admissions due to infections likely caused by gram-positive bacteria up to 1 year following the ACS hospitalization. The base cohort included 3,909 patients. About 2,035 (52.1%) were treated with ticagrelor and 1,874 (47.9%) with clopidogrel. Patients treated with ticagrelor had a 64% lower risk of gram-positive infection during the first year following hospitalization after adjusting for demographic and co-morbidity factors compared with those treated with clopidogrel (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21 to 0.61; p <0.001). In a cohort starting from 1 year (conclusion of DAPT period) and up to 3 years following ACS hospitalization, the risk of gram-positive infection was comparable in both groups (HR, 0.70; 95% CI, 0.41 to 1.19; p = 0.182). Treatment with ticagrelor was not associated with a reduced risk of gram-negative infections (HR, 0.48; 95% CI, 0.21 to 1.06; p = 0.07). In conclusion, DAPT regimen that includes aspirin and ticagrelor is associated with reduced risk of gram-positive infection compared with the combination of aspirin and clopidogrel.

Resection Versus Observation of Small Asymptomatic Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Management of asymptomatic, nonfunctioning small pancreatic neuroendocrine tumors (PNETs) is controversial because of their overall good prognosis, and the morbidity and mortality associated with pancreatic surgery. Our aim was to compare the outcomes of resection with expectant management of patients with small asymptomatic PNETs. METHODS: Retrospective review of patients with nonfunctioning asymptomatic PNETs < 2 cm that underwent resection or expectant management at the Tel-Aviv Medical Center between 2001 and 2018. RESULTS: Forty-four patients with small asymptomatic, biopsy-proven low-grade PNETs with a KI67 proliferative index < 3% were observed for a mean of 52.48 months. Gallium67DOTATOC-PET scan was completed in 32 patients and demonstrated uptake in the pancreatic tumor in 25 (78%). No patient developed systemic metastases. Two patients underwent resection due to tumor growth, and true tumor enlargement was evidenced in final pathology in one of them. Fifty-five patients underwent immediate resection. Significant complications (Clavien-Dindo grade ≥ 3) developed in 10 patients (18%), mostly due to pancreatic leak, and led to one mortality (1.8%). Pathological evaluation revealed lymphovascular invasion in 1 patient, lymph node metastases in none, and a Ki67 index ≥ 3% in 5. No case of tumor recurrence was diagnosed after mean follow-up of 52.8 months. CONCLUSIONS: No patients with asymptomatic low-grade small PNETs treated by expectant management were diagnosed with regional or systemic metastases after a 52.8-month follow-up. Local tumor progression rate was 2.1%. Surgery has excellent long-term outcomes, but it harbors significant morbidity and mortality. Observation can be considered for selected patients with asymptomatic, small, low grade PNETs.

Prediction of Success in External Cephalic Version for Breech Presentation at Term.

OBJECTIVE: To design a clinically based predictive model for the likelihood of successful external cephalic version (ECV). METHODS: This single-center retrospective study was conducted from February 2016 to July 2018 and included all candidates for ECV between 36 and 41 weeks of gestation. Variables with a potential effect on ECV success were collected. These variables include: body mass index, amniotic fluid index, gestational age, parity, location of placenta, fetal trunk posture, time in breech presentation before the procedure and the ultrasonographically measured size of the amniotic fluid preceding the fetal presenting part (fore-bag). Variables' association with ECV success was evaluated using a multivariate logistic regression and a decision tree predicting ECV outcome was developed using 75% of the patients and validated on the remaining 25%. RESULTS: Overall, 250 pregnant women were identified and opted for a trial of ECV by a single operator, with a success rate of 64.8%. Body mass index, size of fore-bag, and parity were independent determinants of the version success, whereas other variables had no statistically significant effect on the success rate. Our decision tree model divided the cohort into five subgroups according to various combinations of the three variables. When evaluated on the internal validation set, the C-Index of the tree was 0.933 (0.863-1) and the prediction accuracy was 91.9% (86.5%-97.3%). CONCLUSION: A prediction model composed of three easily measurable variables enables accurate prediction of successful ECV at term. Fore-bag was identified as the most important discriminator. Our model holds in internal validation and it can be used to support patient counseling and decision making for ECV but should be externally validated.