Diagnostic accuracy of pooling urine, anorectal, and oropharyngeal specimens for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae: a systematic review and meta-analysis.

BACKGROUND: Screening for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) at genital and extragenital sites is needed for most key populations, but molecular diagnostic tests for CT/NG are costly. We aimed to determine the accuracy of pooled samples from multiple anatomic sites from one individual to detect CT/NG using the testing of a single sample from one anatomic site as the reference. METHODS: In this systematic review and meta-analysis, we searched five databases for articles published from January 1, 2000, to February 4, 2021. Studies were included if they contained original data describing the diagnostic accuracy of pooled testing compared with single samples, resource use, benefits and harms of pooling, acceptability, and impact on health equity. We present the pooled sensitivities and specificities for CT and NG using a bivariate mixed-effects logistic regression model. The study protocol is registered in PROSPERO, an international database of prospectively registered systematic reviews (CRD42021240793). We used GRADE to evaluate the quality of evidence. RESULTS: Our search yielded 7814 studies, with 17 eligible studies included in our review. Most studies were conducted in high-income countries (82.6%, 14/17) and focused on men who have sex with men (70.6%, 12/17). Fourteen studies provided 15 estimates for the meta-analysis for CT with data from 5891 individuals. The pooled sensitivity for multisite pooling for CT was 93.1% [95% confidence intervals (CI) 90.5-95.0], I2=43.3, and pooled specificity was 99.4% [99.0-99.6], I2=52.9. Thirteen studies provided 14 estimates for the meta-analysis for NG with data from 6565 individuals. The pooled sensitivity for multisite pooling for NG was 94.1% [95% CI 90.9-96.3], I2=68.4, and pooled specificity was 99.6% [99.1-99.8], I2=83.6. Studies report significant cost savings (by two thirds to a third). CONCLUSION: Multisite pooled testing is a promising approach to improve testing coverage for CT/NG in resource-constrained settings with a small compromise in sensitivity but with a potential for significant cost savings.

Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline-rich transmembrane protein 2 mutations. OBJECTIVE: The objective of this study was to investigate potential causative genes and clinical characteristics in proline-rich transmembrane protein 2-negative patients with paroxysmal kinesigenic dyskinesia. METHODS: We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline-rich transmembrane protein 2-negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. RESULTS: The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium-activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage-gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage-gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl-10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl-10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. CONCLUSIONS: Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society.

The impact of COVID-19 on clinical forensic medicine and forensic psychiatry: A literature review.

Purpose:The COVID-19 pandemic prompted significant challenges in clinical forensic medicine and forensic psychiatry and emphasised the need for sustainable service delivery. Both fields faced difficulties in maintaining services due to COVID-19 precautions and limited referrals. This review examined the changes in forensic practices, aiming to understand their impact and learn from them to inform future strategies. Methods: A search was conducted across Ovid Medline, Ovid Embase, Ovid Emcare and PubMed, and webpages of governments and other organisations. Studies were included if they assessed any change that occurred in clinical forensic medicine or forensic psychiatry during the pandemic. A narrative review with a systematic approach was undertaken. Results: A total of 27 articles were included. There was a notable decrease in the volume of forensic assessments in early 2020. The numbers gradually rebounded with the easing of restrictions yet have not fully returned to pre COVID-19 levels. Telemedicine and COVID-19 precautions were widely incorporated into forensic services, which were seen to disrupt the patient-doctor dynamics, restrict the setting of examinations and complicate work processes and sample handling steps. Conclusion: This is the first review that describes the pandemic-driven changes in clinical forensic medicine and forensic psychiatry in respect of case trends and incorporation of COVID-19 precautions. The pandemic emphasised the need for adaptability and adoption of new assessment approaches in forensic services. Technology, like telemedicine, emerged as a valuable tool, enhancing accessibility for individuals in remote or high-risk areas. It is necessary to review the changes and re-evaluate their impacts in the post COVID-19 era.

Mortality, patient-reported outcome measures, and the health economic burden of prosthetic joint infection.

Prosthetic joint infection (PJI) is one of the most devastating complications for a patient following arthroplasty. This scoping review aims to evaluate the burden of PJI on individual patients and the healthcare system regarding the mortality rate, patient-reported quality of life, and healthcare resource utilisation. Patients with PJI have up to a five-fold higher mortality rate than those who have undergone an uninfected primary arthroplasty. There is an increased use of ambulatory aids and reduced joint function scores in patients with PJI. Global quality of life is poorer, specifically measured by the EQ-5D. Direct hospitalisation costs are two- to five-fold higher, attributed to surgery and prostheses, antibiotics, and a prolonged inpatient stay. There is an immense clinical and health economic burden secondary to PJI worldwide. This is expected to rise exponentially due to the increasing number of primary procedures and an ageing population with comorbidities Improving preventative and treatment strategies is imperative for patients and the healthcare system.

Pathogenic SCN5A Mutation and Thyrotoxicosis-Related Neurological Syndrome: Casual or Causal Relationship?

BACKGROUND: Various neurologic complications of hyperthyroidism are reported, and most of these complications are reversible with the amelioration of thyrotoxicosis. We report a previously undescribed concurrence of hyperthyroid-associated exercise-induced myalgia and stiffness, pyramidal tract dysfunction, and myoclonic movements that make an initial clinical diagnosis difficult. CASE PRESENTATION: A 17-year-old male was hospitalized in the department of neurology, presenting with a 4-year history of severe exercise-induced myalgia and stiffness, weakness of lower limbs, and myoclonic movements. Laboratory investigations unexpectedly revealed hyperthyroidism. MRI of the brain and spine, electrophysiology, and whole exome sequencing were also performed. Antithyroid therapy led to marked improvement of neurologic symptoms, accompanied by a significant improvement of the time-dependent decline in compound muscle action potentials (CMAP) amplitudes after exercise and normalization of the prolonged QTc interval. Genetic analysis identified a rare variant in SCN5A. CONCLUSION: This case report provides important insights into the relationship between hyperthyroidism and neurologic/cardiac complications, particularly in those with a genetic predisposition. SCN5A mutation possibly plays a role in the complex neurological syndrome associated with hyperthyroidism. Further studies are warranted to better understand the underlying mechanisms and potential therapeutic options for these complex conditions.

The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice.

The ε4 allele of apolipoprotein E (APOE4) and aging are the major risk factors for Alzheimer's disease (AD). SUMOylation is intimately linked to the development of AD and the aging process. However, the SUMOylation status in APOE4 mice has not been uncovered. In this study, we investigated SENP1 and SUMOylation changes in the brains of aged APOE3 and APOE4 mice, aiming to understand their potential impact on mitochondrial metabolism and their contribution to cellular senescence in APOE4 mice. Concurrently, SUMO1-conjugated protein levels decreased, while SUMO2/3-conjugated protein levels increased relatively with the aging of APOE4 mice. This suggests that the equilibrium between the SUMOylation and deSUMOylation processes may be associated with senescence and longevity. Our findings highlight the significant roles of SENP1 and SUMOylation changes in APOE4-driven pathology and the aging process.

The diagnostic accuracy of pooled testing from multiple individuals for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae: a systematic review.

OBJECTIVES: Molecular testing for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) is costly. Therefore, we appraised the evidence regarding pooling samples from multiple individuals to test for CT/NG. METHODS: In this systematic review, we searched 5 databases (2000-2021). Studies were included if they contained primary data describing pooled testing. We calculated the pooled sensitivities and specificities for CT and NG using a bivariate mixed-effects logistic regression model. RESULTS: We included 22 studies: most were conducted in high-income countries (81.8%, 18 of 22), among women (73.3%, 17 of 22), and pooled urine samples (63.6%, 14 of 22). Eighteen studies provided 25 estimates for the meta-analysis of diagnostic accuracy, with data from 6,913 pooled specimens. The pooled sensitivity for CT was 98.4% (95% confidence intervals [CI]: 96.8-99.2%, I2=77.5, p<0.001), and pooled specificity was 99.9% (95% CI: 99.6-100.0%, I2=62.6, p<0.001). Only 2 studies reported pooled testing for NG, and both reported similarly high sensitivity and specificity as for CT. Sixteen studies provided data on the cost of pooling, reporting cost-savings ranging from 39%-90%. CONCLUSIONS: Pooled testing from multiple individuals for CT is highly sensitive and specific compared with individual testing. This approach has the potential to reduce the cost of screening in populations for which single anatomic site screening is recommended.

Association Between Blood Biochemical Factors Contributing to Cognitive Decline and B Vitamins in Patients With Alzheimer's Disease.

Background: Malnutrition, metabolism stress, inflammation, peripheral organs dysfunction, and B vitamins deficiency significantly contribute to the progression and mortality of Alzheimer's disease (AD). However, it is unclear which blood biochemical indicators are most closely related to cognitive decline and B vitamins deficiency (thiamine, folate, vitamin B12) in patients with AD. Methods: This was a cross-sectional study of 206 AD patients recruited from six hospitals in China. Thiamine diphosphate (TDP), the bioactive form of thiamine, was measured by high-performance liquid chromatography fluoroscopy (HPLC) at a single center. Levels of biochemical indicators (except TDP) were measured by regular and standard laboratory tests in each hospital. Pearson's rank correlation analysis was used to assess relationships between B vitamins and biochemical indicators. T-test was used to compare the difference between ApoE ε4 and non-ApoE ε4 groups. Differences were considered statistically significant as P < 0.05. Results: Among the biochemical results, in AD population, malnutrition indicators (erythrocyte, hemoglobin, serum albumin, and total protein) were most significantly associated with cognitive function, as was free triiodothyronine (FT3) levels which had been observed in previous study. Malnutrition and FT3 levels depend on age but not apolipoprotein E (ApoE) genotype. Meanwhile, Among the B vitamins, TDP was the most significantly associated with malnutrition indicators and FT3. Conclusion: Our results indicated that TDP reduction could be a modifiable risk factor for malnutrition and FT3 that contributed to cognitive decline in AD patients. Correcting thiamine metabolism could serve as an optional therapy target for AD treatment.

Genomic heterogeneity contributed to different prognosis between adult and pediatric acute lymphoblastic.

The prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to that in children. Hence, ALL remains challenging to cure in the adult population. Aberrant genetic alterations have been observed in ALL, although the patterns of differential gene alterations in adult and pediatric ALL have not been comprehensively determined on a genome-wide scale. We investigated the biologic differences in genomic profiles between adults (n = 64) and children (n = 54) with ALL and relationship between genomic heterogeneity and prognosis. The 2 populations showed similar common mutation types but an increased prevalence of genetic alterations in adult ALL. The median numbers of gene mutations were 17 (range: 1-53) and 4.5 (range: 1-19) per sample in adult and pediatric ALL, respectively (p < 0.001). An increased number of gene mutations and age were significantly correlated (R2  = 0.5853, p < 0.001). We identified 122 and 53 driver genes in adult and pediatric ALL samples, respectively. IKZF1, IDH1, and TTN mutations were significantly enriched in adult patients with ALL. KRAS, ARID1A, and CREBBP mutations were significantly enriched in pediatric patients with ALL (p < 0.05). The incidence of relapse was 40.0% and 9.6% in adult and pediatric patients with ALL, respectively (p = 0.003). The overall survival and relapse-free survival of adult patients with ALL were poorer than those of pediatric patients with ALL (p = 0.002 and p < 0.001, respectively). This genomic landscape enhances the understanding of the biologic differences in ALL between the 2 populations and provides insight for developing therapeutic approaches.

The impact of thiamine deficiency and benfotiamine treatment on Nod-like receptor protein-3 inflammasome in microglia.

Thiamine-dependent processes are critical in cerebral glucose metabolism, it is abnormity induces oxidative stress, inflammation and neurodegeneration. Nod-like receptor protein-3 (NLRP3) inflammasome-mediated inflammation is closely related to neurologic diseases and can be activated by oxidative stress. However, the impact of thiamine deficiency on NLRP3 inflammasome activation remains unknown. In this study, we found that NLRP3 inflammasomes were significantly activated in the microglia of thiamine deficiency mice model. In contrast, benfotiamine dampened inflammation NLRP3 mediated in BV2 cells stimulated with LPS and ATP through reducing mitochondrial reactive oxygen species levels and mitigating autophagy flux defect. These data identify an important role of thiamine metabolism in NLRP3 inflammasome activation, and correcting thiamine metabolism through benfotiamine provides a new therapeutic strategy for NLRP3 inflammasome related neurological, metabolic, and inflammatory diseases.

Dynamic Change of Intracellular Metabolism of Microglia Evaluated by Transcriptomics in an Alzheimer's Mouse Model.

BACKGROUND: Microglia play diverse roles in Alzheimer's disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. OBJECTIVE: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. METHODS: Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining. RESULTS: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. CONCLUSION: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-ß deposition.

Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders.

OBJECTIVES: To describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10-related peroxisomal disorders. PATIENTS AND METHODS: The proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus. An extensive clinical and laboratory evaluation including molecular genetic studies was performed. Genomic DNA was extracted from peripheral blood using the standardized phenol/chloroform extraction method, and the coding region of the PEX10 gene was sequenced in three family members. RESULTS: Cerebral MRI showed cerebellar atrophy. Magnetic resonance spectroscopy revealed a decreased N-acetyl aspartate peak in the cerebellum. Nerve conduction velocity examination found prolonged motor and sensory nerve potential latencies (proximal obvious), decreased potential amplitude, and slow nerve conduction velocity. Routine blood tests and biochemistries were abnormal. The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and c.830 T > C, p. L277 P). The mutation c.830 T > C, p. L277 P has been previously reported, whereas c.209 G > A, p. G70E is novel. CONCLUSION: We identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene. Peroxisome biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia, especially cases with early onset.

Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review.

PURPOSE: To describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. METHODS: The patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. RESULTS: One homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. CONCLUSION: In this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure.

The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia.

Our study aimed to identify the underlying causes in patients with early onset dementia by clinical and genetic exploration. We recruited a group of 38 patients with early-onset dementia. Firstly, hexanucleotide repeat expansions in C9ORF72 gene were screened in all subjects to exclude the possibility of copy number variation. Then, the whole exome sequencing (WES) was conducted, and the data were analyzed focusing on 89 dementia-related causing and susceptible genes. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. There were no pathogenic expansions in C9ORF72 detected. According to the ACMG standards and guidelines, we identified five known pathogenic mutations, PSEN1 P284L, PSEN1c.857-1G>A, PSEN1 I143T, PSEN1 G209E and MAPT G389R, and one novel pathogenic mutation APP K687N. All these mutations caused dementia with the mean onset age of 38.3 (range from 27 to 51) and rapid progression. Eleven variants with uncertain significance were also detected and needed further verification. The clinical phenotypes of dementia are heterogeneous, with both onset ages and clinical features being influenced by mutation position as well as the causative gene. WES can serve as efficient diagnostic tools for different heterogeneous dementia.

The study of exercise tests in paroxysmal kinesigenic dyskinesia.

OBJECTIVE: To unravel if there was muscular ion channel dysfunction in paroxysmal kinesigenic dyskinesia (PKD) patients using the exercises tests (ET). METHODS: Sixty PKD patients including 28 PRRT2 mutations carriers were enrolled in this study, as well as 19 hypokalaemic periodic paralysis (HypoPP) patients as the positive controls and 45 healthy subjects as the negative controls. ET including long exercise test (LET) and short exercise test (SET) was performed in the corresponding subjects. RESULTS: In the LET, both the overall PKD patients and HypoPP patients had greater CMAP amplitude and area increments during exercise than healthy controls. At most 25% of PKD patients were identified from the normality with greater amplitude increment than the area. On the contrary, 50% of HypoPP patients were differentiated with greater area increment than the amplitude. More percentage of PRRT2- patients than PRRT2+ patients had abnormal average amplitude increment. Unexpectedly, five PKD patients had abnormal maximum CMAP amplitude decrements after exercise in the LET, and one had abnormal maximum immediate amplitude decrement in the SET. CONCLUSIONS: Distinct ET manifestations were found in PKD patients compared to normal controls and HypoPP patients. SIGNIFICANCE: Abnormal muscle membrane excitability might be involved in the mechanisms responsible for PKD.