Nevin Manimala

J Am Stat Assoc. 2022;117(537):348-360. doi: 10.1080/01621459.2020.1777138. Epub 2020 Aug 19.

ABSTRACT

We consider estimation of mean and covariance functions of functional snippets, which are short segments of functions possibly observed irregularly on an individual specific subinterval that is much shorter than the entire study interval. Estimation of the covariance function for functional snippets is challenging since information for the far off-diagonal regions of the covariance structure is completely missing. We address this difficulty by decomposing the covariance function into a variance function component and a correlation function component. The variance function can be effectively estimated nonparametrically, while the correlation part is modeled parametrically, possibly with an increasing number of parameters, to handle the missing information in the far off-diagonal regions. Both theoretical analysis and numerical simulations suggest that this hybrid strategy is effective. In addition, we propose a new estimator for the variance of measurement errors and analyze its asymptotic properties. This estimator is required for the estimation of the variance function from noisy measurements.

PMID:35757778 | PMC:PMC9216204 | DOI:10.1080/01621459.2020.1777138

J Am Stat Assoc. 2022;117(537):1-11. doi: 10.1080/01621459.2021.1906684. Epub 2021 May 19.

ABSTRACT

Cross-trait polygenic risk score (PRS) method has gained popularity for assessing genetic correlation of complex traits using summary statistics from biobank-scale genome-wide association studies (GWAS). However, empirical evidence has shown a common bias phenomenon that highly significant cross-trait PRS can only account for a very small amount of genetic variance (R ² can be < 1%) in independent testing GWAS. The aim of this paper is to investigate and address the bias phenomenon of cross-trait PRS in numerous GWAS applications. We show that the estimated genetic correlation can be asymptotically biased toward zero. A consistent cross-trait PRS estimator is then proposed to correct such asymptotic bias. In addition, we investigate whether or not SNP screening by GWAS p-values can lead to improved estimation and show the effect of overlapping samples among GWAS. We analyze GWAS summary statistics of reaction time and brain structural magnetic resonance imaging-based features measured in the Pediatric Imaging, Neurocognition, and Genetics study. We find that the raw cross-trait PRS estimators heavily underestimate the genetic similarity between cognitive function and human brain structures (mean R ² = 1.32%), whereas the bias-corrected estimators uncover the moderate degree of genetic overlap between these closely related heritable traits (mean R ² = 22.42%). Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

PMID:35757777 | PMC:PMC9232179 | DOI:10.1080/01621459.2021.1906684

Front Immunol. 2022 Jun 10;13:910337. doi: 10.3389/fimmu.2022.910337. eCollection 2022.

ABSTRACT

PURPOSE: To report the demographic, clinical, and laboratory characteristics of ocular syphilis based on a 6-year case series study from an eye center in East-China.

METHODS: A total of 131 cases (191 eyes) of ocular syphilis and the annual number of total syphilis cases from January 2016 to December 2021, were included in this study. Detailed medical records including systemic and ophthalmic medical history, a complete ophthalmic examination, color fundus photography, B-type ultrasound, fundus fluorescein angiography (FFA), spectral domain optical coherence tomography (SD-OCT), laboratory tests of the serum and cerebrospinal fluid (CSF) samples, as well as visual field test and orbital or cranial MRI in cases with suspected optic neuritis or optic atrophy, were collected and analyzed. Pearson Chi-square or Fisher’s exact tests was used for statistics analysis.

RESULTS: Of the 131 cases with ocular syphilis, 86 cases were in men and 6 cases had a past medical history or systemic manifestation of syphilis. HIV was found in only 2 of 70 cases undergoing serum HIV test. The average age was 54.0 years, ranging from 26-85 years. The average percentage of ocular syphilis out from the total syphilis cases was 5.1%, the average titer of serum rapid plasma regain (RPR) at presentation was 1:32, ranging from 1:1-1:512. The most predominant manifestation of ocular syphilis was posterior uveitis, followed by optic neuritis, optic atrophy, panuveitis, retinal vasculitis, and retinitis. The median of BCVA of all 191 eyes was 20/200 (ranging from no light perception to 20/20), and 20/40 (ranging from no light perception to 20/20) at presentation and final follow-up, respectively. Ocular syphilis with active inflammation responded well to penicillin therapy, no matter the initial visual acuity, ocular disease type, or RPR titers, as long as it was diagnosed early and treated properly and promptly. However, cases with optic atrophy, acute retinal necrosis, late diagnosis, permanent disruption, or loss of outer segment of photoreceptors of macular retina on SD-OCT showed poor visual improvement after therapy.

CONCLUSIONS: Early diagnosis of ocular syphilis is still challenging in clinical practice and syphilis tests should be routinely performed in patients with uveitis, retinitis, optic neuritis, and optic atrophy.

PMID:35757732 | PMC:PMC9226556 | DOI:10.3389/fimmu.2022.910337

Intern Emerg Med. 2022 Jun 26. doi: 10.1007/s11739-022-03028-3. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategy to curb the coronavirus disease-19 (COVID-19) pandemic. The present study described the clinical status of patients affected by idiopathic inflammatory myopathies (IIM) after COVID-19 vaccination to assess the number of relapses. We included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. They underwent a telephone survey. A total of 119 IIM patients (median, IQR 58 (47-66) years; 32males; 50 dermatomyositis, 39 polymyositis and 30 anti-synthetase syndrome) were consecutively enrolled. Except four patients who refused the vaccination, 94 (81.7%) received Comirnaty, 16 (13.9%) Spikevax, 5 (4.4%) Vaxzevria. Seven (6.1%) patients had flare after vaccination. One of them had life-threatening systemic involvement and died two months after second dose of COVID-19 vaccination. From logistic regression analysis, Chi²-log ratio = 0.045,the variable that most influences the development of flare was the number of organs involved (p = 0.047). Sixty-eight patients received the third dose of COVID-19 vaccination: 51(75%) Comirnaty and 17 (25%) Moderna. No patients had flares after third dose. Our study represents the largest cohort of IIM patients in which the incidence of recurrence after anti-SARS-CoV-2 vaccine was assessed. In line with real-life data from other diseases, we found a clinical non-statistically significant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease.

PMID:35754076 | DOI:10.1007/s11739-022-03028-3

Int Urol Nephrol. 2022 Jun 27. doi: 10.1007/s11255-022-03264-8. Online ahead of print.

ABSTRACT

BACKGROUND: International guidelines vary in terms of their definition and recommendation for management of low-risk non-muscle-invasive bladder cancer (LRNMIBC). The ideal management for this large subset of bladder cancer patient remains unclear.

OBJECTIVE: To evaluate long-term outcomes of patients with LRNMIBC. As a secondary objective, to assess for intergroup heterogeneity in disease-specific outcomes between G1 and G2LG diseases.

METHODS: A multi-centre, retrospective study of patients who met the 2015 NICE definition of LRNMIBC. Timeline of diagnosis ranged from 01/01/2012 to 30/06/2016.

RESULTS: A total 390 patients had available follow-up data (G1: 142, G2LG: 249). Over a median follow-up time of 36 months (IQR 25-50), 29.2% of the patients developed a recurrence. G2LG patients were statistically more likely to develop a recurrence (G1: 26.8%, G2LG: 33.7%, p < 0.05). 51.8% of recurrences occurred after 1 year of surveillance. Progression to high-grade disease occurred in 1.8% (n = 7, G1: 3, G2LG: 4) and a further 1.0% (n = 4, G1:3, G2LG: 1) of patients developed muscle-invasive bladder cancer (MIBC).

CONCLUSION: The majority of recurrences occurred after 1 year of surveillance. The risk of disease progression was low; however, this was observed in a cohort of patients with regular cystoscopic follow-up. The risk may be higher if patients were pre-maturely discharged. If a 5-year surveillance programme were to be followed, 96.5% of recurrences would be captured. Lastly, there appears to be intergroup heterogeneity within LRNMIBC with G2LG patients having a statistically higher risk of recurrence compared to G1.

PMID:35754065 | DOI:10.1007/s11255-022-03264-8

Neuroradiology. 2022 Jun 27. doi: 10.1007/s00234-022-02998-7. Online ahead of print.

ABSTRACT

PURPOSE: To assess the ability of 7 T MRI to detect hippocampal DWI lesions in the acute phase of TGA compared to 1.5 T/3 T MRI.

METHODS: Patients with a clinical diagnosis consistent with TGA and a 1.5/3 T MRI underwent an additional 7 T MRI when the 7 T system was available for clinical use, thus serving as their own controls.

RESULTS: Thirteen TGA patients with a median age of 68.5 years (range 46-77 years) were included and imaged at 1.5/3 T (median 17 h after onset of symptoms, range 3-23 h) and 7 T (median 23 h after onset, range 15-46 h). The 7 T MRIs were performed a median of 15 h after the 1.5/3 T MRIs (range 1-28 h). At 1.5/3 T, six patients (46%) were found to have at least one hippocampal DWI-lesions supporting the TGA diagnosis, which increased to 11 patients (85%) when examined at 7 T (p = 0.03). At 1.5/3 T, nine hippocampal DWI lesions were detected, which increased to 19 at 7 T, giving an increased detection rate of 111% (p = 0.002). Both neuroradiologists found the hippocampal DWI lesions at 7 T to have higher conspicuity and be easier to categorize as true findings compared to 1.5/3 T.

CONCLUSION: Seven-Tesla MRI showed both a statistically significant increase in the total number of detected hippocampal DWI lesions and the proportion of patients with at least one hippocampal DWI lesion supporting the TGA diagnosis compared to 1.5/3 T. Clinical use of 7 T will increase the number of patients having their TGA diagnosis supported by MRI, which can be especially useful in patients with negative 1.5/3 T MRI and low clinical certainty.

PMID:35754063 | DOI:10.1007/s00234-022-02998-7

Eur J Hum Genet. 2022 Jun 27. doi: 10.1038/s41431-022-01138-2. Online ahead of print.

ABSTRACT

Duchenne muscular dystrophy (DMD), an X-linked recessive condition is maternally inherited in two-thirds of affected boys. It is important to establish carrier status of female relatives to restore reproductive confidence for non-carriers and facilitate reproductive options and cardiac surveillance for carriers. This study investigates disease incidence within an Australian model of cascade screening and evolving genetic diagnostic technologies. A retrospective population-based cohort study of all genetically and/or histopathologically confirmed males with DMD, born in New South Wales and the Australian Capital Territory was undertaken from 2002-2012. Cases were identified using state-wide molecular laboratory and clinical databases. The annual disease incidence and “theoretically” preventable cases were extrapolated over the study period. Proband genotype/phenotype, pedigree analysis, carrier-risk and extent of cascade screening were also determined. The cumulative incidence of disease was 19.7 per 100,000 male live births and 1 in 5076 live born males were diagnosed with DMD. Differences in disease incidence were not statistically different when compared between 2002-2007 and 2008-2012 (incidence rate ratio = 1.13, 95% CI 0.76-1.69, p = 0.52). The incidence rate ratio of theoretically preventable cases did not significantly change between 2002-2007 and 2008-2012 (incidence rate ratio = 2.07, 95% CI 0.58-9.21, p = 0.23). Current diagnostic and cascade screening models have limitations in their impact on disease incidence, due to a spectrum of logistical, patient and condition related factors. Innovative approaches to reduce DMD incidence may be better achieved by preconception or early pregnancy carrier screening, prenatal exome sequencing and newborn screening.

PMID:35754057 | DOI:10.1038/s41431-022-01138-2

Syst Rev. 2022 Jun 27;11(1):131. doi: 10.1186/s13643-022-02004-4.

ABSTRACT

BACKGROUND: Cytomegalovirus (CMV) is transmitted by direct contact with body fluids from infected individuals. Transmission of CMV in households, particularly those with young children, contributes significantly to CMV infection in the general population. However, little is known about the contribution of occupational healthcare or childcare exposure to risk of CMV infection.

OBJECTIVES: To determine CMV seroprevalence, incidence of primary infection, and associated risk factors in healthcare and childcare workers.

METHODS: Six electronic databases were searched systematically for publications on CMV infection in healthcare and childcare workers until March 7, 2022. Two authors independently evaluated the literature for quality and inclusion in our analyses. The pooled results for seroprevalence, incidence, and relative risk (RR) were determined using a random effects model. Heterogeneity among studies was quantified and further investigated in subgroup analysis and meta-regression. Publication bias was assessed using funnel plot. Statistical analyses were preformed using R version 4.05.

RESULTS: Forty-eight articles were included in this meta-analysis (quality assessment: 18 good, 14 fair, and 16 poor). Pooled CMV seroprevalence was 59.3% (95% CI: 49.8-68.6) among childcare workers and 49.5% (95% CI: 40.3-58.7) among healthcare workers, and pooled incidences of primary CMV infection per 100 person-years were respectively 7.4 (95% CI: 3.9-11.8) and 3.1 (95% CI: 1.3-5.6). RR for primary infection compared to controls were 3.4 (95% CI: 1.3-8.8) and 1.3 (95% CI: 0.6-2.7) for healthcare and childcare workers, respectively. The odds of CMV seropositivity were 1.6 (95% CI: 1.2-2.3) times higher for childcare workers compared to controls, but not significantly different between healthcare workers and controls (0.9; 95% CI: 0.6-1.2). CMV seropositivity in both groups was significantly associated with having one or more children residing at home, marital status, ethnicity, and age.

CONCLUSIONS: Childcare workers, but not healthcare workers, have an increased risk of prevalent and incident CMV infection, a risk that is further increased with the presence of at least one child living at home. These findings suggest that enforcing simple, conventional hygienic measures in childcare settings could help reduce transmission of CMV, and that special precautionary measures for preventing CMV infection may not be required for pregnant healthcare workers.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020139756.

PMID:35754052 | DOI:10.1186/s13643-022-02004-4

Mol Psychiatry. 2022 Jun 27. doi: 10.1038/s41380-022-01657-w. Online ahead of print.

ABSTRACT

In psychiatric disorders, mismatches between disease states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell types succumb first to challenges, and which exhibit the strongest response to drugs? Are these events coordinated between cell types? How does disease and drug effect this coordination? To address these questions, we analyzed single-nucleus-RNAseq (sn-RNAseq) data from the human anterior cingulate cortex-a region involved in many psychiatric disorders. Density index, a metric for quantifying similarities and dissimilarities across functional profiles, was employed to identify common or salient functional themes across cell types. Cell-specific signatures were integrated with existing disease and drug-specific signatures to determine cell-type-specific vulnerabilities, druggabilities, and responsiveness. Clustering of functional profiles revealed cell types jointly participating in these events. SST and VIP interneurons were found to be most vulnerable, whereas pyramidal neurons were least. Overall, the disease state is superficial layer-centric, influences cell-specific salient themes, strongly impacts disinhibitory neurons, and influences astrocyte interaction with a subset of deep-layer pyramidal neurons. In absence of disease, drugs profiles largely recapitulate disease profiles, offering a possible explanation for drug side effects. However, in presence of disease, drug activities, are deep layer-centric and involve activating a distinct subset of deep-layer pyramidal neurons to circumvent the disease state’s disinhibitory circuit malfunction. These findings demonstrate a novel application of sn-RNAseq data to explain drug and disease action at a systems level.

PMID:35754044 | DOI:10.1038/s41380-022-01657-w

BMC Oral Health. 2022 Jun 26;22(1):256. doi: 10.1186/s12903-022-02287-y.

ABSTRACT

BACKGROUND: Although wisdom-tooth extraction is a routine intervention, the postoperative period remains marked by local inflammation classically manifesting as pain, edema and trismus. Furthermore, there is no consensus on the best operative techniques, particularly for the mucosal closure stage on impacted mandibular wisdom teeth.

METHODS: This parallel, randomized, non-blinded study compared pain following removal of impacted third molars, with and without sutures. Patients were electronically allocated 1:1 to extraction with versus without sutures. Patients ≥ 14 years’ old scheduled for extraction of four impacted wisdom teeth under general anesthesia at three French hospitals were eligible for inclusion. Exclusion criteria included taking antiplatelet agents or anticoagulants, coagulation disorders or immunosuppression, and planned orofacial surgical procedures or emergency pain/infection. The primary objective was pain evaluated by Visual Analogue Scale on Day 3. Secondary outcomes were edema, trismus, healing, complications, painkiller consumption and quality of life on Day 3 and 31.

RESULTS: Between June 2016 and November 2018, 100 patients were randomized. Finally, 44 patients in the Suture group and 50 patients in the Without Suture group were analyzed. Mean age was 16.5 years and 66.6% of patients were female. After adjustment on center, age and smoking, no statistical difference was seen between groups for pain on Day 3 (p = 0.904). No differences were seen for swelling, trismus, consumption of painkillers, healing, complications or quality of life. Smokers had a 3.65 times higher complications rate (p = 0.0244).

CONCLUSIONS: Sutureless removal of third molars is thus a reliable technique without negative consequence on outcomes, and allows shorter operating time. Smoking is a risk factor for postoperative complications. Trial registration www.

CLINICALTRIALS: gov (NCT02583997), registered 22/10/2015.

PMID:35754043 | DOI:10.1186/s12903-022-02287-y