Singleton exome sequencing of 90 fetuses with ultrasound anomalies revealing novel disease-causing variants and genotype–phenotype correlations

Exome sequencing has been increasingly implemented in prenatal genetic testing for fetuses with morphological abnormalities but normal rapid aneuploidy detection and microarray analysis. We present a retrospective study of 90 fetuses with different abnormal ultrasound findings, in which we employed the singleton exome sequencing (sES; 75 fetuses) or to a lesser extent (15 fetuses) a multigene panel analysis of 6713 genes as a primary tool for the detection of monogenic diseases. The detection rate of pathogenic or likely pathogenic variants in this study was 34.4%. The highest diagnostic rate of 56% was in fetuses with multiple anomalies, followed by cases with skeletal or renal abnormalities (diagnostic rate of 50%, respectively). We report 20 novel disease-causing variants in different known disease-associated genes and new genotype–phenotype associations for the genes KMT2D, MN1, CDK10, and EXOC3L2. Based on our data, we postulate that sES of fetal index cases with a concurrent sampling of parental probes for targeted testing of the origin of detected fetal variants could be a suitable tool to obtain reliable and rapid prenatal results, particularly in situations where a trio analysis is not possible.Subject terms: Genetics research, Disease genetics     

Regulated Mycotoxin Occurrence and Co-Occurrence in Croatian Cereals

A total of 209 samples of various cereal crops (maize, wheat, barley, rye and oats) grown in Croatian fields during 2016 and 2017 were collected to analyze and determine the occurrence and co-occurrence of EU regulated mycotoxins in cereals (AFB1, AFB2, AFG1, AFG2, DON, FB1, FB2, ZEA, T-2, HT-2 and OTA). The analysis, performed by a validated confirmatory LC-MS/MS method based on a dilute and shoot principle, highlighted Fusarium mycotoxins as the main contaminants, often co-occurring in samples from both years (50.0% in 2016 and 33.7% in 2017). DON was found to be the most frequent mycotoxin, present in 72.5% of the 2016 samples and 32.6% of the 2017 samples, while maize proved to be the most contaminated cereal type of both years with FUM as the most abundant mycotoxins, with an average concentration of 1180 µg/kg. Moderate temperatures with periods of high humidity favored the accumulation of DON in wheat samples instead of other Fusarium mycotoxins, while similar conditions favored maize contamination with FUM. A total of 8.3% of all the 2016 harvest samples and 7.9% of the 2017 harvest samples were assessed as non-compliant, containing mycotoxins in concentrations higher than the levels set by the EU legislation for food.     

Lung volume reduction surgery as salvage procedure after previous use of endobronchial valves

Open in a separate window OBJECTIVESLung volume reduction (LVR) is an efficient and approved treatment for selected emphysema patients. There is some evidence that repeated LVR surgery (LVRS) might be beneficial, but there are no current data on LVRS after unsuccessful bronchoscopic LVR (BLVR) with endobronchial valves (EBVs). We hypothesize good outcome of LVRS after BLVR with valves.METHODSIn this study, we retrospectively investigated all patients who underwent LVRS between 2015 and 2019 at 2 centres after previous unsuccessful EBV treatment. They were further divided into subgroups with patients who never achieved the intended improvement after BLVR (primary failure) and patients whose benefit was fading over time due to the natural development of emphysema (secondary failure). Patients with severe air leak after BLVR and immediate concomitant LVRS and fistula closure thereafter were analysed separately.RESULTSA total of 38 patients were included. Of these, 19 patients had primary failure, 15 secondary failure and 4 were treated as an emergency due to severe air leak. At 3 months after LVRS, forced expiratory volume in 1 s had improved significantly by 12.5% (P = 0.011) and there was no 90-day mortality. Considering subgroups, patients with primary failure after BLVR seem to profit more than those with secondary failure. Patients with severe air leak after BLVR did not profit from fistula closure with concomitant LVRS.CONCLUSIONSLVRS after previous BLVR with EBVs can provide significant clinical improvement with low morbidity, although results might not be as good as after primary LVRS.     

The Self Test: a screening tool for dementia requiring minimal supervision

BACKGROUND: The main purpose of this study was to correlate a newly developed, simple, but comprehensive screening test for dementia called the Self Test (ST) with the Mini-mental State Examination (MMSE), and establish the reliability and validity of the ST. METHODS: The ST was administered to 42 consecutive new referrals to the memory clinic at the Cole Neuroscience Center, University of Tennessee Medical Center (UTMC), Knoxville, TN, U.S.A. and 41 age-matched control subjects at regular intervals over a 12-month period. RESULTS: The total ST scores correlated well with cognitive severity as measured by the MMSE (r = 0.71, p < 0.01). The area under the receiver-operating characteristic curve (AUROCC) in the group of patients with Alzheimer's disease (AD) with less than a high school education was 0.80, and 0.89 in those with at least a high school education. Reliability analysis showed a mean inter-item correlation of 0.31 for patients with AD, and 0.47 for normal participants. Cronbach's alpha was calculated to be 0.70 for the AD group. Test-retest reliability was determined using intraclass correlation coefficients (ICC = 0.93, p < 0.01). CONCLUSIONS: The ST is an internally consistent, reliable and valid screening test for cognitive impairment in persons exhibiting early symptoms of dementia. In addition, the ST requires minimal nonprofessional supervision and may be administered by an untrained person.     

Academic medicine: what does an outsider have to offer?

One of the many problems of academic medicine is its detachment from actual health problems of the population. Family medicine has a potential of bridging this gap. The paper describes the positive experience from introducing family medicine as a new academic discipline to the medical school in Slovenia. Its introduction was of benefit to family medicine, which has received recognition and has experienced a rapid academic growth. Medical academic establishment has benefited by being exposed to new ideas in research and education. The key to success was the fact that the academic world accepted a newcomer to its midst and that the newcomer managed to integrate its principles into the rules of the academic environment. The next step in this process is to apply some of the positive experiences of the family medicine department to the curriculum reform of the entire faculty.     

Hypothyroidism and pregnancy: still a controversial issue

Abstract

Subclinical hypothyroidism (SCH) in pregnancy is common, according to literature, affecting up to 15% of pregnancies. It still represents a controversy weather levothyroxine has beneficial effects on pregnancy outcomes. In this retrospective and prospective cohort study, we assessed fetal and maternal outcomes in women with known thyroid status pre-pregnancy, and hypothyroidism during pregnancy. We included 393 pregnant women, 90 (22.9%) diagnosed with overt and 303 with SCH (77.1%). A total of 94 (56%) had positive anti-TPO antibodies. Levothyroxine substitution across all observational periods was suboptimal, mostly during first trimester in both groups of patients (85.4%). There was a difference in the number of live births in favor of group with SCH (p?=?.004). Women with overt hypothyroidism were more likely to develop complications during pregnancy (RR = 1.153, 95%CI = 0.775???1.714) and had positive TPO-antibodies more often (p?=?.022). The only significant association was found between fetal outcomes in women with SCH and positive TPO-antibodies (p?=?.018), while positive Tg-antibodies did not affect the pregnancy outcomes of women with SCH. Moreover, no correlation was observed between outcomes and adequacy of levothyroxine substitution. These results indicate that TPO-antibody positivity could be the most important factor of pregnancy outcomes independent of the TSH levels or adequacy of levothyroxine therapy.     

Characteristics of histamine and serotonin release from rat mast cells induced by thymic peptides

Thymopoietin peptides release histamine and serotonin from rat mast cells. The release has the characteristics of other basic secretagogues in that it occurs rapidly, does not require extracellular Ca²⁺ ions, and is inhibited by benzalkonium chloride (BAC). These similarities indicate that chemically different basic compounds have common mechanisms for histamine and serotonin release from rat mast cells.     

Sensitivity of culture and polymerase chain reaction for the etiologic diagnosis of erythema migrans

Skin biopsy samples from 150 patients with typical cutaneous manifestation of Lyme borreliosis, erythema migrans, were cultivated for the presence of Borrelia burgdorferi sensu lato in modified Kelly Pettenkofer (MKP) medium and analysed with two different polymerase chain reactions using either flagellin or nested OspA primers. Cultivation was successful in 75 of 150 (50%) skin samples. Out of 70 strains that were typed using PFGE, B. afzelii was identified in 60 (86%), B. garinii in 10 (14%) specimens, while no B. burgdorferi sensu stricto strains were found. B. burgdorferi sensu lato DNA was detected with polymerase chain reaction in 28% and 61% of skin samples, using flagellin and nested OspA primers, respectively. Concordant results in all three procedures employed in the present study were found in 62 (41%) specimens: 25/150 (17%) were positive with all three methods and 37/150 (25%) samples were completely negative.