Multiple morphological abnormalities of the flagella (MMAF) represent a severe form of sperm defects leading to asthenozoospermia and male infertility. In this study, we identified a novel homozygous splicing mutation (c.871-4 ACA>A) in the adenylate kinase 7 (AK7) gene by whole-exome sequencing in infertile individuals. Spermatozoa from affected individuals exhibited typical MMAF characteristics, including coiled, bent, short, absent, and irregular flagella. Transmission electron microscopy analysis showed disorganized axonemal structure and abnormal mitochondrial sheets in sperm flagella. Immunofluorescence staining confirmed the absence of AK7 protein from the patients' spermatozoa, validating the pathogenic nature of the mutation. This study provides direct evidence linking the AK7 gene to MMAF-associated asthenozoospermia in humans, expanding the mutational spectrum of AK7 and enhancing our understanding of the genetic basis of male infertility.
Humans ; Male ; Sperm Tail/ultrastructure* ; Homozygote ; Consanguinity ; Asthenozoospermia/pathology* ; Infertility, Male/genetics* ; Mutation ; Pakistan ; Adenylate Kinase/genetics* ; Adult ; Pedigree ; RNA Splicing ; Exome Sequencing ; Spermatozoa

Male infertility can result from impaired sperm motility caused by multiple morphological abnormalities of the flagella (MMAF). Distinct projections encircling the central microtubules of the spermatozoal axoneme play pivotal roles in flagellar bending and spermatozoal movement. Mammalian sperm-associated antigen 17 ( SPAG17 ) encodes a conserved axonemal protein of cilia and flagella, forming part of the C1a projection of the central apparatus, with functions related to ciliary/flagellar motility, skeletal growth, and male fertility. This study investigated two novel homozygous SPAG17 mutations (M1: NM_206996.2, c.829+1G>T, p.Asp212_Glu276del; and M2: c.2120del, p.Leu707*) identified in four infertile patients from two consanguineous Pakistani families. These patients displayed the MMAF phenotype confirmed by Papanicolaou staining and scanning electron microscopy assays of spermatozoa. Quantitative real-time polymerase chain reaction (PCR) of patients' spermatozoa also revealed a significant decrease in SPAG17 mRNA expression, and immunofluorescence staining showed the absence of SPAG17 protein signals along the flagella. However, no apparent ciliary-related symptoms or skeletal malformations were observed in the chest X-rays of any of the patients. Transmission electron microscopy of axoneme cross-sections from the patients showed incomplete C1a projection and a higher frequency of missing microtubule doublets 1 and 9 compared with those from fertile controls. Immunofluorescence staining and Western blot analyses of spermatogenesis-associated protein 17 (SPATA17), a component of the C1a projection, and sperm-associated antigen 6 (SPAG6), a marker of the spring layer, revealed disrupted expression of both proteins in the patients' spermatozoa. Altogether, these findings demonstrated that SPAG17 maintains the integrity of spermatozoal flagellar axoneme, expanding the phenotypic spectrum of SPAG17 mutations in humans.
Humans ; Male ; Infertility, Male/pathology* ; Sperm Tail/ultrastructure* ; Homozygote ; Microtubule-Associated Proteins/genetics* ; Axoneme/genetics* ; Spermatozoa/ultrastructure* ; Adult ; Mutation ; Sperm Motility/genetics* ; Pedigree ; Microtubules ; Microtubule Proteins/genetics*

The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is one of the most serious kinds of sperm defects, leading to asthenoteratozoospermia and male infertility. In this study, we use whole-exome sequencing to identify genetic factors that account for male infertility in a patient born from a consanguineous Pakistani couple. A homozygous frameshift mutation (c.1399_1402del; p.Gln468ArgfsTer2) in axonemal dynein light chain domain containing 1 ( AXDND1 ) was identified in the patient. Sanger sequencing data showed that the mutation was cosegregated recessively with male infertility in this family. Papanicolaou staining and scanning electron microscopy analysis of the sperm revealed severely abnormal flagellar morphology in the patient. Immunofluorescence and western blot showed undetectable AXDND1 expression in the sperm of the patient. Transmission electron microscopy analysis showed disorganized sperm axonemal structure in the patient, particularly missing the central pair of microtubules. Immunofluorescence staining showed the absence of sperm-associated antigen 6 (SPAG6) and dynein axonemal light intermediate chain 1 (DNALI1) signals in the sperm flagella of the patient. These findings indicate that AXDND1 is essential for the organization of flagellar axoneme and provide direct evidence that AXDND1 is a MMAF gene in humans, thus expanding the phenotypic spectrum of AXDND1 frameshift mutations.
Humans ; Male ; Sperm Tail/ultrastructure* ; Frameshift Mutation ; Infertility, Male/pathology* ; Pakistan ; Pedigree ; Consanguinity ; Axonemal Dyneins/genetics* ; Adult ; Spermatozoa ; Exome Sequencing

Introduction: Lean sustainability has gained prominence in the health sector for operational and business advantages. However, understanding the link between lean and healthcare sustainability, especially in social and environmental aspects, remains limited. This study introduces a preliminary framework for measuring lean healthcare sustainability in hospitals. The framework aligns Critical Success Factors (CSFs) with sustainability objectives and business strategies to ensure successful and enduring lean deployment. Methods: The study was conducted among 52 Lean Agile Hospitals in Malaysia using a cross-sectional approach. The validated questionnaire was employed for data collection. A reliability test and Exploratory Factor Analysis (EFA) were also performed to assess and validate the framework using Statistical Package for Social Sciences (SPSS) version 27. Results: The content validation was 0.9, which indicates that the instrument is sufficient to measure the research objective. The data screening test was performed to eliminate problem observation. The overall reliability value was over 0.830 which depicts data consistency and stability. The Kaiser-Meyer-Olkin exceeded 0.6, Bartlett’s test was under 0.001 and factor loading was between 0.507 to 0.948, thus indicating a significant correlation matrix among at least some of the variables. Therefore, the latent factors were significant to specific items of the research. Conclusion: It is concluded that important CSF is aligned with the strategic level influence of lean deployment in healthcare, which has a specific impact on certain sustainability performance. Thus, this paper proposed a generic preliminary framework to measure lean healthcare sustainability.

Asthenoteratozoospermia is one of the most severe types of qualitative sperm defects. Most cases are due to mutations in genes encoding the components of sperm flagella, which have an ultrastructure similar to that of motile cilia. Coiled-coil domain containing 103 (CCDC103) is an outer dynein arm assembly factor, and pathogenic variants of CCDC103 cause primary ciliary dyskinesia (PCD). However, whether CCDC103 pathogenic variants cause severe asthenoteratozoospermia has yet to be determined. Whole-exome sequencing (WES) was performed for two individuals with nonsyndromic asthenoteratozoospermia in a consanguineous family. A homozygous CCDC103 variant segregating recessively with an infertility phenotype was identified (ENST00000035776.2, c.461A>C, p.His154Pro). CCDC103 p.His154Pro was previously reported as a high prevalence mutation causing PCD, though the reproductive phenotype of these PCD individuals is unknown. Transmission electron microscopy (TEM) of affected individuals' spermatozoa showed that the mid-piece was severely damaged with disorganized dynein arms, similar to the abnormal ultrastructure of respiratory ciliary of PCD individuals with the same mutation. Thus, our findings expand the phenotype spectrum of CCDC103 p.His154Pro as a novel pathogenic gene for nonsyndromic asthenospermia.
Asthenozoospermia/pathology* ; Dyneins/genetics* ; Homozygote ; Humans ; Male ; Microtubule-Associated Proteins ; Mutation ; Mutation, Missense ; Sperm Tail/metabolism*

Background: and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

Learning is important for the development of children with special needs. Slow learners, which are included in the special-needs category suffer from extreme timidity thus making them unable to actively involved in learning sessions. It is important for them to actively involve in the learning activities as it affects their academic achievement. This study involves two phases of activities which are; Phase 1, identification specification through literature review and expert interview, and Phase 2, model development. From the specification identification phase, suitable elements and components are identified, gathered, analysed and organised to prepare a comprehensive model. Therefore, a robotic-based model for slow learners’ learning is proposed. The model consists of the elements and the components that emphasize interactive student-centred learning. The model is derived from Care-Receiving Robot, Social Development Theory and Triple-D Model which consists of the teacher (More Knowledgable Other), the student, the robot (Care-Receiving Robot), learning by teaching to invoke student-centred learning, and evaluation (Triple-D Model).

Background/Aims: Percutaneous liver biopsy (PCLB) or transjugular liver biopsy (TJLB) have traditionally been performed to obtain a sample of hepatic tissue; however, endoscopic ultrasound-guided liver biopsy (EUSLB) has become an attractive alternative. The aim of this study was to compare the efficacy and safety of EUSLB, PCLB, and TJLB. Methods: Search strategies were developed in accordance with PRISMA and MOOSE guidelines. Major outcomes included the following: adequacy of biopsy specimens (i.e., complete portal triads [CPT], total specimen length [TSL] in mm, and length of longest piece [LLP]) in mm), and rate of adverse events. Only studies comparing all biopsy approaches (i.e., EUSLB, PCLB, and TJLB) were included. Results: Five studies (EUSLB [n=301]; PCLB [n=176]; and TJLB [n=179]) were included. Biopsy cumulative adequacy rates for EUSLB, PCLB, and TJLB were 93.51%, 98.27%, and 97.61%, respectively. Based on the subgroup analysis limited to EUS biopsy needles in current clinical practice, there was no difference in biopsy adequacy or adverse events for EUSLB compared to PCLB and TJLB (all p>0.050). A comparison of EUSLB and PCLB revealed no difference between specimens regarding both CPT (p=0.079) and LLP (p=0.085); however, a longer TSL (p<0.001) was observed. Compared to TJLB, EUSLB showed no difference in LLP (p=0.351), fewer CPT (p=0.042), and longer TSL (p=0.005). Conclusions EUSLB appears to be a safe, minimally invasive procedure that is comparable to PCLB and TJLB regarding biopsy specimens obtained and rate of adverse events associated with each method.

Introduction: Factory and Machinery Act (Noise Exposure) Regulation 1989 (FMA [Noise] 1989) has been implemented in Malaysia for nearly 30 years, but noise-induced hearing loss (NIHL) cases is still rising. Fault tree analysis is a top-down approach to analyzing incidences of 'failures', starting with establishing the single top event that will eventually cause NIHL, followed by identification of the contributing factors to the top event which are the immediate or basic events. Through its visual, structural and deductive approach; FTA is able to depict the temporal sequence of events and their interactions in a formal and logical hierarchy. Materials and Methods: Employees with permanent standard threshold shifts (PSTS) underwent further assessment confirming the presence of NIHL. A single common fault tree was constructed based on six cases of PSTS. The top event is the PSTS. Intermediate and basic events were identified and mapped with relevance to the provisions in the FMA (noise) 1989 indicating how failed control measures have resulted in the PSTS cases. Results: The constructed fault tree with its branches illustrated how breach or noncompliance of FMA (Noise) 1989 resulted in the eventual top event (NIHL). Conclusion: FTA provides a standardized perspective of errors within the system in preventing NIHL.