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Concept: Congenital disorder

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Recent epidemics of Zika virus (ZIKV) have been associated with congenital malformation during pregnancy and Guillain-Barré syndrome. There are two ZIKV lineages (African and Asian) that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas.

Concepts: Immune system, Antibody, Protein, Neutralizing antibody, Bacteria, Acid, Antibodies, Congenital disorder

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OBJECTIVE: To evaluate the scale and clinical importance of loss to follow-up of past patients with serious congenital heart disease, using a common malformation as an example. To better understand the antecedents of loss to specialist follow-up and patients' attitudes to returning. DESIGN: Cohort study using NHS number functionality. Content and thematic analysis of telephone interviews of subset contacted after loss to follow-up. PATIENTS, INTERVENTION AND SETTING: Longitudinal follow-up of complete consecutive list of all 1085 UK patients with repair of tetralogy of Fallot from single institution 1964-2009. MAIN OUTCOME MEASURES: Survival, freedom from late pulmonary valve replacement, loss to specialist follow-up, shortfall in late surgical revisions related to loss to follow-up. Patients' narrative about loss to follow-up. RESULTS: 216 (24%) of patients known to be currently alive appear not to be registered with specialist clinics; some are seen in general cardiology clinics. Their median age is 32 years and median duration of loss to follow-up is 22 years; most had been lost before Adult Congenital services had been consolidated in their present form. 48% of the late deaths to date have occurred in patients not under specialist follow-up. None of those lost to specialist follow-up has had secondary pulmonary valve replacement while 188 patients under specialist care have. Patients lost to specialist follow-up who were contacted by telephone had no knowledge of its availability. CONCLUSIONS: Loss to specialist follow-up, typically originating many years ago, impacts patient management.

Concepts: Cohort study, Longitudinal study, Hospital, Heart, Congenital disorder, Congenital heart defect, Congenital heart disease, Tetralogy of Fallot

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Colloid cysts are rare congenital, intracranial neoplasms, commonly located in the third ventricle. Colloid cysts are endodermal congenital malformations. The cysts commonly range in size from 1–2 cm in diameter, although large cysts >3 cm in size have been reported. The components of the cyst include an outer fibrous capsule over an inner epithelium. The epithelium is usually a single layer of mucin-producing or ciliated cells. Such cysts contain mucoid and gelatinous material, which is positive for both Periodic acid Schiff (PAS) and mucicarmen staining. Although colloid cysts usually represent histopathologically benign neoplasms, they can result in sudden, unexpected and potentially lethal complications. The mechanism(s) of death is still a controversial subject and several mechanisms have been postulated to explain the sudden onset of severe symptoms and of fatal rapid deterioration in patients with colloid cysts. In this case, macroscopic and histological findings addressed the diagnosis of colloid cyst of the third ventricle with diffuse myocardial injury (coagulative myocytolysys or contraction band necrosis, CBN) and led us to conclude that acute cardiac arrest due to hypothalamus stimulation in the context of colloid cyst of the third ventricle was the cause of death. As the hypothalamic structures which are involved in neuroendocrine and autonomic regulation playing a key role in cardiovascular control are located close to the walls of the third ventricle which is the most frequent anatomical site of colloid cyst, this may suggest that reflex cardiac effects due to the compression of the hypothalamic cardiovascular regulatory centers by the cyst explain the sudden death in patients harboring a colloid cyst when signs of hydrocephalus or brain herniation are lacking.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4915842848034158.

Concepts: Hypothalamus, Blood, Myocardial infarction, Heart, Intracranial pressure, Benign tumor, Congenital disorder, Colloid cyst

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To investigate the proposed synergistic teratogenic effect of use of selective serotonin receptor inhibitors (SSRI) together with sedatives or hypnotics, primarily benzodiazepines, during pregnancy.

Concepts: Developmental biology, Serotonin, Selective serotonin reuptake inhibitor, Congenital disorder, Tricyclic antidepressant, Reuptake inhibitor, Congenital disorders, Congenital

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Congenital absence of the abductor pollicis brevis is a very rare condition and is usually associated with other congenital anomalies. Here we report a case of bilateral congenital absence of the abductor pollicis brevis without any other abnormalities, which has not been previously reported. A 24-year-old Caucasian male patient presented to our clinic with flattening in the palmar region, pain and discomfort in writing, and weakness in both hands. USG and MRI revealed bilateral absence of the abductor pollicis brevis muscle. Bilateral congenital absence of the abductor pollicis brevis muscle requires no treatment due to satisfactory hand function, and results in cosmetic problems. Congenital absence of the abductor pollicis brevis muscle should be kept in mind in patients with flattening of the thenar eminences.

Concepts: Congenital disorder, Congenital disorders, Congenital, Adductor pollicis muscle, Abductor pollicis brevis muscle

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Objective To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (≥40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy.Design Population based cohort study.Setting Nationwide Swedish registries.Participants 1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages.Exposure Maternal BMI at the first prenatal visit.Main outcome measures Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year.Results A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.Conclusions Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range.

Concepts: Obesity, Relative risk, Body mass index, Congenital disorder, Centers for Disease Control and Prevention, Congenital disorders, Congenital, Congenital abnormality

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Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).

Concepts: Childbirth, Developmental biology, Evaluation, The Canon of Medicine, Retrospective, Cerebral cortex, Assessment, Congenital disorder

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Zika virus (ZIKV) is a flavivirus that is responsible for an unprecedented current epidemic in Brazil and the Americas(1,2). ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans(3-8) and mice(9-11). The rapid development of a safe and effective ZIKV vaccine is a global health priority(1,2), but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization of a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a ZIKV outbreak strain from northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice(11). We produced DNA vaccines expressing full-length ZIKV pre-membrane and envelope (prM-Env) as well as a series of deletion mutants. The full-length prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV as measured by absence of detectable viremia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and CD4 and CD8 T lymphocyte depletion in vaccinated mice did not abrogate protective efficacy. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans will likely be readily achievable.

Concepts: Immune system, DNA, Developmental biology, Vaccine, Vaccination, Immunology, Congenital disorder, DNA vaccination

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Gastroschisis is a serious congenital defect in which the intestines protrude through an opening in the abdominal wall. Gastroschisis requires surgical repair soon after birth and is associated with an increased risk for medical complications and mortality during infancy. Reports from multiple surveillance systems worldwide have documented increasing prevalence of gastroschisis since the 1980s, particularly among younger mothers (1,2); however, since publication of a multistate U.S. report that included data through 2005 (1), it is not known whether prevalence has continued to increase. Data on gastroschisis from 14 population-based state surveillance programs were pooled and analyzed to assess the average annual percent change (AAPC) in prevalence and to compare the prevalence during 2006-2012 with that during 1995-2005, stratified by maternal age and race/ethnicity. The pooled data included approximately 29% of U.S. births for the period 1995-2012. During 1995-2012, gastroschisis prevalence increased in every category of maternal age and race/ethnicity, and the AAPC ranged from 3.1% in non-Hispanic white (white) mothers aged <20 years to 7.9% in non-Hispanic black (black) mothers aged <20 years. These corresponded to overall percentage increases during 1995-2012 that ranged from 68% in white mothers aged <20 years to 263% in black mothers aged <20 years. Gastroschisis prevalence increased 30% between the two periods, from 3.6 per 10,000 births during 1995-2005 to 4.9 per 10,000 births during 2006-2012 (prevalence ratio = 1.3, 95% confidence interval [CI]: 1.3-1.4), with the largest increase among black mothers aged <20 years (prevalence ratio = 2.0, 95% CI: 1.6-2.5). Public health research is urgently needed to identify factors contributing to this increase.

Concepts: Age, United States, Ageing, White American, White people, Congenital disorder, Hispanic and Latino Americans, Congenital disorders

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Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015 and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. Using next generation sequencing we generated seven Brazilian ZIKV genomes, sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, estimated to have occurred between May-Dec 2013, more than 12 months prior to the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV endemic areas, and with reported outbreaks in Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology in the Americas of this emerging virus.

Concepts: Gene, Epidemiology, Evolution, Organism, Congenital disorder, Brazil, South America, Americas