Nevin Manimala

Hum Reprod. 2022 Apr 12:deac075. doi: 10.1093/humrep/deac075. Online ahead of print.

ABSTRACT

STUDY QUESTION: Are there genetic variants that interact with smoking to reduce reproductive lifespan in East-Asian women?

SUMMARY ANSWER: Our study corroborates several recently identified genetic loci associated with reproductive lifespan and highlights specific genetic predispositions that may interact with smoking status to adversely affect reproductive lifespan in East-Asian women.

WHAT IS KNOWN ALREADY: Epidemiological data as well as evaluations on genetic predisposition to smoke indicate on the importance of smoking in adverse effects on reproductive lifespan in women. However, there are no previous smoking and gene interaction studies for reproductive traits in East-Asian women.

STUDY DESIGN, SIZE, DURATION: This population-based prospective cohort study comprised 11 643 East-Asian Chinese women with overlapping genome-wide genotyping and reproductive data.

PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a genome-wide association study for reproductive lifespan in women (n = 11 643) from the Singapore Chinese Health Study (SCHS) and carried out a genome-wide interaction study to identify loci that interacted with smoking status to affect age of natural menopause and reproductive-time.

MAIN RESULTS AND THE ROLE OF CHANCE: Two known loci associated with menopause, rs113430717 (near HMCES, chromosome 3, Pmeta = 5.72 × 10-15) and rs3020136 (near RAD21, chromosome 8, Pmeta = 1.38 × 10-8) were observed beyond genome-wide levels of association with age at menopause in this study. For reproductive lifespan, the genome-wide association observed at rs79784106 (chromosome 3, Pmeta = 5.05 × 10-12) was in linkage disequilibrium with the menopause lead single-nucleotide polymorphism (SNP) (rs113430717). Four additional loci, first reported to be associated with menopause, were also associated with reproductive lifespan in our study (PAdj between 7.42 × 10-5 to 4.51 × 10-3). A significant interaction was observed between smoking and an East-Asian specific SNP, rs140146885, for reduced reproductive lifespan, per copy of the minor C allele (beta = -1.417 years, Pinteraction = 2.31 × 10-10). This interaction was successfully replicated in additional independent samples (beta = -1.389 years, Pinteraction = 6.78 × 10-3). Another known variant associated with menopause, rs11031006 (near FSHB), was also observed to interact with smoking status to reduce age at menopause in our dataset (beta = -0.450 years, Padj = 0.042).

LIMITATIONS, REASONS FOR CAUTION: The modest sample size of the replication datasets used likely affected the statistical power to firmly replicate all identified novel loci observed in our smoking interaction analyses.

WIDER IMPLICATIONS OF THE FINDINGS: Age of natural menopause and reproductive lifespan have clear genetic predispositions with distinct ethnic differences, and they may be adversely truncated by lifestyle factors such as smoking, which can pose a significant impact on the reproductive lifespan and future health outcomes in women.

STUDY FUNDING/COMPETING INTEREST(S): The Singapore Chinese Health Study is funded by the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016), National Institutes of Health (R01 CA144034 and UM1 CA182876) and National Research Foundation, Singapore (Project Number 370062002). W.-P.K. is supported by the National Medical Research Council, Singapore (MOH-CSASI19nov-0001). The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors do not report conflicts of interest.

TRIAL REGISTRATION NUMBER: N/A.

PMID:35413122 | DOI:10.1093/humrep/deac075

Hum Reprod. 2022 Apr 12:deac068. doi: 10.1093/humrep/deac068. Online ahead of print.

ABSTRACT

STUDY QUESTION: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children?

SUMMARY ANSWER: In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children.

WHAT IS KNOWN ALREADY: DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day.

STUDY DESIGN, SIZE, DURATION: This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception).

PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing.

MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10-7), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age).

LIMITATIONS, REASONS FOR CAUTION: This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results.

WIDER IMPLICATIONS OF THE FINDINGS: This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort.

STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER: N/A.

PMID:35413117 | DOI:10.1093/humrep/deac068

PLoS One. 2022 Apr 12;17(4):e0266686. doi: 10.1371/journal.pone.0266686. eCollection 2022.

ABSTRACT

INTRODUCTION: Students generally struggle to build a good career after their graduation in developing countries like Bangladesh. Due to the COVID-19 pandemic, such struggle increased and faced with stress and depression. We aimed to inquire about the amplitude of depression and stress among university students during the COVID-19 pandemic regarding their future careers and to identify the factors associated with this depression and stress.

METHODS: A total of 516 students at various universities participated in this cross-sectional survey. From October 2020 to February 2021, data was collected through an online survey. An e-questionnaire with socio-demographic, Patient Health Questionnaire (PHQ-9) and Perceived Stress Scale (PSS-10) questions was created using Google Forms and distributed via Facebook, WhatsApp, and other social media platforms. The universities included into the sample were selected randomly from eight divisions of Bangladesh. Descriptive statistics and Pearson chi-square tests were carried out and the association between the risk factors and the outcome (e.g. depression and stress) was assessed by the odds ratio (OR) including 95% confidence interval (CI) obtained from the binary logistic regression model.

RESULTS: Among 516 participants, 380 (73.6%) were male and 136 (26.4%) were female. Around 414 (80.2%) participants had mild to severe depression and 399 (77.3%) reported having low to moderately perceived stress. Female students were 2.1 (95% CI: 1.21-3.76) times more depressed and 3.6 (95% CI: 1.87-6.76) times more stressed than the counterpart. Students, who think delaying graduation due to COVID-19 will reduce the chance of getting a job, were 1.72 (95% CI: 1.07-2.76) times more depressed. Respondents, whose department offers any internship were 36% less depressed (p = 0.053), while skilled students were 46% less stressed though it was not statistically significant (p = 0.43).

CONCLUSION: According to our findings, there is an increasing prevalence of depression and stress among students, particularly among female students and those who do not receive job-related facilities from their institutions or who are unskilled. Universities can provide mental health programs and strive to have enough space for students to participate in internships. In addition, the government and educational institutions should work together to address the growing challenge.

PMID:35413076 | DOI:10.1371/journal.pone.0266686

PLoS One. 2022 Apr 12;17(4):e0266662. doi: 10.1371/journal.pone.0266662. eCollection 2022.

ABSTRACT

BACKGROUND: High dietary salt intake is recognized as a risk factor for several non-communicable diseases (NCDs), in particular cardiovascular diseases (CVDs), including heart attack and stroke. Accurate measurement of population level salt intake is essential for setting targeted goals and plans for salt reduction strategies. We used a spot urine sample to estimate the mean population salt intake in Nepal and evaluated the association of salt intake with excess weight, hypertension, raised blood sugar and hypercholesterolemia, and a number of socio-demographic characteristics.

METHODS: A population-based cross-sectional study was carried out from February to May 2019 using a WHO STEPwise approach to surveillance. Spot urine was collected from 4361 participants aged 15-69 years for the analysis of salt intake. We then used the INTERSALT equation to calculate population salt intake. Student’s ‘t’ test, one-way ANOVA and multivariable linear regression were used to assess the association between salt intake and a number of factors. Statistical significance was accepted at P < .05.

RESULTS: The average (±SD) age of participants was 40 (14.1) years. Mean salt intake, derived from spot urine samples, was estimated to be 9.1g/d. A total of 70.8% of the population consumed more than the WHO’s recommended amount of 5g salt per day, with almost one third of the population (29%) consuming more than 10g of salt per day. Higher salt intake was significantly associated with male gender (β for male = 0.98g; 95%CI:0.87,1.1) and younger age groups (β25-39 years = 0.08; 95%CI:-0.08,0.23) and higher BMI (β = 0.19; 95%CI:0.18,0.21). Participants who were hypertensive and had raised blood cholesterol consumed less salt than people who had normal blood pressure and cholesterol levels (P<0.001).

CONCLUSIONS: Salt consumption in Nepal is high, with a total of 70.8% of the population having a mean salt intake >5g/d, well above the World Health Organization recommendation. High salt intake was found to be associated with sex, age group, education, province, BMI, and raised cholesterol level of participants These findings build a strong case for action to reduce salt consumption in Nepal in order to achieve the global target of 30% reduction in population salt intake by 2025.

PMID:35413065 | DOI:10.1371/journal.pone.0266662

PLoS One. 2022 Apr 12;17(4):e0265904. doi: 10.1371/journal.pone.0265904. eCollection 2022.

ABSTRACT

The event related P300 potentials, positive waveforms in electroencephalography (EEG) signals, are often utilized in brain computer interfaces (BCI). Many studies have been carried out to improve the performance of P300 speller systems either by developing signal processing algorithms and classifiers with different architectures or by designing new paradigms. In this study, a new paradigm is proposed for this purpose. The proposed paradigm combines two remarkable properties of being a 3D animation and utilizing column-only flashings as opposed to classical paradigms which are based on row-column flashings in 2D manner. The new paradigm is utilized in a traditional two-layer artificial neural networks model with a single output neuron, and numerous experiments are conducted to evaluate and compare the performance of the proposed paradigm with that of the classical approach. The experimental results, including statistical significance tests, are presented for single and multiple EEG electrode usage combinations in 1, 3 and 15 flashing repetitions to detect P300 waves as well as to recognize target characters. Using the proposed paradigm, the best average classification accuracy rates on the test data are improved from 89.97% to 93.90% (an improvement of 4.36%) for 1 flashing, from 97.11% to 98.10% (an improvement of 1.01%) for 3 flashings and from 99.70% to 99.81% (an improvement of 0.11%) for 15 flashings when all electrodes, included in the study, are utilized. On the other hand, the accuracy rates are improved by 9.69% for 1 flashing, 4.72% for 3 flashings and 1.73% for 15 flashings when the proposed paradigm is utilized with a single EEG electrode (P8). It is observed that the proposed speller paradigm is especially useful in BCI systems designed for few EEG electrodes usage, and hence, it is more suitable for practical implementations. Moreover, all participants, given a subjective test, declared that the proposed paradigm is more user-friendly than classical ones.

PMID:35413050 | DOI:10.1371/journal.pone.0265904

Plast Reconstr Surg. 2022 Apr 12:PRS.0000000000009143. doi: 10.1097/PRS.0000000000009143. Online ahead of print.

ABSTRACT

BACKGROUND: It is important to determine whether sagittal synostosis-associated scaphocephaly is static in the presurgical period, or whether there are morphologic differences with time to include in surgical decision-making. The authors’ purpose was to perform cross-sectional analysis of cranial morphology before any surgical intervention in children with sagittal synostosis younger than 9 months compared to matched controls.

METHODS: The authors performed morphometric analysis on computed tomographic scans from 111 untreated isolated sagittal synostosis patients younger than 9 months and 37 age-matched normal controls. The authors divided the patients into three age groups and performed statistical comparison between sagittal synostosis and controls for each group.

RESULTS: Sagittal synostosis cephalic indices were stable and lower in patients than in controls across groups. Total cranial volume was equivalent, but sagittal synostosis patients had a greater posterior volume than controls at all ages and a smaller middle fossa volume at older ages. Pterional width was greater in sagittal synostosis patients than in controls for each age group. Frontal bossing vectors were most severe in the youngest age groups and least in the older group. Occipital protuberance was consistent across the age groups.

CONCLUSIONS: Upper parietal narrowing and occipital protuberance were the consistent deformities across age groups, with the most parietal constriction seen in older patients. Frontal bossing was not consistent and was more severe in the younger patients. The authors did not detect significant pterional constriction, and the appearance of constriction is relative to adjacent morphology and not absolute.

CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

PMID:35413045 | DOI:10.1097/PRS.0000000000009143

Pediatr Emerg Care. 2022 Apr 13. doi: 10.1097/PEC.0000000000002719. Online ahead of print.

ABSTRACT

OBJECTIVE: Early hypocalcemia (EH) is common in adult major trauma patients and has been associated with coagulopathy, shock, increased transfusion requirements, and mortality. The incidence of EH in pediatric severe trauma has not been investigated. We aimed to explore the incidence of EH among severely injured children.

METHODS: We conducted a retrospective cohort study at a tertiary children’s hospital and a level 1 pediatric trauma center. We extracted the medical records of all pediatric major trauma patients, defined as an age less than 18 years and an Injury Severity Score (ISS) greater than 15, admitted after trauma team activation from January 2010 to December 2020.The primary outcome was the presence of EH. Patients were classified into 3 groups: severe hypocalcemia (ionized calcium [iCa] <1 mmol/L), hypocalcemia (1 < iCa < 1.16 mmol/L), and normal calcium (iCa ≥1.16 mmol/L).

RESULTS: During the study period, 5126 children were hospitalized because of trauma. One hundred eleven children met the inclusion criteria. The median age was 11 years (interquartile range [IQR], 4-15), and 78.4% (87) were male. The median ISS was 21 (IQR, 17-27).Hypocalcemia was found in 19.8% (22) and severe hypocalcemia in 2.7% (3) of the patients.Although not statistically significant, hypocalcemic pediatric trauma patients had higher ISS (25.5 [IQR, 17-29] vs 21 [IQR, 17-26], P = 0.39), lower Glasgow Coma Scale (11 [IQR, 3-15] vs 13 [IQR, 7-15], P = 0.24), a more prolonged hospital stay (8 days [IQR, 2-16] vs 6 days [IQR, 3-13], P = 0.36), a more frequent need for blood products (27.3% vs 20.2%, P = 0.74), and higher mortality rates (9.1% vs 1.1%, P = 0.18) compared with normocalcemic patients.

CONCLUSIONS: Our data suggest that in the setting of major trauma, EH is less frequent in children than previously reported in adults. Our preliminary data suggest that pediatric patients with EH may be at risk of increased morbidity and mortality compared with children with normal admission iCa requiring further studies.

PMID:35413033 | DOI:10.1097/PEC.0000000000002719

J Acquir Immune Defic Syndr. 2022 Apr 12. doi: 10.1097/QAI.0000000000003002. Online ahead of print.

ABSTRACT

OBJECTIVE: We sought to validate the D:A:D risk score for chronic kidney disease (CKD) in people living with HIV (PLWH) in a cohort from Harare, Zimbabwe. Additionally, we aimed to evaluate proteinuria as a predictive variable in the risk score model, being the first study to do so.

DESIGN: Data from PLWH attending a clinic in Harare was evaluated. Those with a baseline estimated glomerular filtration rate >60ml/min/1.73m2 and at least two subsequent eGFR measurements were included. A modified version of the D:A:D risk score model was applied to categorise participants as ‘low’, ‘medium’ and ‘high-risk’ of progression to CKD. Potential predictors of renal impairment were assessed by logistic regression in univariate and multivariate models. Proteinuria was evaluated in a nested model using D:A:D risk categories.

RESULTS: 2793 participants were included. 40 participants (1.4% of the cohort) progressed to CKD during the median follow-up time of 4.2 years. Progression rates were 1%, 3% and 12% in the low, medium, and high-risk groups respectively. Proteinuria data was available for 2251 participants. Presence of proteinuria was strongly associated with progression to CKD [OR 7.8, 95% CI 3.9-15.7], and its inclusion in the risk score improved the discrimination of the model with the c-statistic increasing from 0.658 to 0.853).

CONCLUSION: A modified version of the D:A:D CKD risk score performed well in predicting CKD events among this Sub-Saharan African cohort of people living with HIV. Inclusion of proteinuria into the risk score model significantly improved predictability.

PMID:35413019 | DOI:10.1097/QAI.0000000000003002

IEEE J Biomed Health Inform. 2022 Apr 12;PP. doi: 10.1109/JBHI.2022.3166826. Online ahead of print.

ABSTRACT

Distinguishing bipolar depression (BD) from unipolar depression (UD) based on symptoms only is challenging. Brain functional connectivity (FC), especially dynamic FC, has emerged as a promising approach to identify possible imaging markers for differentiating BD from UD. However, most of such studies utilized conventional FC and group-level statistical comparisons, which may not be sensitive enough to quantify subtle changes in the FC dynamics between BD and UD. In this paper, we present a more effective individualized differentiation model based on machine learning and the whole-brain high-order functional connectivity (HOFC) network. The HOFC, capturing temporal synchronization among the dynamic FC time series, a more complex chronnectome metric compared to the conventional FC, was used to classify 52 BD, 73 UD, and 76 healthy controls (HC). We achieved a satisfactory accuracy (70.40%) in BD vs. UD differentiation. The resultant contributing features revealed the involvement of the coordinated flexible interactions among sensory (e.g., olfaction, vision, and audition), motor, and cognitive systems. Despite sharing common chronnectome of cognitive and affective impairments, BD and UD also demonstrated unique dynamic FC synchronization patterns. UD is more associated with abnormal visual-somatomotor inter-network connections, while BD is more related to impaired ventral attention-frontoparietal inter-network connections. Moreover, we found that the illness duration modulated the BD vs. UD separation, with the differentiation performance hampered by the secondary disease effects. Our findings suggest that BD and UD may have divergent and convergent neural substrates, which further expand our knowledge of the two different mental disorders.

PMID:35412995 | DOI:10.1109/JBHI.2022.3166826

Bioengineered. 2022 Apr;13(4):10001-10009. doi: 10.1080/21655979.2022.2062536.

ABSTRACT

Triple-negative breast cancer (TNBC) is a malignant tumor that threatens women’s health. Exploring novel development-associated biomarkers could help improve the survival rate of TNBC. This study evaluated the significance and mechanism of LINC01315 in TNBC progression aiming to identify a potential biomarker. There were 103 TNBC patients that provided clinical tissues in this study. The expression of LINC01315 was assessed by PCR and its association with clinical data was evaluated by statistical analyses. The in vitro cell experiments were conducted to estimate the biological effect of LINC01315 and its molecular mechanism. A significant upregulation of LINC01315 was observed in TNBC, which was associated with disease development and severity of patients. The upregulation of LINC01315 could be a symptom of the poor prognosis of patients. The knockdown of LINC01315 suppressed the main cellular processes of TNBC progression. Additionally, miR-876-5p was demonstrated to be a target of LINC01315 and regulate the expression of GRK5, through which LINC01315 modulated the progression of TNBC. Upregulated LINC01315 in TNBC indicated the malignant development and poor survival rate of patients. Inhibition of LINC01315 might be a potential therapeutic strategy of TNBC.

PMID:35412954 | DOI:10.1080/21655979.2022.2062536