Nevin Manimala

Am J Hum Genet. 2021 May 11:S0002-9297(21)00150-6. doi: 10.1016/j.ajhg.2021.04.019. Online ahead of print.

ABSTRACT

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-β protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-β signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8^-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-β signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8^-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-β signaling pathway in TAA development. Because importin 8 is the most downstream TGF-β-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

PMID:34010605 | DOI:10.1016/j.ajhg.2021.04.019

Depress Anxiety. 2021 May 19. doi: 10.1002/da.23169. Online ahead of print.

ABSTRACT

BACKGROUND: Rates of depression among Pakistani mothers are high, leading to poor developmental outcomes in their children. This study tested the effectiveness of a manualized integrated parenting program; Learning through Play Plus (LTP+) for maternal depression in Karachi, Pakistan.

METHODS: A cluster randomized control trial conducted from January 2014 to December 2015 across 120 villages in Karachi. A total of 774 depressed mothers aged 18-44 years with children aged 0-30 months old, were included. Villages were randomized to receive LTP+ added to treatment as usual (TAU) or TAU alone. Primary outcomes were severity of maternal depression at 3 and 6 months measured by the Edinburgh Postnatal Depression Scale and child socio-emotional development at 6 months measured by the Ages and Stages Questionnaire (ASQ). Secondary outcomes included maternal anxiety, quality of life, social support, parenting competence, and knowledge about child development.

RESULTS: Mothers in the LTP+ group reported significantly lower depression scores compared to those in the TAU group (6.6 vs. 13.8, effect size [ES]: -7.2; 95% confidence interval [CI]: -8.2, -6.1) at 3 and 6 months (7.2 vs. 12.00; ES: -4.6; 95% CI: -5.9, -3.4). Child socio-emotional development at 6 months was significantly better in the LTP+ group on all domains of the ASQ. There were also statistically significant improvements on all secondary outcomes at 3- and 6-month follow-up.

CONCLUSION: In low-resource settings like Pakistan, low-cost integrated parenting interventions delivered by lay health workers can provide effective treatment for depressed mothers, leading to improvements in child development.

PMID:34010505 | DOI:10.1002/da.23169

Pediatr Transplant. 2021 May 19:e13993. doi: 10.1111/petr.13993. Online ahead of print.

ABSTRACT

Impaired renal function after pediatric (LT) is a recognized problem. Accurate monitoring of (GFR) is imperative to detect declining renal function. GFR can be estimated via s-creatinine and/or p-cystatin C or measured by inulin and or/iohexol clearances. We retrospectively compared eGFRcrea and eGFRcyst, to mGFRiohex after LT. Data from 91 children with 312 concomitant measurements of s-creatinine, p-cystatin C, and iohexol clearance, obtained between 2007 and 2015, were analyzed. eGFR was calculated by using the p-cystatin C-based CAPA and CKD-EPI formulas, and the s-creatinine-based Schwartz-LYON, FAS, revised Schwartz and MDRD formulas. Also, the arithmetic means of cystatin C-based and creatinine-based equations were used. Every calculated eGFR was compared to mGFRiohex in statistical correlation, accuracy, precision, bias, and misclassifications. Among the different equations, p-cystatin C-based formulas (CAPA and CKD-EPI) as well as the s-creatinine-based Schwartz-LYON formula showed the most correct estimates regarding accuracy (84-87.5%), bias (0.19-4.0 ml/min/1.73 m² ), and misclassification rate (24.7-25%). In patients with renal function <75 ml/min/1.73 m² , cystatin C-based formulas were significantly more accurate and less biased than creatinine-based formulas. In conclusion, S-creatinine could be used in a clinical setting on a regular basis in liver transplanted pediatric patients, with reliable results, if eGFR is calculated by the Schwartz-LYON formula. When suspected renal dysfunction, cystatin C-based eGFR should be calculated, since it gives more accurate and less biased estimates than creatinine-based eGFR, and should be confirmed by mGFR (iohexol).

PMID:34010490 | DOI:10.1111/petr.13993

Biometrics. 2021 May 19. doi: 10.1111/biom.13487. Online ahead of print.

ABSTRACT

The human microbiome plays an important role in our health and identifying factors associated with microbiome composition provides insights into inherent disease mechanisms. By amplifying and sequencing the marker genes in high-throughput sequencing, with highly similar sequences binned together, we obtain Operational Taxonomic Units (OTU) profiles for each subject. Due to the high-dimensionality and non-normality features of the OTUs, the measure of diversity is introduced as a summarization at the microbial community level, including the distance-based Beta-diversity between individuals. Analyses of such between-subject attributes are not amenable to the predominant within-subject based statistical paradigm, such as t-tests and linear regression. In this paper, we propose a new approach to model Beta-diversity as a response within a regression setting by utilizing the functional response models (FRM), a class of semiparametric models for between- as well as within-subject attributes. The new approach not only addresses limitations of current methods for Beta-diversity with cross-sectional data, but also provides a premise for extending the approach to longitudinal and other clustered data in the future. The proposed approach is illustrated with both real and simulated data. This article is protected by copyright. All rights reserved.

PMID:34010477 | DOI:10.1111/biom.13487

Biometrics. 2021 May 19. doi: 10.1111/biom.13486. Online ahead of print.

ABSTRACT

In the form of multi-dimensional arrays, tensor data have become increasingly prevalent in modern scientific studies and biomedical applications such as computational biology, brain imaging analysis, and process monitoring system. These data are intrinsically heterogeneous with complex dependencies and structure. Therefore, ad-hoc dimension reduction methods on tensor data may lack statistical efficiency and can obscure essential findings. Model-based clustering is a cornerstone of multivariate statistics and unsupervised learning; however, existing methods and algorithms are not designed for tensor-variate samples. In this article, we propose a Tensor Envelope Mixture Model (TEMM) for simultaneous clustering and multiway dimension reduction of tensor data. TEMM incorporates tensor-structure-preserving dimension reduction into mixture modeling and drastically reduces the number of free parameters and estimative variability. An EM-type algorithm is developed to obtain likelihood-based estimators of the cluster means and covariances, which are jointly parameterized and constrained onto a series of lower-dimensional subspaces known as the tensor envelopes. We demonstrate the encouraging empirical performance of the proposed method in extensive simulation studies and a real data application in comparison with existing vector and tensor clustering methods. This article is protected by copyright. All rights reserved.

PMID:34010459 | DOI:10.1111/biom.13486

Endokrynol Pol. 2021 May 19. doi: 10.5603/EP.a2021.0046. Online ahead of print.

ABSTRACT

BACKGROUND: There are publications with contrasting results on the relationship between night eating syndrome and obesity. The aim of this study was to investigate the frequency and relationship between night eating syndrome (NES) in obese and non-obese participants.

MATERIAL AND METHODS: Between 1 January 2018 and 1 May 2018, 420 people ages 18-65 years who applied to İzmir Katip Çelebi University Atatürk Training and Research Hospital Family Medicine and Endocrinology outpatient clinics for any reason enrolled in this study. Body mass index (BMI = weight [kg]/height² [m²]) was calculated by measuring participants’ height and weight. BMI values between 18.50 and 24.99 were normal weight, between 25.0 and 29.99 were overweight, between 30.0 and 39.99 were obese, and 40.0 and above were considered morbidly obese. Participants’ sociodemographic data, the Night Eating Questionnaire (NEQ), and the Beck Depression Inventory (BDI) were administered by face-to-face interview technique.

RESULTS: The average age of the participants was 42 ± 13 years and 68.6% were female. The mean body mass index (BMI) of the participants was 31.8 ± 8.2. The prevalence of NES was determined: 10% of the participants had NES. The higher frequency of NES in patients with morbid obesity was found to be statistically significant compared to those without morbid obesity (p < 0.05). The mean BDS score was 23.5 ± 10.86 (min: 0, max: 46) in the NES group and 12.18 ± 88.95 (min: 0, max: 49) in the non-NES group. There was a significant difference between the two groups in terms of BDS scores (p < 0.001).

CONCLUSIONS: Because obesity has an important place in primary health care services, it is important to know the relationship between NES and depression. Recognition of NES and consideration of planned follow-up and treatment in the applicants will help to treat obesity more effectively.

PMID:34010444 | DOI:10.5603/EP.a2021.0046

Endokrynol Pol. 2021 May 19. doi: 10.5603/EP.a2021.0034. Online ahead of print.

ABSTRACT

Introduction Elevated serum parathormone (PTH) levels have been observed in acute kidney injury and are related to calcium-phosphate metabolism disturbance, decreased renal production of 1,25 dihydroxyvitamin D3, impaired renal PTH excretion and other renal-independent factors. There are no data regarding PTH concentration kinetics in critically ill patients undergoing continuous renal replacement therapies (CRRT) in an intensive care setting. The primary objective of this study was to investigate trends in PTH serum levels in critically ill patients with multiorgan failure, undergoing CRRT by performing periodic PTH measurements in the acute phase of critical illness. Material and methods Single center, prospective, observational study conducted in an mixed, university affiliated, intensive care unit. Critically ill patients were included who fulfilled all of the following criteria: respiratory failure; circulatory failure; acute kidney injury treated by CRRT; sequential organ failure assessment score (SOFA score) of 5 or more. Patients who met any of the following criteria were excluded: acute liver failure; hypercalcemia at admission (total calcium serum level > 10.6 mg/dl; total ionized calcium plasma level > 1.35 mmol/l); parathyroid gland disease, end-stage renal disease, patients undergoing therapeutic plasma exchange or extracorporeal membrane oxygenation procedures, aged under 18 years, pregnant, life expectancy after admission to the intensive care unit anticipated to be less than 72 hours as assessed by the investigator. Results Thirty patients met the inclusion criteria. A statistically significant change in PTH over time was observed (Friedman ANOVA; p=0.0001). The post-hoc test showed a statistically significant decrease in PTH: measurements 5-8 relative to measurement 1, measurements 4-8 relative to measurement 2 (p.

PMID:34010434 | DOI:10.5603/EP.a2021.0034

J Parasitol. 2021 May 1;107(3):404-410. doi: 10.1645/20-142.

ABSTRACT

Foodborne pathogens continue to pose a public health risk and can cause serious illness and outbreaks of disease in consumers. The consumption of raw or undercooked infected meat, such as pork containing infectious stages of Toxoplasma gondii, may be a major route of transmission to humans. Given the occasional presence of T. gondii in pork meat and the frequent use of pork for products not intended to be cooked, such as dry-cured ham, a potential risk exists for T. gondii transmission to consumers of these products. The purpose of this study was to determine the seroprevalence of T. gondii in U.S. market hogs and sows at slaughter. A total of 20,209 sera samples collected from 22 U.S. slaughterhouses, including 15 of the top 25 largest slaughter plants in the United States, were tested for T. gondii antibodies using a commercial ELISA assay. Seroprevalence in this study was 0.74%, with a herd prevalence of 10.86%. We compared seroprevalence of T. gondii in market hogs vs. sows from a separate but geographically similar set of slaughterhouse locations, with serum samples screened using the T. gondii modified agglutination test. This set of market hogs demonstrated 0% seroprevalence for T. gondii, while sows from geographically similar but separate slaughter facilities demonstrated a seroprevalence of 1.03%. Overall, both analyses show low seroprevalence of T. gondii in U.S market hogs and sows, respectively, and a marked drop in prevalence in market hogs and sows compared to previous studies.

PMID:34010426 | DOI:10.1645/20-142

J Natl Cancer Inst. 2021 May 19:djab095. doi: 10.1093/jnci/djab095. Online ahead of print.

ABSTRACT

BACKGROUND: The prognostic significance of patients with low-risk Recurrence Score (RS) results in the context of the American Joint Committee on Cancer (AJCC) 8th-edition pathologic prognostic staging has not been investigated. We evaluated if expanded RS criteria can be considered for downstaging in AJCC pathologic prognostic staging.

METHODS: Using Surveillance, Epidemiology, and End Results data we identified patients with T1-3N0-3M0 HR-positive/HER2-negative breast cancer treated from 2010-2015 with follow-up data through 2016. We evaluated TNM categories, grade, and RS result. The primary outcome measured was 5-year disease-specific survival (DSS) of patients with low-risk RS results not already pathologic prognostic stage IA, determined by T and N categories per AJCC 8th edition. All statistical tests were 2-sided.

RESULTS: Of 154,050 patients with median follow-up of 49 months (range = 0-83), RS results were obtained in 60,886 (39.5%): RS was <11 in 13,570 (22.3%), 11-17 in 22,719 (37.3%), 18-25 in 16,521 (27.1%), and ≥ 26 in 8,076 (13.3%). Five-year DSS for pathologic prognostic stage IA patients (n = 114,910, 74.6%) was 98.8%. Among N0-1 patients with RS < 18 not staged as pathologic prognostic stage IA by current criteria, 5-year DSS was excellent and not statistically significantly different than for pathologic prognostic stage IA patients (97.2%-99.7%, P > .05). For those with RS 18-25, there was a small decrease in DSS for T2N0 (2.3%) and modest decrease for T1-2N1 (4.2%-6.4%) compared to pathologic prognostic stage IA patients (P < .001).

CONCLUSION: Patients with RS < 18 have excellent 5-year DSS regardless of T category for N0-1 disease suggesting further modification of the AJCC staging system using this cutoff.

PMID:34010423 | DOI:10.1093/jnci/djab095

J Natl Cancer Inst. 2021 May 19:djab079. doi: 10.1093/jnci/djab079. Online ahead of print.

ABSTRACT

BACKGROUND: Recent trends of hepatocellular carcinoma (HCC) mortality and outcome remain unknown in the United States (US). We investigated the recent trends of primary liver cancer (excluding intrahepatic cholangiocarcinoma) mortality and HCC stage, treatment, and overall survival (OS) in the US.

METHODS: US Cancer Mortality database was analyzed to investigate the trend of primary liver cancer mortality. We analyzed the SEER 18 database to assess the temporal trend of tumor size, stage, treatment, and OS of HCC. Cox regression analysis investigated the association between HCC diagnosis year and OS. All statistical tests were 2-sided.

RESULTS: During 2000-2018, liver cancer mortality rates increased until 2013, plateaued during 2013-2016 (annual percent change [APC] = 0.1%/yr, 95% confidence interval [CI] = -2.1% to 2.4%; P=0.92), and started to decline during 2016-2018 (APC = -1.5%/yr, 95% CI= -3.2% to 0.2%; P=0.08). However, mortality continues to increase in American Indians/Alaska Natives, individuals aged 65 or older, and in 33 states. There was a 0.61% (95% CI = 0.53% to 0.69%; P<0.001) increase in localized stage HCC and 0.86 mm (95% CI= -1.10 to -0.62; P<0.001) decrease in median tumor size per year. One-year OS rate increased from 36.3% (95% CI = 34.3% to 38.3%) to 58.1% (95% CI = 56.9% to 59.4%) during 2000-2015, and five-year OS rate almost doubled from 11.7% (95% CI = 10.4% to 13.1%) to 21.3% (95% CI = 20.2% to 22.4%) during 2000-2011. Diagnosis year (per year) (adjusted hazard ratio = 0.96; 95% CI = 0.96 to 0.97) was independently associated with OS in multivariable analysis.

CONCLUSIONS: Primary liver cancer mortality rates have started to decline in the US with demographic and state-level variation. With an increasing detection of localized HCC, the OS of HCC has improved over the past decades.

PMID:34010422 | DOI:10.1093/jnci/djab079