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Objective: Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods: This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions: Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

Objectives: To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants. Methods: A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta‐analysis, only studies with ≥ three ACC cases were included. Meta‐analysis of proportions was employed using a random‐effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria. Results: A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta‐analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35–73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30–57%)) and isolated ACC (32% (95% CI, 18–51%)). Conclusions: ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The authors of the article titled "Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype" respond to comments made by Dr. Finsterer. They clarify that their study did not report on cases of intrauterine fetal death, but rather on cases of termination due to fetal anomalies. They also explain that functional or biochemical testing is not mandatory for determining variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines. The authors provide evidence supporting the pathogenicity of the NDUFAF5 variants they studied and acknowledge the need for further research on one of the variants. They assert that their study contributes to the understanding of prenatal presentations of NDUFAF5-associated disorders and emphasize the challenges of studying prenatal phenotypes. The authors address Dr. Finsterer's mention of other possible abnormalities associated with NDUFAF5 variants and state that the lack of demonstration does not negate their assumption that these variants are causative of the congenital anomalies described in their study. They also clarify that family history and parental carrier status were included in their original manuscript. [Extracted from the article]

Objective: Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly.Methods: This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs).Results: CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs.Conclusions: In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This has been discussed in detail in a recent systematic review by Mellis I et al i .[2], demonstrating that the incremental diagnostic yield of ES over CMA/karyotyping was 15% for non-selected fetal anomalies, 42% for selected anomalies and 17% for CNS anomalies. While patients were offered concurrent chromosomal microarray analysis (CMA) and exome sequencing (ES), most opted for termination of pregnancy even before receiving a genetic test result due to the severity of anomalies and because ES in pregnancy is currently not covered by the Israeli healthcare system. Even if the fetal phenotype may not appear to be severe enough to warrant termination of pregnancy, a genetic test result may point to a severe neurodevelopmental issue that has only mild physical manifestations. [Extracted from the article]

In addition to ventriculomegaly, abnormal corpus callosum and adducted thumbs, fetal MRI has also detected diencephalic and midbrain-hindbrain malformations in most fetuses affected by the L1 syndrome. L1 syndrome includes a spectrum of X-linked disorders caused by pathogenic variants of L1CAM gene, which encodes a cell adhesion molecule involved in the central nervous system (CNS) development. In addition to the evaluation of lateral ventricles, corpus callosum and cortical development, thalami and midbrain-hindbrain were investigated. [Extracted from the article]

OC12.05: Early second trimester diagnosis of fetal midbrain-hindbrain malformations: a transvaginal neurosonographic study To describe the clinical and neurosonographic features of fetal midbrain-hindbrain (MBHB malformation diagnosed at 14-18 weeks. The MBHB abnormalities include; kinking of the brainstem (KBS) (n = 3), Joubert syndrome (JS) (n = 2), aqueductal stenosis (AS) (n = 11), rhombencephalosynapsis (RES) (n = 3), "open" fourth ventricle (OFV) (n = 6), and Mobius syndrome (MS) (n = 1). [Extracted from the article]

The article considers the benefits of contingent screening against primary screening by cell-free DNA testing. Topics discussed include non-invasive prenatal testing (NIPT) via cell-free DNA analysis, NIPT implementation in public-health-based programs, and the lack of evidence for additional perceived benefits of serum screening or nuchal translucency (NT) measurement.

Variants of unknown significance (VUS) poses a dilemma in prenatal genetic testing and counselling. Methods Cases were selected from a cohort of 87 patients who underwent TOP for major CNS anomalies and presented VUS either in genetic assessment. [Extracted from the article]

The article presents the author's views on the non-invasive prenatal testing (NIPT) for pregnant women who want to detect trisomy 21 in their unborn child. It states that NIPT improve the quality of prenatal testing for fetal abnormalities. It further discusses aneuploidy screening, chromosomal microarray analysis and testing in pregnancy.

Fetal imaging findings (US, MRI or both) of fetuses with copy number variants (CNVs) or pathogenic/likely pathogenic sequence variants (SVs) were compared to the classical phenotype described by the literature. OC01.02: Genotype-phenotype correlation in fetuses with major brain malformations using whole-exome sequencing When performing fetal ultrasound (US) we are confronted with the difficult task of finding a correlation between imaging findings, diagnosis and prognosis. [Extracted from the article]

OC06.07: Maternal plasma genome-wide cell-free DNA testing can detect fetal aneuploidy in pregnancy loss and can be used to guide further work-up in recurrent losses However, the most common cause of miscarriage, even in RPLs, is random chromosomal aberrations (trisomy, monosomy, triploidy). We suggest that cfDNA-based testing serve to guide management in RPLs: if cfDNA in the 2nd and subsequent RPL demonstrates aneuploidy, no further action is taken; if cfDNA demonstrates an unbalanced rearrangement, parental karyotypes is recommended; and if no abnormality is detected, then the recommended RPL workup is performed. [Extracted from the article]

Background: As exposure to UV radiation is the primary modifiable environmental risk factor associated with skin cancer, it remains the principal focus of most prevention strategies. Numerous sun protection campaigns have been implemented worldwide; however, their impact on the actual incidence and mortality rates of skin cancer seems to be limited. To create successful skin cancer prevention campaigns, it is important to have a comprehensive understanding of individuals' attitudes and behaviours regarding sun protection. The aim of the current study was to determine and report on the prevalence of self-reported attitudes, knowledge and behaviours regarding two of the major sun protection recommendations-avoidance of sun exposure and use of sunscreens-in an international representative sample across five continents., Methods: This cross-sectional study was conducted in 20 countries using a web-based online survey., Findings: A total of 50,552 individuals, comprising 25,388 men (50.22%) and 25,164 women (49.78%), participated in the survey. Among them, 83.2% reported having been voluntarily exposed to the sun (for sun-basking reasons) at least once in the last 12 months, and 47.96% acknowledged being exposed to the sun between the hours of 10 AM and 4 PM. The primary reason for non-adherence was that these hours were the most convenient times (32.28%). Only 24.05% reported applying sunscreen every 2 h when outdoors. Forgetfulness was the primary reason as provided by 27.79% of participants. Males and older age groups were less likely to adopt sun-protective behaviours around the world. Forgetfulness and the challenges posed by time constraints seem to be the biggest barriers to proper adherence., Interpretation: These findings should prompt the collaboration with health authorities and the manufacturers to enhance adherence by setting reasonable sunscreen prices and creating formulations that make their application less burdensome., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Data science methodologies can be utilized to ascertain and analyze clinical genetic data that is often unstructured and rarely used outside of patient encounters. Genetic variants from all genetic testing resulting to a large pediatric healthcare system for a 5-year period were obtained and reinterpreted utilizing the previously validated Franklin© Artificial Intelligence (AI). Using PowerBI©, the data were further matched to patients in the electronic healthcare record to associate with demographic data to generate a variant data table and mapped by ZIP codes. Three thousand and sixty-five variants were identified and 98% were matched to patients with geographic data. Franklin© changed the interpretation for 24% of variants. One hundred and fifty-six clinically actionable variant reinterpretations were made. A total of 739 Mendelian genetic disorders were identified with disorder prevalence estimation. Mapping of variants demonstrated hot-spots for pathogenic genetic variation such as PEX6-associated Zellweger Spectrum Disorder. Seven patients were identified with Bardet-Biedl syndrome and seven patients with Rett syndrome amenable to newly FDA-approved therapeutics. Utilizing readily available software we developed a database and Exploratory Data Analysis (EDA) methodology enabling us to systematically reinterpret variants, estimate variant prevalence, identify conditions amenable to new treatments, and localize geographies enriched for pathogenic variants., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background/objectives: Recent literature highlights the potential of biologics in the management of inherited disorders of keratinisation. In this study, we conducted a systematic review of existing literature on treatment outcomes of inherited keratinisation disorders treated with biologics., Methods: Eligible records were retrieved through searches of the electronic databases MEDLINE, Embase, PubMed and Scopus. Databases were searched from inception to July 2023 for eligible records. A snowballing method was employed to search the references of the retrieved records for the identification of potentially relevant articles., Results: One hundred and four eligible studies consisting of a total of 166 patients with an inherited disorder of keratinisation were included. Patients had a median age of 19 years (range: 0.5 to 70 years). The most common disorders were Netherton syndrome (n = 63; 38%), autosomal recessive congenital ichthyoses (n = 27; 16%), CARD14-associated papulosquamous eruptions (n = 17; 10%) and familial pityriasis rubra pilaris (PRP) (n = 15; 9%).Of the 207 times biologics were employed, the three most frequently employed biologics were secukinumab (n = 47; 23%), dupilumab (n = 44; 21%) and ustekinumab (n = 37; 18%). Complete remission was observed in 10 (5%) instances, partial remission in 129 (62%), no or limited response to biologic therapy in 68 (32%) cases, and results are still pending in one case. A total of 33 adverse events were reported., Conclusions: Whilst biologics may be considered in cases of inherited keratinisation disorders recalcitrant to standard therapy, definitive conclusions are prohibited by the low-level of evidence and substantial heterogeneity in methodology across the included studies. Establishment of consensus definitions, and randomised clinical trials may help ascertain the efficacy and safety of biologic therapy in this context and establish the best agent and dosing protocol for each disorder., (© 2023 The Authors. Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

Transgender and gender diverse (TGD) individuals are a group that experiences significant health disparities. In the multidisciplinary management of TGD patients, dermatologists may participate in managing skin- and hair-related issues which contribute to gender affirmation and to the cutaneous sequelae of gender-affirming hormone therapy. This review aims to highlight the unique needs of TGD patients, particularly from the perspective of Australian dermatologists. We review appropriate terminology critical for TGD care, gender affirmation in the Australian healthcare landscape, dermatological considerations for TGD patients and considerations for management., (© 2023 The Authors. Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

Background and Aims: Fatty liver is common in obesity as well as in partial lipodystrophy (PL) syndromes, characterized by deficient adipose tissue. Insulin resistance is key to fatty liver pathogenesis in both entities. We aimed to compare the contributions of insulin resistance and adipose tissue to hepatic steatosis in PL and non-syndromic, obesity-associated non-alcoholic fatty liver disease (NS-NAFLD)., Methods: In a cross-sectional comparison of people with NS-NAFLD (N = 73) and PL (N = 27), liver fat was measured by FibroScan ® controlled attenuation parameter (CAP) and insulin resistance by HOMA-IR, Adipo-IR, and NMR-based LP-IR., Results: Insulin resistance was greater in PL versus NS-NAFLD by HOMA-IR (p = 0.005), Adipo-IR (p = 0.01) and LP-IR (p = 0.05) while liver fat was comparable (304 vs. 324 dB/m, p = 0.12). Liver fat correlated with HOMA-IR in both groups, but CAP values were lower by 32 dB/m in PL compared with NS-NAFLD for any given HOMA-IR. In contrast, Adipo-IR and LP-IR correlated with CAP only in the NS-NAFLD group, suggesting different pathways for fat accumulation. Plasma free fatty acids, reflecting substrate input from the adipose tissue, were comparable between groups. However, the levels of β-hydroxybutyrate, a marker of β-oxidation, and large triglyceride-rich lipoprotein particles, a marker of VLDL secretion, were both higher in PL (p < 0.001 for both)., Conclusion: Liver fat content was comparable in subjects with PL-associated NAFLD and NS-NAFLD, despite worse insulin resistance in partial lipodystrophy. Our data demonstrate higher triglyceride oxidation and export in PL, suggesting a compensatory shift of fat from liver storage into the circulation that does not occur in NS-NAFLD., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Men harboring prolactinomas frequently suffer from central hypogonadism with secondary anemia. They present insidious and nonspecific symptoms of hypogonadism, making it difficult to diagnose the disease and determine its duration. The result is a delay in diagnosis, which may have harmful hormonal and metabolic consequences. We hypothesized that a decrease in hemoglobin (HB) levels prior to prolactinoma diagnosis, may signal hyperprolactinemia onset and estimate disease duration., Methods: We retrospectively evaluated the prediagnosis temporal trends in HB levels of 70 males with prolactinoma, diagnosed from January 2010 to July 2022. Men without hypogonadism, patients that received testosterone, and those with unrelated anemia were excluded., Results: Sixty-one of seventy men (87%) with prolactinoma presented with hypogonadism, and forty men (57%) had HB levels ≤13.5 g/dL at diagnosis. We identified 25 patients with "informative" HB curves (mean age, 46.1±14.9 years; median prolactin, 952 ng/mL; median follow-up, 14.0 years), demonstrating an obvious prediagnosis HB decrease (greater than 1.0 g/dL), from a prediagnosis baseline HB of 14.4 ± 0.3 to 12.9 ± 0.5 g/dL at diagnosis. The median "low-HB duration" (from the first low HB measurement to hyperprolactinemia diagnosis) was 6.1 years (IQR, 3.3-8.8 years). In symptomatic patients, we identified a correlation between "low-HB duration" and patient-reported sexual dysfunction duration (n = 17, R = 0.502, p = 0.04). The "low-HB duration" was significantly longer than the reported sexual dysfunction duration (7.0 ± 4.5 vs. 2.9 ± 2.5 years, p = 0.01)., Conclusions: In our cohort of men with prolactinomas and hypogonadism, we found a marked decrease in HB levels that preceded prolactinoma diagnosis by a median of 6.1 years, with a mean delay of 4.1 years between HB decrease and hypogonadal symptoms appearance. These results suggest that HB decline prior to prolactinoma diagnosis may serve as a marker for hyperprolactinemia onset in a subset of hypogonadal men and allow a more accurate assessment of disease duration., (© 2023 American Society of Andrology and European Academy of Andrology.)

Background Little is known about the impact of transcatheter mitral valve edge-to-edge repair on changes in left ventricular ejection fraction (LVEF) and the effect of an acute reduction in LVEF on prognosis. We aimed to assess changes in LVEF after transcatheter mitral valve edge-to-edge repair for both primary and secondary mitral regurgitation (PMR and SMR, respectively), identify rates and predictors of LVEF reduction, and estimate its impact on prognosis. Methods and Results In this international multicenter registry, patients with both PMR and SMR undergoing transcatheter mitral valve edge-to-edge repair were included. We assessed rates of acute LVEF reduction (LVEFR), defined as an acute relative decrease of >15% in LVEF, its impact on all-cause mortality, major adverse cardiac event (composite end point of all-cause death, mitral valve surgery, and residual mitral regurgitation grade ≥2), and LVEF at 12 months, as well as predictors for LVEFR. Of 2534 patients included (727 with PMR, and 1807 with SMR), 469 (18.5%) developed LVEFR. Patients with PMR were older (79.0±9.2 versus 71.8±8.9 years; P <0.001) and had higher mean LVEF (54.8±14.0% versus 32.7±10.4%; P <0.001) at baseline. After 6 to 12 months (median, 9.9 months; interquartile range, 7.8-11.9 months), LVEF was significantly lower in patients with PMR (53.0% versus 56.0%; P <0.001) but not in patients with SMR. The 1-year mortality was higher in patients with PMR with LVEFR (16.9% versus 9.7%; P <0.001) but not in those with SMR ( P =0.236). LVEF at baseline (odds ratio, 1.03 [95% CI, 1.01-1.05]; P =0.002) was predictive of LVEFR for patients with PMR, but not those with SMR ( P =0.092). Conclusions Reduction in LVEF is not uncommon after transcatheter mitral valve edge-to-edge repair and is correlated with worsened prognosis in patients with PMR but not patients with SMR. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05311163.

Background Various hemodynamic changes occur following transcatheter aortic valve implantation (TAVI) that may impact therapeutic decisions. NICaS is a noninvasive bioimpedance monitoring system aimed at hemodynamic assessment. We used the NICaS system in patients with severe aortic stenosis (AS) to evaluate short-term hemodynamic changes after TAVI. Methods and Results We performed hemodynamic analysis using NICaS on 97 patients with severe AS who underwent TAVI using either self-expandable (68%) or balloon-expandable (32%) valves. Patients were more often women (54%) and had multiple comorbidities including hypertension (83%), coronary artery disease (46%), and diabetes (37%). NICaS was performed at several time points-before TAVI, soon after TAVI, at hospital discharge, and during follow-up. Compared with baseline NICaS measurements, we observed a significant increase in systolic blood pressure and total peripheral resistance (systolic blood pressure 132±21 mm Hg at baseline versus 147±23 mm Hg after TAVI, P <0.001; total peripheral resistance 1751±512 versus 2084±762 dynes*s/cm 5 , respectively, P <0.001) concurrent with a decrease in cardiac output and stroke volume (cardiac output 4.2±1.5 versus 3.9±1.3 L/min, P =0.037; stroke volume 61.4±14.8 versus 56.2±15.9 mL, P =0.001) in the immediate post-TAVI period. At follow-up (median 59 days [interquartile range, 40.5-91]) these measurements returned to values that were not different from the baseline. A significant improvement in echocardiography-based left ventricular ejection fraction was observed from baseline to follow-up (55.6%±11.6% to 59.4%±9.4%, P <0.001). Conclusions Unique short-term adaptive hemodynamic changes were observed using NICaS in patients with AS soon after TAVI. Noninvasive hemodynamic evaluation immediately following TAVI may contribute to the understanding of complex hemodynamic changes and merits favorable consideration.

Aim: The aetiology and pathogenesis of peri-implantitis are currently under active research. This study aimed to dissect the pathogenesis of murine experimental peri-implantitis and assess Resolvin D2 (RvD2) as a new treatment modality., Materials and Methods: Four weeks following titanium implant insertion, mice were infected with Porphyromonas gingivalis using single or multiple oral lavages. RvD2 was administrated following infection, and tissues were analysed using flow cytometry, quantitative RT-PCR, taxonomic profiling, and micro-computed tomography., Results: Repeated infections with Pg resulted in microbial dysbiosis and a higher influx of innate and adaptive leukocytes to the peri-implant mucosa (PIM) than to gingiva surrounding the teeth. This was accompanied by increased expression levels of IFN-α, IL-1β, and RANKL\OPG ratio. Interestingly, whereas repetitive infections resulted in bone loss around implants and teeth, a single infection induced bone loss only around implants, suggesting a higher susceptibility of the implants to infection. Treatment with RvD2 prevented Pg-driven bone loss and reduced leukocyte infiltration to the PIM., Conclusions: Murine dental implants are associated with dysregulated local immunity and increase susceptibility to pathogen-induced peri-implantitis. However, the disease can be prevented by RvD2 treatment, highlighting the promising therapeutic potential of this treatment modality., (© 2022 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)

Background: There is limited ability to predict the severity of allergic reactions in children. Data derived predominantly from adults have implicated the platelet-activating factor pathway as a potential contributor to severe anaphylaxis. In this study, we sought to prospectively assess involvement of key components of the platelet-activating factor pathway in pediatric patients with anaphylaxis., Methods: Forty-six pediatric patients (<18 years) presenting with acute anaphylaxis were assessed. Anaphylaxis severity was graded and serum anaphylaxis markers were measured acutely and in 36 children who returned for follow-up >4 weeks after their acute presentation. These markers were compared with pediatric laboratory reference sera., Results: Severe anaphylaxis was experienced by 12/46 (26%) and mild-moderate anaphylaxis in 34/46 (74%) children. Platelet-activating factor acetylhydrolase (PAF-AH) activity was inversely associated with severe anaphylaxis: 9/12 children with severe anaphylaxis had reduced PAF-AH activity as compared with 14/34 with mild-moderate anaphylaxis (p < .05). Furthermore, 3/3 children who required intensive care had markedly reduced mean PAF-AH (nmol/ml/min) (13.73, 95%CI: 7.42-20.03) versus 20/23 who required ward/emergency department care (17.81, 95%CI: 16.80-18.83; p < .05). In children with anaphylaxis, PAF-AH during acute anaphylaxis was unchanged relative to the child's basal levels (mean, 17.26, 95%CI: 16.10-18.42 vs 17.50, 95%CI: 16.21-18.78, p = .63) and was lower than healthy pediatric controls (mean 19.21; 95%CI:18.21-20.21; p < .05)., Conclusion: Decreased serum PAF-AH activity is a biomarker of severe anaphylaxis. Levels of this enzyme do not change from basal levels during acute anaphylaxis. Our results show that PAF-AH is a biomarker of anaphylaxis severity in children. This key regulatory enzyme may modulate susceptibility to severe anaphylaxis., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: In view of inconsistencies in threshold values of severe aortic stenosis (AS) hemodynamic indices, it is unclear what is the relative contribution of each variable in a binary classification of AS based on aortic valve replacement (AVR) indication. We aimed to assess relative discriminative value and optimal threshold of each constituent hemodynamic parameter for this classification and confirm additional prognostic value., Methods: Echocardiography studies of 168 patients with ≥ moderate AS were included. AS types were dichotomized into Group-A, comprising moderate and Normal-Flow Low-Gradient (NFLG), and Group-B, comprising High-Gradient(HG), Low Ejection Fraction Low-Flow Low-Gradient(Low EF-LFLG), and Paradoxical Low-Flow Low-Gradient(PLFLG) AS. Aortic valve area (AVA), Doppler velocity index (DVI), peak aortic velocity, mean gradient, stroke volume index and transaortic flow rate(TFR) were assessed for A/B Group discrimination value and optimal thresholds were determined. Dichotomized values were assessed for predictive value for AVR or death., Results: C-statistic values for binary AS classification was .74-.9 for the tested variables. AVA and DVI featured the highest score, and SVI the lowest one. AVA≤.81 cm 2 and DVI≤.249 had 87.6% and 86% respective sensitivity for Group B patients, and a similar specificity of 80.9%. During a mean follow-up of 9.1±10.1 months, each of the tested dichotomized variables except for SVI predicted AVR or death on multivariate analysis., Conclusion: An AVA value ≤.81 cm 2 or a DVI ≤ .249 threshold carry the highest discriminative value for severe AS in patients with aortic stenosis, translating into an independent prognostic value, and can be helpful in making clinical decisions., (© 2021 Wiley Periodicals LLC.)

Aim: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence (BE) of MYL-1601D biosimilar with originator, NovoLog (Ref-InsAsp-US), and NovoRapid (Ref-InsAsp-EU)., Materials and Methods: This was a double-blind, randomized, crossover study that enrolled 71 healthy subjects to receive a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycaemic clamp conditions (ClampArt, level 81 mg/dL, duration 12 hours postdose). Primary PK endpoints were area under the plasma insulin aspart concentration-time curve from 0 to 12 hours (AUC 0-12h ) and maximum plasma insulin aspart concentration (C max ). Primary PD endpoints were area under the glucose infusion rate (GIR) time curve from 0 to 12 hours (AUC GIR0-12h ) and maximum GIR (GIR max ). Insulin aspart in plasma was quantified using immunoaffinity purification followed by ultraperformance liquid chromatography and tandem mass spectrometric detection. The pairwise comparisons of geometric least square mean (LS-mean) ratio for a 90% confidence interval (CI) of primary PK, and 90% CIs (MYL-1601D vs. Ref-InsAsp-US) and 95% CIs (MYL-1601D vs. Ref-InsAsp-EU) of primary PD variables, were to be within 80% to 125% to show BE., Results: MYL-1601D showed PK BE to both Ref-InsAsp-US (AUC 0-12h geometric LS-mean ratio 102.17, 90% CI [100.26; 104.11]; C max 106.13 [100.71; 111.85]) and Ref-InsAsp-EU (AUC 0-12h 101.84 [100.04; 103.67]; C max 105.74 [101.09; 110.60]). Likewise, MYL-1601D showed PD BE to Ref-InsAsp-US (AUC GIR&#95;0-last 99.93; 90% CI [95.74; 104.30]; GIR &#95;max 100.12 [94.46; 106.12]) and Ref-InsAsp-EU (AUC GIR&#95;0-last 96.42; 95% CI [91.17; 101.98]; GIR &#95;max 95.10 [89.37; 101.19]). All three insulin aspart products were well tolerated., Conclusion: MYL-1601D showed BE to Ref-InsAsp-US and Ref-InsAsp-EU with a comparable safety profile., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Hepatitis delta virus (HDV) infection is the most aggressive form of chronic viral hepatitis. Response rates to therapy with 1- to 2-year courses of pegylated interferon alpha (peginterferon) treatment are suboptimal., Aims: To evaluate the long-term outcomes of patients with chronic hepatitis D after an extended course of peginterferon., Methods: Patients were followed after completion of trial NCT00023322 and classified based on virological response defined as loss of detectable serum HDV RNA at last follow-up. During extended follow-up, survival and liver-related events were recorded., Results: All 12 patients who received more than 6 months of peginterferon in the original study were included in this analysis. The cohort was mostly white (83%) and male (92%) and ranged in age from 18 to 58 years (mean = 42.6). Most patients had advanced but compensated liver disease at baseline, a median HBV DNA level of 536 IU per mL and median HDV RNA level of 6.86 log 10 genome equivalents per mL. The treatment duration averaged 6.1 years (range 0.8-14.3) with a total follow-up of 8.8 years (range 1.7-17.6). At last follow-up, seven (58%) patients had durable undetectable HDV RNA in serum, and four (33%) cleared HBsAg. Overall, one of seven (14%) responders died or had a liver-related event vs four of five (80%) non-responders., Conclusions: With further follow-up, an extended course of peginterferon therapy was found to result in sustained clearance of HDV RNA and favourable clinical outcomes in more than half of patients and loss of HBsAg in a third., (Published 2021. This article is a U.S.Government work and is in the public domain in the USA.)

Ever since its first documented live birth in 2014, the use of uterine transplantation (UTx) for the treatment of absolute uterine factor infertility (UFI) has seen major clinical advances, which include the use of alternative surgical approaches, different donor states, and diverse patient populations. In addition to the thorough research programs that developed the technique, this accomplishment has occurred in large part following a number of ethical frameworks, such as the Montreal Criteria and the Indianapolis Consensus, which paved the way to transition from experimental animal trials to human ones. To date, over 60 uterine transplants have been performed in the world, and at least 18 births have been thus far confirmed. While the procedure remains experimental, the vast knowledge and procedural experience amassed over the last 20 years of rigorous research have hinted at the next step of discovery. In particular, advancing social circumstances have prompted the question regarding the use of this technology in transgender individuals. Though the potential use of uterine transplants in the transgender population has been hypothesized, no in-depth ethical framework has been developed towards this purpose. Herein, we explore the ethical issues revolving around the use of this technology in this patient population and provide key insights that may advance this cause., (© 2021 John Wiley & Sons Ltd.)

SCYL1 disease results from biallelic pathogenic variants in SCYL1. We report two new patients with severe hepatic phenotype requiring liver transplantation. Patient charts reviewed. DNA samples and skin fibroblasts were utilized. Literature was reviewed. 13-year-old boy and 9-year-old girl siblings had acute liver insufficiency and underwent living related donor liver transplantation in infancy with no genetic diagnosis. Both had tremor, global developmental delay, and cognitive dysfunction during their follow-up in the medical genetic clinic for diagnostic investigations after their liver transplantation. Exome sequencing identified a likely pathogenic variant (c.399delC; p.Asn133Lysfs*136) in SCYL1. Deletion/duplication analysis of SCYL1 identified deletions of exons 7-8 in Patient 1. Both variants were confirmed in Patient 2 and the diagnosis of SCYL1 disease was confirmed in both patients at the age of 13 and 9 years, respectively. SCYL1 protein was not expressed in both patients' fibroblast using western blot analysis. Sixteen patients with SCYL1 disease reported in the literature. Liver phenotype (n = 16), neurological phenotype (n = 13) and skeletal phenotype (n = 11) were present. Both siblings required liver transplantation in infancy and had variable phenotypes. Exome sequencing may miss the diagnosis and phenotyping of patients can help to diagnose patients., (© 2021 Wiley Periodicals LLC.)

Background: Increased survival among active cancer patients exposes a wide range of side effects, including cardiotoxicity, manifested by systolic dysfunction and associated with morbidity and mortality. Early diagnosis of subclinical function changes and cardiac damage is essential in the management of these patients. Diastolic dysfunction is considered common among cancer patients; however, its effect on systolic dysfunction or mortality is still unknown., Methods: Data were collected as part of the Israel Cardio-Oncology Registry, enrolling and prospectively following all patients evaluated in the cardio-oncology clinic in the Tel Aviv Sourasky Medical Center. All patients underwent echocardiographic examinations including evaluation of diastolic parameters and global longitudinal strain (GLS). Systolic dysfunction was defined as either an absolute reduction >10% in left ventricular ejection fraction to a value below 53% or GLS relative reduction >10% between the 1st and 3rd echocardiography examinations., Results: Overall, 190 active cancer patients were included, with a mean age of 58 ± 15 years and a female predominance (78%). During a median follow-up of 243 days (interquartile ranges [IQR]: 164-401 days), 62 (33%) patients developed systolic dysfunction. Over a median follow-up of 789 days (IQR: 521-968 days), 29 (15%) patients died. There were no significant differences in baseline cardiac risk factors between the groups. Using multivariate analysis, E/e' lateral and e' lateral emerged as significantly associated with systolic dysfunction development and all-cause mortality (P = .015)., Conclusion: Among active cancer patients, evaluation of diastolic function may provide an early marker for the development of systolic dysfunction, as well as all-cause mortality., (© 2021 Wiley Periodicals LLC.)

Background Several studies have examined hospitalizations among patients with adult congenital heart disease (ACHD). Few investigated other services or utilization patterns. Our aim was to study service utilization patterns and predictors among patients with ACHD. Methods and Results We identified 11 653 patients with ACHD aged ≥18 years (median, 47 years), through electronic records of 2 large Israeli healthcare providers (2007-2011). The association between patient, disease, and sociogeographic characteristics and healthcare resource utilization were modeled as recurrent events accounting for the competing death risk. Patients with ACHD had high healthcare utilization rates compared with the general population. The highest standardized service utilization ratios (SSRs) were found among patients with complex congenital heart disease including primary care visits (SSR, 1.53; 95% CI, 1.47-1.58), cardiology outpatient visits (SSR, 5.17; 95% CI, 4.69-5.64), hospitalizations (SSR, 6.68; 95% CI, 5.82-7.54), and days in hospital (SSR, 15.37; 95% CI, 14.61-16.12). Adjusted resource utilization hazard increased with increasing lesion complexity. Hazard ratios (HRs) for complex versus simple disease were: primary care (HR, 1.14; 95% CI, 1.06-1.23); cardiology outpatient visits (HR, 1.40; 95% CI, 1.24-1.59); emergency department visits (HR, 1.19; 95% CI, 1.02-1.39); and hospitalizations (HR, 1.75; 95% CI, 1.49-2.05). Effects attenuated with age for cardiology outpatient visits and hospitalizations and increased for emergency department visits. Female sex, geographic periphery, and ethnic minority were associated with more primary care visits, and female sex (HR versus men, 0.89 [95% CI, 0.84-0.94]) and periphery (HR, 0.72 [95% CI, 0.58-0.90] for very peripheral versus very central) were associated with fewer cardiology visits. Arab minority patients also had high hospitalization rates compared with the majority group of Jewish or other patients. Conclusions Healthcare utilization rates were high among patients with ACHD. Female sex, geographic periphery, and ethnicity were associated with less optimal service utilization patterns. Further research should examine strategies to optimize service utilization in these groups.

Background Contrast-associated acute kidney injury (CA-AKI) is associated with substantial morbidity and may be prevented by using less contrast during percutaneous coronary intervention (PCI). However, tools for determining safe contrast volumes are limited. We developed risk models to tailor safe contrast volume limits during PCI. Methods and Results Using data from all PCIs performed at 18 hospitals from January 2015 to March 2018, we developed logistic regression models for predicting CA-AKI, including simpler models ("pragmatic full," "pragmatic minimum") using only predictors easily derivable from electronic health records. We prospectively validated these models using PCI data from April 2018 to December 2018 and compared them to preexisting safe contrast models using the area under the receiver operating characteristic curve (AUC). The model derivation data set included 20 579 PCIs with 2102 CA-AKI cases. When applying models to the separate validation data set (5423 PCIs, 488 CA-AKI cases), prior safe contrast limits (5*Weight/Creatinine, 2*CreatinineClearance) were poor measures of safety with accuracies of 53.7% and 56.6% in predicting CA-AKI, respectively. The full, pragmatic full, and pragmatic minimum models performed significantly better (accuracy, 73.1%, 69.3%, 66.6%; AUC, 0.80, 0.76, 0.72 versus 0.59 for 5 * Weight/Creatinine, 0.61 for 2*CreatinineClearance). We found that applying safe contrast limits could meaningfully reduce CA-AKI risk in one-quarter of patients. Conclusions Compared with preexisting equations, new multivariate models for safe contrast limits were substantially more accurate in predicting CA-AKI and could help determine which patients benefit most from limiting contrast during PCI. Using readily available electronic health record data, these models could be implemented into electronic health records to provide actionable information for improving PCI safety.

Background: Although diastolic dysfunction is common among patients treated with cancer therapy, no clear evidence has been shown that it predicts systolic dysfunction. This study evaluated the correlation of diastolic strain time (Dst) with the routine echocardiography diastolic parameters and estimated its role in the early detection of cardiotoxicity among patients with active breast cancer., Methods: Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling all adult patients referred to the cardio-oncology clinic. All patients with breast cancer, planned for Doxorubicin therapy, were included. Echocardiography, including global longitudinal systolic strain (GLS) and Dst, was assessed at baseline before chemotherapy (T1), during Doxorubicin therapy (T2) and after the completion of Doxorubicin therapy (T3). Cardiotoxicity was determined by GLS relative reduction of ≥15%. Dst was assessed as the time measured (ms) of the myocardium lengthening during diastole., Results: Among 69 patients, 67 (97.1%) were females with a mean age of 52 ± 13 years. Dst was significantly associated with the routine diastolic parameters. Significant GLS reduction was observed in 10 (20%) patients at T3. Both in a univariate and a multivariate analyses, the change in Ds basal time from T1 to T2 emerged to be significantly associated with GLS reduction at T3 (P < .04)., Conclusions: Among breast cancer patients, Dst showed high correlation to the routine diastolic echocardiography parameters. Change in Ds basal time emerged associated with clinically significant systolic dysfunction as measured by GLS reduction., (© 2020 Wiley Periodicals LLC.)

Introduction: Sternal wound infection (SWI) is a devastating postcardiac surgical complication. D-PLEX 100 (D-PLEX) is a localized prolonged release compound applied as a prophylactic at the completion of surgery to prevent SWI. The D-PLEX technology platform is built as a matrix of alternating layers of polymers and lipids, entrapping an antibiotic (doxycycline). The objective of this study was to assess the safety profile and pharmacokinetics of D-PLEX in reducing SWI rates postcardiac surgery., Method: Eighty-one patients were enrolled in a prospective single-blind randomized controlled multicenter study. Sixty patients were treated with both D-PLEX and standard of care (SOC) and 21 with SOC alone. Both groups were followed 6 months for safety endpoints. SWI was assessed at 90 days., Results: No SWI-related serious adverse events (SAEs) occurred in either group. The mean plasma C max in patients treated with D-PLEX was about 10 times lower than the value detected following the oral administration of doxycycline hyclate with an equivalent overall dose, and followed by a very low plasma concentration over the next 30 days. There were no sternal infections in the D-PLEX group (0/60) while there was one patient with a sternal infection in the control group (1/21, 4.8%)., Conclusion: D-PLEX was found to be safe for use in cardiac surgery patients. By providing localized prophylactic prolonged release of broad-spectrum antibiotics, D-PLEX has the potential to prevent SWI postcardiac surgery and long-term postoperative hospitalization, reducing high-treatment costs, morbidity, and mortality., (© 2020 Wiley Periodicals LLC.)

Background and Aim: Revascularization guidelines support routine Heart Team (HT) discussion of appropriate patients. The effect of HT on decision making and clinical outcomes has not been explored. The aim of our study is to investigate the impact of the HT on the mode and delay to revascularization., Methods: We compared data from a prospective cohort of consecutive patients with multivessel coronary artery disease (CAD) referred for HT discussion between 2016 and 2017 (HT group) with a historic control group of patients matched according to clinical and angiographic characteristics treated between 2005 and 2015 (No HT group)., Results: There were 93 patients in each group. The HT group and the No HT groups had a similar rate of ACS as well as cardiovascular risk factors and significant left ventricular (LV) dysfunction. No difference was observed in the mean Society of Thoracic Surgery score (2.5 ± 3 vs 3 ± 3; P = .32) and the mean SYNTAX score was low and similar in both groups (21 ± 6 vs 19 ± 6; P = .59). The treatment recommendations changed greatly, with 63% of patients being referred for coronary artery bypass grafting (CABG) after HT discussion but only 23% in the No HT group (P < .01). HT discussion led to a significant delay to PCI (8 ± 5 vs 1.8 ± 4 days; P = .02), while surgical revascularization times were not affected., Conclusion: HT discussion in patients with multivessel CAD was associated with an increased referral to CABG but led to a significant delay in revascularization by angioplasty. The impact of these findings on patient satisfaction and outcome should be further investigated., (© 2020 Wiley Periodicals LLC.)

Background & Aims: Liver fibrosis assessed by liver biopsy is predictive of clinical liver events in patients with nonalcoholic fatty liver disease (NAFLD). Magnetic resonance elastography (MRE) correlates with liver biopsy in assessing liver fibrosis. However, data assessing the relationship between MRE and clinical liver events are lacking. We investigated the association between MRE and clinical liver events/death and identified the cut-off to predict clinical liver events in NAFLD patients., Methods: We conducted a multicenter retrospective study of NAFLD patients who underwent MRE between 2016 and 2019. Clinical liver events were defined as decompensation events and death. We categorized patients into noncirrhosis, compensated cirrhosis and decompensated cirrhosis. Fisher's exact test was used to test association strength. Receiver operative curve methods were used to determine the optimal cut-off of MRE liver stiffness and to maximize the accuracy for classifying noncirrhosis, compensated cirrhosis and decompensated cirrhosis. Logistic regression modelling was used to predict decompensation., Results: The study included 320 NAFLD patients who underwent MRE. The best threshold for distinguishing cirrhosis from noncirrhosis was 4.39 kPa (AUROC 0.92) and from decompensated cirrhosis was 6.48 kPa (AUROC 0.71). Odds of decompensation increased as liver stiffness increased (OR 3.28) (P < .001). Increased liver stiffness was associated with ascites, hepatic encephalopathy, oesophageal variceal bleeding and mortality (median 7.10, 10.15 and 10.15 kPa respectively)., Conclusion: In NAFLD patients, liver stiffness measured by MRE with a cut-off of ≥6.48 kPa is associated with decompensation and mortality, and specific MRE cut-offs are predictive of individual clinical liver events., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Experience in Helicobacter pylori eradication treatment of patients allergic to penicillin is very scarce. A triple combination with a PPI, clarithromycin (C), and metronidazole (M) is often prescribed as the first option, although more recently the use of a quadruple therapy with PPI, bismuth (B), tetracycline (T), and M has been recommended., Aim: To evaluate the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin in the "European Registry of H pylori management" (Hp-EuReg)., Methods: A systematic prospective registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H pylori infection. An e-CRF was created on AEG-REDCap. Patients with penicillin allergy were analyzed until June 2019., Results: One-thousand eighty-four patients allergic to penicillin were analyzed. The most frequently prescribed first-line treatments were as follows: PPI + C + M (n = 285) and PPI + B + T + M (classic or Pylera ® ; n = 250). In first line, the efficacy of PPI + C + M was 69%, while PPI + B + T + M reached 91% (P < .001). In second line, after the failure of PPI + C + M, two rescue options showed similar efficacy: PPI + B + T + M (78%) and PPI + C + levofloxacin (L) (71%) (P > .05). In third line, after the failure of PPI + C + M and PPI + C + L, PPI + B + T + M was successful in 75% of cases., Conclusion: In patients allergic to penicillin, a triple combination with PPI + C + M should not be generally recommended as a first-line treatment, while a quadruple regimen with PPI + B + T + M seems to be a better option. As a rescue treatment, this quadruple regimen (if not previously prescribed) or a triple regimen with PPI + C + L could be used but achieved suboptimal (<80%) results., (© 2020 John Wiley & Sons Ltd.)

Aims: To assess the efficacy, insulin dose, safety and immunogenicity when people with type 1 diabetes mellitus switched between MYL-1501D and reference insulin glargine (Lantus®; Sanofi-Aventis US LLC, Bridgewater, New Jersey)., Materials and Methods: Eligible participants from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n = 63; reference insulin glargine for 36 weeks) or to the treatment-switching sequence (n = 64; MYL-1501D [weeks 0-12], reference insulin glargine [weeks 12-24] and MYL-1501D [weeks 24-36]). Change in glycated haemoglobin (HbA1c) from baseline to week 36 was the primary efficacy endpoint used to demonstrate equivalence between the two treatment sequences. Secondary endpoints included: change in fasting plasma glucose (FPG), self-monitored blood glucose (SMBG) and insulin dose; immunogenicity; and adverse events, including hypoglycaemia., Results: Mean changes in HbA1c (least squares [LS] mean [SE]) from baseline to week 36 were -0.05 (0.032) and -0.06 (0.034) for the treatment-switching and reference sequences, respectively (LS mean difference 0.01 [95% CI -0.085 to 0.101]). Treatment sequences were comparable in terms of secondary endpoints, including FPG, SMBG and insulin dose, and the safety and immunogenicity profiles of the two sequences were similar., Conclusions: Switching participants between MYL-1501D and reference insulin glargine demonstrated equivalent efficacy and similar safety and immunogenicity, showing that people taking reference insulin glargine can safely switch to MYL-1501D., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background & Aim: Hepatic fat excess in non-alcoholic fatty liver disease (NAFLD) reflects an imbalance between fat accumulation and disposal. Conflicting data exist for the role of fatty acid oxidation (FAO), one of the disposal pathways, and have mostly come from the studies delivering fatty acids (FAs) intravenously. Whether FAO of orally provided FAs is affected in NAFLD is unknown., Methods: We performed a breath test study to measure FAO in subjects with NAFLD and healthy controls. Subjects ingested [1- 13 C] palmitic acid (PA, 10 mg/kg) in a liquid meal and the rate of 13 CO 2 appearance in expired air was measured over 6 hours by a BreathID device (Exalenz) to obtain the cumulative percent dose recovered (CPDR), the total amount of ingested 13 C recovered. CPDR was corrected by the results of a [1- 13 C] acetate breath test, performed 1-4 weeks later, to calculate the rate of PA β-oxidation., Results: Palmitic acid oxidation was 27% lower in 43 subjects with NAFLD compared to 11 controls (CPDR 9.5 ± 2.4% vs 13.1 ± 3.7%, P = .0001) and this persisted after correcting for acetate (29.3 ± 10.5 vs 36.6 ± 13.9, P = .03). The decrease in FAO was not because of the delayed transit as the time to peak 13 C detection did not differ between groups (4.9 ± 1.2 hours vs 4.7 ± 0.8 hours, P = .7). Rates of PA oxidation were not correlated with obesity, hepatic or adipose insulin resistance, alanine aminotransferase, liver fat content and NAFLD histology., Conclusion: Fatty acid oxidation of orally delivered FA is decreased in NAFLD compared to healthy controls, likely reflecting decreased β-oxidation. The use of a breath test offers non-invasive dynamic assessment of FAO., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This review covers recent publications investigating the relationship between Helicobacter pylori infection and gastroesophageal reflux disease, Barrett's esophagus, eosinophilic esophagitis, peptic ulcer disease (PUD), H pylori gastritis, and functional dyspepsia. In the area of gastroesophageal reflux disease, new data suggest that reflux may have a role in the transmission of H pylori infection. In addition to several observational studies, data on alterations in esophageal physiology in patients with H pylori infection are presented. Further evidence for the inverse relationship between H pylori infection and Barrett's esophagus is available in the form of a meta-analysis from the North American Barrett's and Esophageal Carcinoma Consortium. The relationship between H pylori infection and eosinophilic esophagitis remains uncertain. Although new data do not indicate a significantly lower prevalence of H pylori among patients with eosinophilic esophagitis, a meta-analysis showed a 37% reduced risk of eosinophilic esophagitis among H pylori-infected patients. Novel data are presented on the genetic variability of bacterial virulence factors and their relationship with PUD. We also report data on plasma biomarkers, which may detect progression to gastric cancer in H pylori-associated PUD. A new meta-analysis was published, which assessed the risk of PUD in low-dose aspirin users with H pylori infection. Finally, we report on the ongoing attempts to stratify patients with gastritis using endoscopic methods when compared to standard biopsy examination., (© 2019 John Wiley & Sons Ltd.)

Aims: To assess the non-inferiority of MYL-1501D, a proposed biosimilar or follow-on biological agent to marketed insulin glargine, to reference insulin glargine (Lantus®; Sanofi-Aventis US LLC, Bridgewater, New Jersey) based on change in glycated hemoglobin (HbA1c)., Materials and Methods: INSTRIDE 2 was a multicentre, open-label, randomized, parallel-group, phase III non-inferiority study comparing the efficacy and safety of MYL-1501D with those of reference insulin glargine in insulin-naive and insulin-non-naive patients with type 2 diabetes mellitus receiving oral antidiabetic drugs (OADs). The primary efficacy endpoint was change in HbA1c from baseline to week 24. Secondary endpoints included metabolic readouts (eg, changes in fasting plasma glucose, insulin dosage, self-monitored blood glucose), immunogenicity and adverse events, including hypoglycaemia and nocturnal hypoglycaemic events., Results: In all, 560 patients were randomized to MYL-1501D or insulin glargine in combination with OADs for 24 weeks. The mean change in HbA1c from baseline to week 24 was -0.60% (95% CI -0.78, -0.41) and - 0.66% (95% CI -0.84, -0.48) for MYL-1501D and reference insulin glargine, respectively. MYL-1501D was well tolerated and had a safety profile similar to that of reference insulin glargine., Conclusions: Demonstration of non-inferiority between MYL-1501D and reference insulin glargine for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycaemia and nocturnal hypoglycaemia, local and systemic reactions, other safety variables, and immunogenicity., (© 2018 John Wiley & Sons Ltd.)

This review provides the most recent data concerning the epidemiology of Helicobacter pylori infection. Overall, the trend of declining prevalence of H. pylori infection is continuing, with major evidence available from studies in Europe. However, in some parts of the world, for example, in some countries in the Middle East, the prevalence has remained relatively stable. A number of systematic reviews and meta-analyses have been published during the past year indicating the lowest prevalence rates of the infection in Oceania (24.4%), the highest in Africa (79.1%), and the global annual recurrence rate of H. pylori (4.3%). The recurrence rates were found to be directly related to the human development index and prevalence of infection. Several studies have addressed the correlation between H. pylori infection and sociodemographic conditions, source of drinking water and dietary factors. A hypothesis on the role of insects and yeasts in transmitting H. pylori has been suggested and addressed. Helicobacter sp. have been found in flow flies in Brazil. So far there is no evidence available that H. pylori may survive and persist on the outer body of the fly., (© 2018 John Wiley & Sons Ltd.)

The annual rate of Down syndrome (DS) births in Jerusalem is stable, regardless of prenatal screening, and diagnostic measures. We aimed to evaluate our historical cohort for obstetrical characteristics and the neonatal course and complications. We reviewed computerized medical files of neonates with the diagnosis of DS born in the four main hospitals in Jerusalem between the years 2000 and 2010 and evaluated for maternal history and primary neonatal hospitalization. A total of 403 neonates were diagnosed with DS. The average maternal age was 35.6 years, 73% were born via spontaneous vaginal delivery. In all gestational ages, the mean birth weight and head circumference percentiles were significantly lower than the general population (P < 0.001 for both) and at each week the HC percentile was lower than the weight percentile (P < 0.0001), worse among males. Mortality during the primary hospitalization was 3.7%. The most common anomalies were cardiac (79%) with either congenital defects or functional abnormalities, neither influenced the length of hospitalization. The main reasons for prolonged hospitalization were prematurity and anomalies of other (non-cardiac) organs. Common perinatal complications included respiratory failure or need for oxygen supplementation (32%), hyperbilirubinemia (23%), sepsis (6.4%), and feeding difficulties (13%). About 84% were fed by human milk; of those, two thirds were exclusively breast-fed and one third were supplemented with infant formula. In conclusion, infants with DS were small for gestational age with relatively reduced head circumference. Despite the increased rate of congenital anomalies and perinatal complications, most infants were discharged home in good medical condition and were exclusively breastfed., (© 2017 Wiley Periodicals, Inc.)

Currently, blood pressure (BP) measurement is obtained noninvasively in patients with continuous flow left ventricular assist device (LVAD) by placing a Doppler probe over the brachial or radial artery with inflation and deflation of a manual BP cuff. We hypothesized that replacing the Doppler probe with a finger-based pulse oximeter can yield BP measurements similar to the Doppler derived mean arterial pressure (MAP). We conducted a prospective study consisting of patients with contemporary continuous flow LVADs. In a small pilot phase I inpatient study, we compared direct arterial line measurements with an automated blood pressure (ABP) cuff, Doppler and pulse oximeter derived MAP. Our main phase II study included LVAD outpatients with a comparison between Doppler, ABP, and pulse oximeter derived MAP. A total of five phase I and 36 phase II patients were recruited during February-June 2014. In phase I, the average MAP measured by pulse oximeter was closer to arterial line MAP rather than Doppler (P = 0.06) or ABP (P < 0.01). In phase II, pulse oximeter MAP (96.6 mm Hg) was significantly closer to Doppler MAP (96.5 mm Hg) when compared to ABP (82.1 mm Hg) (P = 0.0001). Pulse oximeter derived blood pressure measurement may be as reliable as Doppler in patients with continuous flow LVADs., (© 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

The progression of liver disease may be unique among organ system diseases in that progressive fibrosis compromises not only the sufficiency of hepatocyte mass but also impairs blood flow to the liver, resulting in porto-systemic shunting. Although liver biopsy as an assessment of fibrosis has become the key biomarker of and target for new therapies, it is invasive and subject to sampling error, and cannot quantify metabolic function or porto-systemic shunting. Measurement of the hepatic venous pressure gradient accommodates some of the deficiencies of biopsy but requires expertise not widely available and misses minor changes in hepatocellular mass and thereby information about metabolic function. Thus, an unmet need in clinical hepatology remains unfulfilled: a noninvasive biomarker which quantitates both the hepatocellular insufficiency and porto-systemic shunting inherent in progressive hepatic fibrosis. Ideally, such a biomarker should correlate with clinical endpoints including liver-related survival and cirrhotic complications, be performed at the point-of-care, and be affordable and easy to use. This review, an expert opinion, summarizes background and recent data suggesting that metabolic breath tests may now meet these requirements and have a valid place in clinical hepatology to supplant the time-honoured assessment of hepatic fibrosis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)