Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Unveiling contextual influences of maternal satisfaction with labour care services in Nigeria: A qualitative inquiry.

BACKGROUND: In light of the rising global effort to lower maternal mortality rates, it is crucial for low- and middle-income countries with poor maternal indices to investigate the problem of maternal satisfaction and the key elements that affect it. To this effect, this study explored the experiences of postnatal women in relation to labour services and investigated the factors that contribute to their overall satisfaction. AIM: The study set out to explore factors influencing maternal satisfaction with labour care services in Ogbomoso, Oyo State, Nigeria. This study ultimately seeks to advance our understanding of this phenomenon to impact labour care and policy. SETTING: The study was conducted among multiparous women who had their antenatal care and delivery in Ogbomoso, Oyo State, Nigeria. METHODS: A qualitative study was performed using in-depth interviews among postnatal women. RESULTS: The results revealed a number of variables that could affect the women's satisfaction with labour care, including the choice of health facility, healthcare providers, environment of the facility, assurance of privacy, treating patients with dignity, provision of needed amenities and having a well-planned postnatal care assessment. CONCLUSION: The study revealed that the costs of care, the skill of the caregiver, the provision of confidential and dignified care, and the availability of supplies all have an impact on maternal satisfaction. Hospital administration should address these issues to enhance the experience of women and labour care services.Contribution: The study's findings provide insights that will inform strategies to improve the quality of care being provided to parturients in Nigeria.

Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

Neurosarcoidosis Presenting as Longitudinally Extensive Transverse Myelitis and Orbital Mass: A Case Report.

We describe a case of neurosarcoidosis in a 64-year-old female who presented with proptosis and orbital inflammation together with bilateral lower extremity neuropathy and longitudinally extensive transverse myelitis. These two entities are not commonly associated, and the etiology of the transverse myelitis was facilitated by an orbital biopsy. The transverse myelitis caused numbness in her lower extremities and tightness in her chest and abdomen, which progressed over weeks to difficulty walking and bilateral neuromuscular weakness. Magnetic resonance imaging (MRI) revealed longitudinally extensive transverse myelitis in the cervical and thoracic spine. Computed tomography (CT) imaging of the chest revealed right hilar and mediastinal lymphadenopathy and calcified subcarinal nodes. Positron emission tomography (PET) scan revealed hypermetabolism in the mediastinum and medial left orbit. Orbital biopsy revealed non-necrotizing granulomatous inflammation suggestive of sarcoidosis. The neurologic deficits and orbital inflammation responded well to intravenous corticosteroids. Neurosarcoidosis can present with unusual clinical manifestations, as evidenced by this patient.

Datasets on the elastic and mechanical properties of hydroxyapatite: A first principle investigation, experiments, and pedagogical perspective.

The purpose of this data article is to report the quantum mechanical analysis by generalized gradient approximation (GGA) exchange-correlation functional using density functional theory (DFT). The predictions were based on the elastic constants and mechanical properties of stoichiometric hydroxyapatite (HAp) crystal. The elastic stiffness constants in hexagonal symmetry were obtained by fitting the Hookes' law for the energy-strain and stress-stain relations. Some of the theoretical datasets were compared to measured mechanical properties of produced HAp pellets obtained through micro and nanoindentation experiments. The datasets show considerable anisotropy in the stress-strain behaviour and are discussed in the context of the mechanical properties of HAp which are useful for tissue engineering. We also provide a pedagogical snapshot on the use of the datasets herein to teach and interpret DFT based atomistic simulations in a typical blended online teaching set-up for engineering students using a new pedagogy, CACPLA (Communicate, Active, Collaborate, Practice, Learning and Assessment).

The genetic overlap between osteoporosis and craniosynostosis.

Osteoporosis is the most prevalent bone condition in the ageing population. This systemic disease is characterized by microarchitectural deterioration of bone, leading to increased fracture risk. In the past 15 years, genome-wide association studies (GWAS), have pinpointed hundreds of loci associated with bone mineral density (BMD), helping elucidate the underlying molecular mechanisms and genetic architecture of fracture risk. However, the challenge remains in pinpointing causative genes driving GWAS signals as a pivotal step to drawing the translational therapeutic roadmap. Recently, a skull BMD-GWAS uncovered an intriguing intersection with craniosynostosis, a congenital anomaly due to premature suture fusion in the skull. Here, we recapitulate the genetic contribution to both osteoporosis and craniosynostosis, describing the biological underpinnings of this overlap and using zebrafish models to leverage the functional investigation of genes associated with skull development and systemic skeletal homeostasis.

TBX3 and EFNA4 Variant in a Family with Ulnar-Mammary Syndrome and Sagittal Craniosynostosis.

Ulnar-mammary syndrome (UMS) is a rare, autosomal dominant disorder characterized by anomalies affecting the limbs, apocrine glands, dentition, and genital development. This syndrome is caused by haploinsufficiency in the T-Box3 gene (TBX3), with considerable variability in the clinical phenotype being observed even within families. We describe a one-year-old female with unilateral, postaxial polydactyly, and bilateral fifth fingernail duplication. Next-generation sequencing revealed a novel, likely pathogenic, variant predicted to affect the canonical splice site in intron 3 of the TBX3 gene (c.804 + 1G > A, IVS3 + 1G > A). This variant was inherited from the proband's father who was also diagnosed with UMS with the additional clinical finding of congenital, sagittal craniosynostosis. Subsequent whole genome analysis in the proband's father detected a variant in the EFNA4 gene (c.178C > T, p.His60Tyr), which has only been reported to be associated with sagittal craniosynostosis in one patient prior to this report but reported in other cranial suture synostosis. The findings in this family extend the genotypic spectrum of UMS, as well as the phenotypic spectrum of EFNA4-related craniosynostosis.

First trimester sex hormone-binding globulin predicts gestational diabetes mellitus in a population of Nigerian women.

There has been a steady rise in the disease burden of Gestational Diabetes Mellitus (GDM) in the sub-Saharan African region over time. Diagnostic testing for GDM is currently recommended at 24 - 28 weeks of gestation, leaving a narrow window for intervention before delivery. Hence the need for early prediction and preventive intervention. The performance of first trimester serum sex hormone-binding globulin (SHBG) assay as a predictor of GDM was determined by binary logistic regression. Women with GDM (n = 49) had a significantly lower mean first trimester SHBG level (104.7 ± 61.6 nmol/L) than did those without GDM (n = 180; 265.2 ± 141.5 nmol/L; p < .001). First trimester SHBG was significantly negatively correlated (rpb = -0.460, p value = <.001) with subsequent development of GDM and an area under receiver operator characteristics (ROC) curve of 0.874 (p < .001). A cut-off value of 158.0 nmol/L predictive of GDM had a diagnostic sensitivity of 81.5%, a specificity of 80.1%, and an overall diagnostic efficiency of 80.3%.IMPACT STATEMENTWhat is already known on this subject? GDM is associated with high risk of various complications and is commonly diagnosed at 24-28 weeks of gestation, leaving a narrow window for intervention. The performance of current maternal clinical and demographic risk factor-based prediction approaches is unreliable. Thus, more favourable prediction approaches need to be developed. Previous studies have suggested that SHBG, a readily assessable marker, has potential to predict GDM; however, these studies have mostly involved Caucasian and other non-African populations.What the results of this study add? SHBG may serve as a reliable first trimester screening tool for GDM development in Nigerian women with singleton pregnancies. This study demonstrates that first trimester SHBG can predict GDM development in sub-Saharan African women despite racial, ethnic and geographical differences.What are the implications of these findings for clinical practice and/or further research? Effective first trimester prediction of GDM using SHBG may enable preventive interventions, thereby mitigating the high burden of the disease in the sub-Saharan African region. It may also provide relevant information that may guide adaptation of current management guidelines to ensure effective management of GDM in the region.

Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis.

Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal non-syndromic CS (sNCS), identifying associations downstream from BMP2 on 20p12.3 and intronic to BBS9 on 7p14.3; analyses of imputed variants in DLG1 on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to BMP7 on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes (BMP2 and BMPER) near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS cohorts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in craniofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies.

Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum.

SEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A-D) in vertebrates, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations in SEC24D cause osteogenesis imperfecta with craniofacial dysplasia in humans. sec24d mutant fish also recapitulate the phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient-derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. Using Sec24d KO mice and cultured cells, we show that SEC24A and SEC24B also contribute to endoplasmic reticulum (ER) export of procollagen. In contrast, fibronectin 1 requires either SEC24C or SEC24D for ER export. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency.

Influence of seasonal changes on asthma exacerbation in a sudan savanna region: An analysis of 87 cases.

Background: Asthma accounts for 1 out of every 250 deaths worldwide. Many of these deaths are preventable as they occur as a result of suboptimal long-term medical care and delay in seeking help during severe exacerbation. It is believed that increased concentrations of dust, high winds, low temperatures, and low humidity may cause exacerbation of asthma. Objective: The aim of this study is to assess seasonal variation in asthma exacerbation among patients attending Usmanu Danfodiyo University Teaching Hospital, Sokoto. Materials and Methods: Eighty-seven patients aged 16 years and above with physician-diagnosed asthma were selected by systematic random sampling. Clinical information was obtained from each participant about history of asthma exacerbation and health-care utilization. Meteorological data were obtained from the Nigerian Meteorological Agency corresponding to period of patient's recruitment. Results: Eighty-seven patients comprising 60 females and 27 males aged 32.1 ± 10.8 years participated in the study. Among the study participants, 50.6%, 28.7%, and 20.7% had exacerbation during harmattan, rainy, and dry (hot) seasons, respectively. Correlation analysis shows a significant negative relationship between temperature and asthma exacerbation (r = -0.372, P < 0.01). Conclusion: This study shows that asthma exacerbation is most frequent during the harmattan season and low temperature is associated with its exacerbation.

RésuméContexte: L'asthme est responsable de 1 décès sur 250 dans le monde. Beaucoup de ces décès sont évitables car ils surviennent à la suite de soins médicaux à long terme sous-optimaux et retard dans la recherche d'aide en cas d'exacerbation grave. On pense que l'augmentation des concentrations de poussière, les vents, les basses températures et une faible humidité peuvent provoquer une exacerbation de l'asthme. Objectif: Le but de cette étude est d'évaluer la variation saisonnière exacerbation de l'asthme chez les patients fréquentant l'hôpital universitaire Usmanu Danfodiyo, Sokoto. Matériel et méthodes: quatre-vingt-sept les patients âgés de 16 ans et plus souffrant d'asthme diagnostiqué par un médecin ont été sélectionnés par échantillonnage aléatoire systématique. L'information clinique était obtenu de chaque participant sur les antécédents d'exacerbation de l'asthme et l'utilisation des soins de santé. Les données météorologiques ont été obtenues à partir du Agence météorologique nigériane correspondant à la période de recrutement des patients. Résultats: quatre-vingt-sept patients dont 60 femmes et 27 hommes âgés de 32,1 ± 10,8 ans ont participé à l'étude. Parmi les participants à l'étude, 50,6%, 28,7% et 20,7% ont eu une exacerbation pendant les saisons harmattan, pluvieuse et sèche (chaude), respectivement. L'analyse de corrélation montre une relation négative significative entre la température et exacerbation de l'asthme (r = −0,372, p <0,01). Conclusion: Cette étude montre que l'exacerbation de l'asthme est la plus fréquente pendant l'harmattan la saison et les basses températures sont associées à son exacerbation. Mots-clés: asthme, exacerbation, saison.

Identification of differentially expressed proteins between fused and open sutures in sagittal nonsyndromic craniosynostosis during suture development by quantitative proteomic analysis.

PURPOSE: Nonsyndromic craniosynostosis (NCS), the premature fusion of cranial sutures, results in an abnormal skull shape and is associated with a significant morbidity. Proteomics is a promising tool for disease characterization and biomarker discovery; we aimed to identify biologically relevant differentially expressed proteins for NCS. EXPERIMENTAL DESIGN: Label-based quantitative proteomic profiling using TMT was performed on protein extracted from mesenchymal stem cells, osteoblasts and bone tissue of five open and five fused sutures of sagittal NCS (sNCS) and analyzed using quantitative LC-MS/MS based bottom-up proteomics. Differential protein abundance between open and fused sutures was determined to identify biologically relevant proteins of interest. Proteins were validated in an independent sample set by western blot and immunohistochemistry. RESULTS: We observed 838 differentially expressed proteins between open and fused sutures of sNCS. Decorin, lumican, and asporin were significantly downregulated while COL4A1 and TGFß1|1 were upregulated in fused compared to open sutures. CONCLUSIONS AND CLINICAL RELEVANCE: The majority of significantly differentially expressed proteins between open and fused sutures were observed in the proteomes of osteoblasts suggesting that protein changes contributing to premature sagittal suture fusion occur predominantly at the osteoblast level. Our findings suggest a possible ineffective ECM deposition at the osteoblast cell stage.

Correction: SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation.

PURPOSE: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. METHODS: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. RESULTS: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. CONCLUSION: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

Gain-of-function variants and overexpression of RUNX2 in patients with nonsyndromic midline craniosynostosis.

Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a relatively common congenital anomaly, occurring in 3-5 per 10,000 live births. Nonsyndromic CS (NCS) accounts for up to 80% of all CS cases, yet the genetic factors contributing to the disorder remain largely unknown. The RUNX2 gene, encoding a transcription factor critical for bone and skull development, is a well known CS candidate gene, as copy number variations of this gene locus have been found in patients with syndromic craniosynostosis. In the present study, we aimed to characterize RUNX2 to better understand its role in the genetic etiology and in the molecular mechanisms underlying midline suture ossification in NCS. We report four nonsynonymous variants, one intronic variant and one 18 bp in-frame deletion in RUNX2 not found in our study control population. Significant difference in allele frequency (AF) for the deletion variant RUNX2 p.Ala84-Ala89del (ClinVar 257,095; dbSNP rs11498192) was observed in our sagittal NCS cohort when compared to the general population (P = 1.28 × 10-6), suggesting a possible role in the etiology of NCS. Dual-luciferase assays showed that three of four tested RUNX2 variants conferred a gain-of-function effect on RUNX2, further suggesting their putative pathogenicity in the tested NCS cases. Downregulation of RUNX2 expression was observed in prematurely ossified midline sutures. Metopic sites showed significant downregulation of promoter 1-specific isoforms compared to sagittal sites. Suture-derived mesenchymal stromal cells showed an increased expression of RUNX2 over matched unfused suture derived cells. This demonstrates that RUNX2, and particularly the distal promoter 1-isoform group, are overexpressed in the osteogenic precursors within the pathological suture sites.

Monte Carlo Aggregation Code (MCAC) Part 2: Application to soot agglomeration, highlighting the importance of primary particles.

During the agglomeration of nanoparticles and in particular, soot, a change in both the flow regime (from free molecular to near continuum) as well as the change of agglomeration regime (from ballistic to diffusive) is expected. However, these effects are rarely taken into account in numerical simulations of particle agglomeration and yet, they are suspected to have an important impact on the agglomeration kinetics, particle morphologies, and size distributions. This work intends to study these properties by using the Monte Carlo Aggregation Code (MCAC) presented in the preceding work (part 1), focusing on the physical impacts of varying the particle volume fraction and monomers size and polydispersity. The results show an important sensitivity of the kinetics of agglomeration, coagulation homogeneity, and agglomerate morphology to the size of monomers. First, for smaller monomer diameters, the agglomeration kinetic is enhanced and agglomerates are characterized by larger fractal dimensions. Second, for large monomer diameters, fractal dimensions down to 1.67 can be found being smaller than the classical 1.78 for Diffusion Limited Cluster Agglomeration (DLCA) mechanism. One important conclusion is that variation in time of both regimes has to be considered for a more accurate simulation of the agglomerate size distribution and morphology.

A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

African indigenous contraception: A review.

In Africa, indigenous methods of contraception continue to play a significant role in preventing unwanted pregnancies despite the introduction and popularity of modern contraceptives. The current review identified the common techniques and practices of African indigenous contraception, and examined their mechanisms and reasons for use. We searched data bases such as Google Scholar, Scopus, Web of Science, EBSCohost, African Journals, Science Direct, textbooks, thesis and dissertations for research articles on African indigenous contraception. The six common techniques of African indigenous contraception included periodic abstinence, withdrawal, breastfeeding, use of herbs, postpartum abstinence and waist bands, whilst practices relate to child (birth) spacing, postponement of first birth (virginity), stopping of reproduction and indigenous emergency contraception. Mother and infant health was stated as one of the reasons for using African indigenous contraception. African indigenous contraception continues to play a critical reproductive role in preventing unwanted pregnancies. However, there is lack of clarity regarding mechanisms, the safety, and efficacy of some techniques.

Information transmission process for disease notification and feedback in the community-based disease surveillance system in Anambra State, Nigeria

Disease surveillance and notification (DSN) system has been shown to be weak in Nigeria and still needs to be built up for effective detection and response to some communities. The aim of this paper is to assess the reporting and feedback mechanisms in the Community-based surveillance System (CBSS) in Anambra State, Nigeria. This was a cross-sectional descriptive study of 360 community-based focal points in Anambra State selected by multistage sampling technique. Data collection was by interview using a pre-tested, semi-structured questionnaire. Data were analysed using SPSS version 20, associations between variables were tested using Chi square, Fisher's exact and t tests as appropriate (p<0.05). Forty-one (13.1%) focal points sent in reports for at least four times, (72.2%) received feedback within the last one year and (44.6%) was via the phone. However, 229 (63.6%) of the respondents gave the feedback to the community mainly via the village health committees (44.1%). Respondents' occupation, ever detected notifiable disease; source of information; person the detected disease was reported to; records of notified disease kept by focal points; number of times reports were sent in the last one year, received feedback given to community members, availability of supervisors for focal points and volunteer benefit from being focal points were found to have associations with receipt of feedback on disease case notification (p<0.05). This study found poor reporting but good feedback mechanisms. However, there is need to reform the State CBSS in line with the above findings in order to make it more functional.

Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial.

Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m2 at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity.