Nevin Manimala

J Pediatr Nurs. 2021 Mar 17;61:34-39. doi: 10.1016/j.pedn.2021.03.011. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this study was to examine patterns of health and developmental outcomes in children with prenatal opioid exposure (POE) and neonatal abstinence syndrome (NAS) compared to children without exposure during the first three years of life.

DESIGN AND METHODS: This was a secondary data analysis of the Maternal and Infant Data Hub (MIDH), a de-identified dataset originating from the Midwest region of the United States, consisting of newborn billing records and corresponding maternal and child electronic medical records. For these analyses, the repository included data on more than 20,000 children born between 2013 and 2019. Diagnoses were identified with International Classification of Diseases, ninth and tenth Revision, Clinical Modification codes (ICD-9/10-CM). Firth logistic regression was used to assess whether incidence of each diagnosis code differed by exposure group.

RESULTS: Among 20,389 children in the dataset, 13,173 were unexposed; 455 were POE, and 199 were POE + NAS. There were significant differences in frequency of diagnoses between groups, specifically regarding growth and development, infection, mental health, musculoskeletal, neonatal, sensory, and social issues. When comparing exposed groups, children with POE + NAS experienced more negative health outcomes than children with only POE across all years.

CONCLUSIONS: This study implicates POE as a significant variable associated with many health and developmental outcomes of children during the first three years of life.

PRACTICE IMPLICATIONS: It is crucial to understand and identify health risks observed more frequently in exposed children during such a critical period of growth and brain development.

PMID:33743318 | DOI:10.1016/j.pedn.2021.03.011

Diagn Microbiol Infect Dis. 2021 Feb 19;100(2):115351. doi: 10.1016/j.diagmicrobio.2021.115351. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the accuracy of the rapid diagnostic test for malaria diagnosis in children under 5 years of age.

METHODS: As of August 31, 2020, PubMed, Web of Science and Cochrane Library databases had been systematically searched. Relevant data were extracted and meta-analysis was carried out. A random effects model was used for subgroup analysis.

RESULTS: According to the inclusion criteria, a total of 26 studies were included in this meta-analysis. The pooled sensitivity and specificity were 0.92 (95% confidence interval 0.83-0.96) and 0.92 (0.86-0.95), the parasite-specific lactate dehydrogenase-based test were 0.96 (0.85-0.98) and 0.93 (0.86-0.95), the histidine-rich protein 2-based test were 0.94 (0.84-0.98) and 0.86 (0.77-0.91).

CONCLUSIONS: This meta-analysis showed that rapid diagnostic test had good accuracy in diagnosing malaria in children under 5 years of age. And the diagnostic performance of parasite-specific lactate dehydrogenase test was better than that of the histidine-rich protein 2 test.

PMID:33743294 | DOI:10.1016/j.diagmicrobio.2021.115351

Clin Nutr. 2021 Feb 23;40(4):1562-1570. doi: 10.1016/j.clnu.2021.02.021. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: The degradation of muscle mass and loss of functional proteins due to catabolism are associated with adverse outcomes in critically ill patients. While an adequate supply of protein within a medical nutrition concept is suggested to minimize proteolysis, the specificities on appropriate dosage and timing are still under debate. The current study aimed to evaluate the effect of two different quantities of protein as part of a standardized energetically controlled nutrition therapy for the preservation of muscle mass in the later phase of critical illness.

METHODS: A randomized controlled trial was conducted in 42 critically ill patients (age 65 ± 15; 12 females; SAPS 45 ± 11; TISS 20 ± 7; SOFA-score 7 ± 3). The subjects were randomly assigned to either the intervention (1.8 g protein/kg body weight [BW]/d) or standard (1.2 g protein/kg BW/d) group. Nutrient supply via enteral and/or parenteral nutrition was calculated based on the individual energy expenditure measured by indirect calorimetry and target protein content. Quadriceps muscle layer thickness (QMLT) was observed through sonography at inclusion, and during the follow-up period, two and four weeks after inclusion. The measurement points were fixed on two sides at the midpoint and two-thirds between the anterior superior iliac spine and top of the patella. The data were analyzed descriptively wherein chi-squared tests or unpaired two-samle t-tests checked group differences. Daily changes in muscle mass were estimated using a linear mixed model. All data are shown as the mean ± standard deviation (SD).

RESULTS: Actual protein intake reached 1.5 ± 0.5 g and 1.0 ± 0.5 g/kg BW/d in the intervention and standard group, respectively. Mean values of all measurements of QMLT at inclusion (day 13 ± 2 after ICU admission) were 13.5 ± 7.4 mm and 13.4 ± 7.1 mm in the intervention and standard group, respectively (P = 0.967). In both the groups, QMLT decreased over time (P < 0.001), while the estimated mean values of daily QMLT changes were -0.15 ± 0.08 mm (intervention) and -0.28 ± 0.08 mm (standard) without significant between-group differences (intervention effect, P = 0.368; time x intervention effect, P = 0.242). Illness scores and clinical outcomes showed no group differences.

CONCLUSION: In this single-center trial the increased amounts of protein (1.5 g vs. 1.0 g/kg BW/d) provided through medical nutrition therapy in the late phase of critical illness did not achieve a statistically significant impact on the loss of muscle mass in long-term immobilized ICU patients. Larger multi-center trials are needed to evaluate whether observed numerical differences in muscle mass could be a true finding, and will translate into improved clinical outcomes.

TRIAL REGISTRATION: German Clinical Trials Register (http://www.drks.de/), DRKS-ID: DRKS00013594.

PMID:33743292 | DOI:10.1016/j.clnu.2021.02.021

Clin Nutr. 2021 Feb 27;40(4):1537-1545. doi: 10.1016/j.clnu.2021.02.033. Online ahead of print.

ABSTRACT

AIMS: To study whether the consumption of ultra-processed foods and drinks is associated with breast, colorectal, and prostate cancers.

METHODS: Multicentric population-based case-control study (MCC-Spain) conducted in 12 Spanish provinces. Participants were men and women between 20 and 85 years of age with diagnoses of colorectal (n = 1852), breast (n = 1486), or prostate cancer (n = 953), and population-based controls (n = 3543) frequency-matched by age, sex, and region. Dietary intake was collected using a validated food frequency questionnaire. Foods and drinks were categorized according to their degree of processing based on the NOVA classification. Unconditional multivariable logistic regression was used to evaluate the association between ultra-processed food and drink consumption and colorectal, breast, and prostate cancer.

RESULTS: In multiple adjusted models, consumption of ultra-processed foods and drinks was associated with a higher risk of colorectal cancer (OR for a 10% increase in consumption: 1.11; 95% CI 1.04-1.18). The corresponding odds for breast (OR 1.03; 95% CI 0.96-1.11) and prostate cancer (OR 1.02; 95% CI 0.93-1.12) were indicative of no association.

CONCLUSIONS: Results of this large population-based case-control study suggest an association between the consumption of ultra-processed foods and drinks and colorectal cancer. Food policy and public health should include a focus on food processing when formulating dietary guidelines.

PMID:33743289 | DOI:10.1016/j.clnu.2021.02.033

Knee. 2021 Mar 17;29:478-485. doi: 10.1016/j.knee.2021.02.025. Online ahead of print.

ABSTRACT

BACKGROUND: The bone healing in open-wedge high tibial osteotomy (OWHTO) proceeds gradually by a filling of the osteotomy gap. This can comprise several risk factors.

METHODS: A retrospective study analysed the clinical and radiological course of 101 consecutive OWHTOs in 96 patients. The following risk factors were considered: age, body mass index, tobacco consumption, amount of tobacco consumption, severity of comorbidities, infection of the surgical area, occurrence of a lateral hinge fracture and the degree of correction. The bone healing was evaluated by using the modified Radiographic Union Score for Tibial fractures (RUST).

RESULTS: A disturbance in bone healing was observed in 16 of the 101 osteotomies. Binary logistic regression analysis showed a correlation between the angle of the opening wedge and the development of a disturbance in bone healing (P = 0.002). The odds ratio indicated an increase in the risk of a disturbance in bone healing of 56% with each additional degree of correction. For the risk factor ‘age’ a statistical trend was recognizable (P = 0.077) with the risk of a disturbance in bone healing in higher age.

CONCLUSION: Lateral hinge fractures seem not to have a detrimental effect on the filling of the osteotomy gap. An increase in the opening wedge bears the risk of a disturbance in bone healing.

PMID:33743262 | DOI:10.1016/j.knee.2021.02.025

Lancet Neurol. 2021 Apr;20(4):294-303. doi: 10.1016/S1474-4422(21)00024-7.

ABSTRACT

BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.

METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602.

FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models.

INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted.

FUNDING: British Heart Foundation and Stroke Association.

PMID:33743239 | DOI:10.1016/S1474-4422(21)00024-7

Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6.

ABSTRACT

BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.

METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10¹⁴ vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).

FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).

INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.

FUNDING: Novartis Gene Therapies.

PMID:33743238 | DOI:10.1016/S1474-4422(21)00001-6

Lancet. 2021 Mar 17:S0140-6736(21)00575-4. doi: 10.1016/S0140-6736(21)00575-4. Online ahead of print.

ABSTRACT

BACKGROUND: The degree to which infection with SARS-CoV-2 confers protection towards subsequent reinfection is not well described. In 2020, as part of Denmark’s extensive, free-of-charge PCR-testing strategy, approximately 4 million individuals (69% of the population) underwent 10·6 million tests. Using these national PCR-test data from 2020, we estimated protection towards repeat infection with SARS-CoV-2.

METHODS: In this population-level observational study, we collected individual-level data on patients who had been tested in Denmark in 2020 from the Danish Microbiology Database and analysed infection rates during the second surge of the COVID-19 epidemic, from Sept 1 to Dec 31, 2020, by comparison of infection rates between individuals with positive and negative PCR tests during the first surge (March to May, 2020). For the main analysis, we excluded people who tested positive for the first time between the two surges and those who died before the second surge. We did an alternative cohort analysis, in which we compared infection rates throughout the year between those with and without a previous confirmed infection at least 3 months earlier, irrespective of date. We also investigated whether differences were found by age group, sex, and time since infection in the alternative cohort analysis. We calculated rate ratios (RRs) adjusted for potential confounders and estimated protection against repeat infection as 1 – RR.

FINDINGS: During the first surge (ie, before June, 2020), 533 381 people were tested, of whom 11 727 (2·20%) were PCR positive, and 525 339 were eligible for follow-up in the second surge, of whom 11 068 (2·11%) had tested positive during the first surge. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0·65% [95% CI 0·51-0·82]) tested positive again during the second surge compared with 16 819 (3·27% [3·22-3·32]) of 514 271 who tested negative during the first surge (adjusted RR 0·195 [95% CI 0·155-0·246]). Protection against repeat infection was 80·5% (95% CI 75·4-84·5). The alternative cohort analysis gave similar estimates (adjusted RR 0·212 [0·179-0·251], estimated protection 78·8% [74·9-82·1]). In the alternative cohort analysis, among those aged 65 years and older, observed protection against repeat infection was 47·1% (95% CI 24·7-62·8). We found no difference in estimated protection against repeat infection by sex (male 78·4% [72·1-83·2] vs female 79·1% [73·9-83·3]) or evidence of waning protection over time (3-6 months of follow-up 79·3% [74·4-83·3] vs ≥7 months of follow-up 77·7% [70·9-82·9]).

INTERPRETATION: Our findings could inform decisions on which groups should be vaccinated and advocate for vaccination of previously infected individuals because natural protection, especially among older people, cannot be relied on.

FUNDING: None.

PMID:33743221 | DOI:10.1016/S0140-6736(21)00575-4

Cell Stem Cell. 2021 Mar 16:S1934-5909(21)00108-9. doi: 10.1016/j.stem.2021.03.002. Online ahead of print.

ABSTRACT

Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras. We created Dnmt3a-mosaic mice by transplanting Dnmt3a^-/- and WT HSCs into WT mice and observed the substantial expansion of Dnmt3a^-/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a^-/- HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a^-/- clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thus demonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-function CH.

PMID:33743191 | DOI:10.1016/j.stem.2021.03.002

Hum Cell. 2021 Mar 20. doi: 10.1007/s13577-021-00520-4. Online ahead of print.

ABSTRACT

The polymorphism rs2853669 in the telomerase reverse transcriptase gene (TERT) promoter region is widely investigated for the risk of different cancers. However, previous results remained inconclusive. Thus, we performed this updated meta-analysis to comprehensively evaluate the association between rs2853669 and the susceptibility of human cancer. A systematic literature search via PubMed, EMBASE, Cochrane Library, and Web of Science databases was conducted that produced a total of 19 eligible studies containing 23,085 subjects. The relationship was calculated with the odds ratio (OR) and 95% confidence intervals (CIs). Statistical analyses were performed using the RevMan 5.4 software. The analysis indicated that rs2853669 is associated with an enhanced risk of overall cancer risk. From subgroup analysis, a significantly increased association in five genetic models (p < 0.05) was found among Asians, but no association was observed in Caucasians. Although we did not find any significant correlation between rs2853669 and breast cancer, an increased and statistically significant association was found for both lung cancer and acute myeloid leukemia. We did not find any association in other cancer types during stratified analysis. Our meta-analysis suggests that rs2853669 polymorphism in TERT gene is associated with an increased risk of overall cancer susceptibility, particularly in the Asian population. Moreover, rs2853669 is significantly associated with lung cancer and acute myeloid lymphoma. However, large-scale studies are needed to confirm our findings.

PMID:33743166 | DOI:10.1007/s13577-021-00520-4