Role of Imaging Genetics in Alzheimer's Disease: A Systematic Review and Current Update.

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder characterized by severe cognitive, behavioral, and psychological symptoms, such as dementia, cognitive decline, apathy, and depression. There are no accurate methods to diagnose the disease or proper therapeutic interventions to treat AD. Therefore, there is a need for novel diagnostic methods and markers to identify AD efficiently before its onset. Recently, there has been a rise in the use of imaging techniques like Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) as diagnostic approaches in detecting the structural and functional changes in the brain, which help in the early and accurate diagnosis of AD. In addition, these changes in the brain have been reported to be affected by variations in genes involved in different pathways involved in the pathophysiology of AD. METHODOLOGY: A literature review was carried out to identify studies that reported the association of genetic variants with structural and functional changes in the brain in AD patients. Databases like PubMed, Google Scholar, and Web of Science were accessed to retrieve relevant studies. Keywords like 'fMRI', 'Alzheimer's', 'SNP', and 'imaging' were used, and the studies were screened using different inclusion and exclusion criteria. RESULTS: 15 studies that found an association of genetic variations with structural and functional changes in the brain were retrieved from the literature. Based on this, 33 genes were identified to play a role in the development of disease. These genes were mainly involved in neurogenesis, cell proliferation, neural differentiation, inflammation and apoptosis. Few genes like FAS, TOM40, APOE, TRIB3 and SIRT1 were found to have a high association with AD. In addition, other genes that could be potential candidates were also identified. CONCLUSION: Imaging genetics is a powerful tool in diagnosing and predicting AD and has the potential to identify genetic biomarkers and endophenotypes associated with the development of the disorder.

Neuroimaging Genomics a Predictor of Major Depressive Disorder (MDD).

Depression is a complex psychiatric disorder influenced by various genetic and environmental factors. Strong evidence has established the contribution of genetic factors in depression through twin studies and the heritability rate for depression has been reported to be 37%. Genetic studies have identified genetic variations associated with an increased risk of developing depression. Imaging genetics is an integrated approach where imaging measures are combined with genetic information to explore how specific genetic variants contribute to brain abnormalities. Neuroimaging studies allow us to examine both structural and functional abnormalities in individuals with depression. This review has been designed to study the correlation of the significant genetic variants with different regions of neural activity, connectivity, and structural alteration in the brain as detected by imaging techniques to understand the scope of biomarkers in depression. This might help in developing novel therapeutic interventions targeting specific genetic pathways or brain circuits and the underlying pathophysiology of depression based on this integrated approach can be established at length.

Intraluminal arterial transit artifact as a predictor of intracranial large artery stenosis on 3D time of flight MR angiography: Expanding the application of arterial spin labeling MRI in ischemic stroke.

Objectives: The objective of this study was to evaluate the diagnostic value of "intraluminal arterial transit artifact" in the prediction of intracranial large artery stenosis and to determine if this finding is predictive of ischemic stroke in the territory of the involved artery. Material and Methods: The presence of arterial transit artifact (ATA) within the lumen of an intracranial large vessel was noted on three-dimensional time of flight (3D-TOF) magnetic resonance angiography (MRA) (ATA group). The patients with stenosis but with no ATA (no-ATA group), patients with total occlusion (total occlusion group), and patients with no stenosis/occlusion (normal group) were included in the analysis. Results: There were four groups of patients included in the final analysis, the ATA group (n = 22), the no-ATA group (n = 23), the normal group (n = 25), and the total occlusion group (n = 9). Among patients with any demonstrable stenosis (n = 45), the presence of ATA within the stenotic segment was predictive of stenosis of ≥56% (Sensitivity of 100% [85.2-100, 95% CI], specificity of 100% [86.4-100, 95% CI]), with area under curve of 1.0 (0.92-.0, 95% CI). The presence of intra-arterial ATA signal was significantly associated with ischemic stroke as compared with the no-ATA group (86.36% vs. 26.08%, P = 0.0003). Intraluminal ATA was found to be an independent predictor of infarction in the territory of the involved artery. Conclusion: Intraluminal ATA is predictive of stenosis of at least 56% in the involved artery on 3D-TOF MRA. Intraluminal ATA sign may be an independent predictor of infarction in the territory of the involved artery.

Projected health and economic outcomes of extending public funding of pharmacy services to include administration of Pneu23 and Td/Tdap immunizations by pharmacy practitioners in New Brunswick.

Background: Although legislation permits New Brunswick pharmacy professionals to administer a wide range of immunizations, public funding for these services is currently limited to immunizations against influenza and COVID-19 and was recently extended to include pneumococcal immunization (Pneu23) in individuals aged 65 years or older. We used administrative data to project health and economic outcomes associated with the current Pneu23 program and with extension of public funding to include: 1) younger adults aged 19 years or older in the Pneu23 program, and 2) tetanus boosters (Td/Tdap). Methods: Two model scenarios were compared: a Physician-Only model in which physicians remain the only practitioners to administer publicly funded Pneu23 and Td/Tdap, and a Blended model in which this service is also provided by pharmacy professionals. Immunization rates by practitioner type were projected based on physician billing data accessed via the New Brunswick Institute for Research, Data and Training in conjunction with trends observed with influenza immunization by pharmacists. These projections were used along with published data to estimate health and economic outcomes under each model. Results: Public funding of Pneu23 (65+), Pneu23 (19+) and Td/Tdap (19+) administration by pharmacy professionals is projected to yield increased immunization rates and physician time savings compared with the Physician-Only model. Public funding of Pneu23 and Td/Tdap administration by pharmacy professionals in those aged ≥19 years would result in cost savings, owing primarily to productivity losses avoided in the working age population. Discussion: Increased immunization rates, physician time savings and cost savings may be realized if public funding were extended to include administration of Pneu23 in younger adults and Td/Tdap, by pharmacy practitioners.

Genomic Variation Affecting MPV and PLT Count in Association with Development of Ischemic Stroke and Its Subtypes.

Platelets play a significant role in the pathophysiology of ischemic stroke since they are involved in the formation of intravascular thrombus after erosion or rupture of the atherosclerotic plaques. Platelet (PLT) count and mean platelet volume (MPV) are the two significant parameters that affect the functions of platelets. In the current study, MPV and PLT count was evaluated using flow cytometry and a cell counter. SonoClot analysis was carried out to evaluate activated clot timing (ACT), clot rate (CR), and platelet function (PF). Genotyping was carried out using GSA and Sanger sequencing, and expression analysis was performed using RT-PCR. In silico analysis was carried out using the GROMACS tool and UNAFold. The interaction of significant proteins with other proteins was predicted using the STRING database. Ninety-six genes were analyzed, and a significant association of THPO (rs6141) and ARHGEF3 (rs1354034) was observed with the disease and its subtypes. Altered genotypes were associated significantly with increased MPV, decreased PLT count, and CR. Expression analysis revealed a higher expression in patients bearing the variant genotypes of both genes. In silico analysis revealed that mutation in the THPO gene leads to the reduced compactness of protein structure. mRNA encoded by mutated ARHGEF3 gene increases the half-life of mRNA. The two significant proteins interact with many other proteins, especially the ones involved in platelet activation, aggregation, erythropoiesis, megakaryocyte maturation, and cytoskeleton rearrangements, suggesting that they could be important players in the determination of MPV values. In conclusion, the current study demonstrated the role of higher MPV affected by genetic variation in the development of IS and its subtypes. The results of the current study also indicate that higher MPV can be used as a biomarker for the disease and altered genotypes, and higher MPV can be targeted for better therapeutic outcomes.

Relative remoteness and wage differentials in the Canadian allied health professional workforce.

INTRODUCTION: Health workforces around the world are characterized with geographic maldistribution, often leading to inequalities in rural health outcomes. Monetary incentives are frequently raised as a policy option to bolster recruitment of healthcare practitioners to rural and underserved communities; however, few rural health workforce studies focus on allied health professionals (AHPs), include urban comparators, integrate gender considerations, or measure rural diversity. This population-based observational study examines trends in the geographic and gender distribution and earnings of AHPs in Canada across the rural-urban continuum. METHODS: Nationally representative data from the 2006 and 2016 Canadian population censuses were pooled and linked with the geocoded Index of Remoteness for all inhabited communities. Five groups of university-educated AHPs providing prevention, diagnostic evaluation, therapy, and rehabilitation services were identified by occupation. Multiple linear regression models were used to estimate the associations between relative remoteness and annual earnings of AHPs aged 25-54 years, controlling for gender and other personal and professional characteristics. RESULTS: The density of AHPs was found to be 15 times higher in more urbanized and accessible parts of the country (23.6-25.6 per 10 000 population in 2016) compared to the most rural and remote areas (1.6 per 10 000 population), a pattern that changed little over the previous decade. A positive correlation was seen across occupations in terms of the degree of feminization and their geographic dispersion by relative remoteness. While pharmacists residing in more rural and remote communities earned 9% (95% confidence interval 4-15%) more than those in core urban centers, relative remoteness contributed little to wage differentials among dentists, physiotherapists and occupational therapists, or other AHPs in therapy and assessment (no significant difference at p<0.05). Women earned significantly less than men in dentistry, pharmacy, and physical or occupational therapy, after adjusting for remoteness and other characteristics. CONCLUSION: This study did not find consistent wage disparities by relative remoteness as characterizing allied health professions in Canada. The evidence base to support financial incentives to AHPs to reduce perceived opportunity costs associated with working and living in rural and underserved areas remains limited. More research is needed on the intersections of rurality, gender, and wage differentials among AHPs in different national contexts.

External occipital protuberance classification with special reference to spine type and its clinical implications.

PURPOSE: This investigation aimed to study the types of external occipital protuberance (EOP) with special reference to Type 3 (spine type). Detailed information will be useful for clinicians to manage occipital headaches or issues related to the biomechanics of the neck and for accurate radiological interpretations. METHODS: Thirty-one dry intact cadaveric skulls were studied for EOP classification. In Type III EOP cases, the size of EOP was noticed using different modalities and compared. The superior nuchal lines and external occipital crest were observed for their prominence and any variation. RESULTS: 42% of the skulls belong to Type 1, 51.5% to Type 2, and 6.5% to Type 3 EOP. Superior nuchal lines and external occipital crest were more prominent in Types 2 and 3 EOP. In Type 3 EOP cases, the mean length, width, and thickness of the spine as measured directly on the skull were 16.63 mm; 20.1 mm, and 7.82 mm respectively, the same as radiograph findings. CT examination revealed the average volume as 0.95 cm3. Out of two Type 3 EOP cases, the spine with larger values for its size was having a lesser volume value in CT. CONCLUSIONS: Plain lateral radiography is a reliable method to measure the length and thickness of spinous EOP. However, more values of these parameters for morphometry of the EOP spine do not mean more volume of EOP and vice versa. Detailed information regarding the occurrence of occipital spur and its morphology will be of great importance to neurosurgeons, sports, physicians, emergency departments, and radiologists.

A case report of successful percutaneous aspiration, injection, and re-aspiration (PAIR) technique for treatment of retrovesical pelvic hydatid cyst.

Pelvis is a rare location for occurrence of hydatid cyst with only a few cases reported in the literature. All the previous reports of pelvic hydatid cysts were managed with either surgical exploration and excision or laparoscopic intervention. In this case report, we describe the successful treatment of a large pelvic hydatid cyst located in the retrovesical space using the percutaneous aspiration, injection, and respiration (PAIR) technique. To the best of our knowledge, this is the first successful demonstration of the PAIR technique in the treatment of retrovesical pelvic hydatid cyst. Percutaneous treatment of hydatid cyst in this case yielded desirable reduction in the size of the cyst with subsequent involution and relief of the pressure symptoms on the urinary bladder and obviated the need for a surgical procedure.

Cerebrofacial venous metameric syndrome type 2+3: face is the index of brain.

We describe a rare case of a 20-year-old man who presented with an extensive facial and orbital venous malformation associated with multiple intracranial venous malformations. The co-existence of cerebrofacial venous malformations points towards a common final pathway in development of these malformations. Our findings are consistent with few previous similar case descriptions. In addition, we describe some novel observations which, to the best of our knowledge, have not been described in the literature. This case reinforces the concept of metameric and segmental distribution of cerebrofacial vasculature, and the aberrations thereof leading to the metameric venous malformations, as proposed by Lasjaunias et al.

Role of tRNA-Derived Fragments in Neurological Disorders: a Review.

tRFs are small tRNA derived fragments that are emerging as novel therapeutic targets and regulatory molecules in the pathophysiology of various neurological disorders. These are derived from precursor or mature tRNA, forming different subtypes that have been reported to be involved in neurological disorders like stroke, Alzheimer's, epilepsy, Parkinson's, MELAS, autism, and Huntington's disorder. tRFs were earlier believed to be random degradation debris of tRNAs. The significant variation in the expression level of tRFs in disease conditions indicates their salient role as key players in regulation of these disorders. Various animal studies are being carried out to decipher their exact role; however, more inputs are required to transform this research knowledge into clinical application. Future investigations also call for high-throughput technologies that could help to bring out the other hidden aspects of these entities. However, studies on tRFs require further research efforts to overcome the challenges posed in quantifying tRFs, their interactions with other molecules, and the exact mechanism of function. In this review, we are abridging the current understanding of tRFs, including their biogenesis, function, relevance in clinical therapies, and potential as diagnostic and prognostic biomarkers of these neurological disorders.

Looking beyond parity: Gender wage gaps and the leadership labyrinth in the Canadian healthcare management workforce.

It is important for health organizations to monitor progress toward gender equity and inclusion goals among health human resources. Within the Canadian healthcare management workforce, however, recent investigations are lacking. This study examines gender differences in composition and compensation among health leadership in Canada using national census data. Findings show that although women represent over half (57%) of senior managers in health and social services, the pipeline from middle management (72%) suggests persistent career barriers disproportionately affect women. Women health and social care managers' earnings averaged $0.83-.89 for every dollar that a man earned. The gender wage gap remained statistically significant, with women health managers earning 12-20% less than men, after adjusting for age, education and other characteristics. Dynamic decomposition analyses highlighted that most of the gender wage gap could not be explained within the available data-a finding attributable, at least in part, to (unmeasured and unmeasurable) gender discrimination.

Pharmacogenomics of GLP-1 receptor agonists: Focus on pharmacological profile.

Type 2 Diabetes mellitus (T2DM) is a multifactorial metabolic disorder also known as a silent killer disease. Macrovascular and microvascular complications associated with diabetes worsen the condition leading to higher comorbidity and mortality rate. Currently, available treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4 (dipeptidyl-peptidase-4) inhibitors, SGLT-2 inhibitors, and Glucagon Like Peptide-1 receptor agonists (GLP-1RAs). Synthetic agonists of GLP-1 hormone, GLP-1RAs are an emerging class of anti-diabetic drugs which target the pathophysiology of diabetes through various mechanisms and at multiple sites. They promote insulin secretion from beta cells, and the proliferation of beta cells inhibits glucagon secretion, delays gastric emptying and induces satiety. However, treatment is reported to be associated with inter-individual variations and adverse drug reactions, which are also influenced by genetic variations. There have been a few pharmacogenetic studies have been carried out on this drug class. This review discusses all the available GLP-1RAs, their pharmacokinetics, pharmacodynamics and genetic variation affecting the inter-individual variation.

Gender composition and wage gaps in the Canadian health policy research workforce in comparative perspective.

BACKGROUND: Gendered challenges have been shown to persist among health practitioners in countries at all levels of development. Less is known about non-clinical professionals, that is, those who do not deliver services directly but are essential to health systems performance, such as health policy researchers. This national observational study examined gender occupational segregation and wage gaps in the Canadian health policy research workforce using a cross-domain comparative labour market analysis approach. METHODS: Sourcing data from the 2016 population census, we applied linear regression and Oaxaca-Blinder decomposition techniques to assess wage differentials by sex, traditional human capital measures (e.g., age, education, place of work), and social identity variables intersecting with gender (household head, childcare, migrant status) among health policy researchers aged 25-54. We compared the gender composition and wage gap with seven non-health policy and programme domains, as mapped under the national occupational classification by similarity in the types of work performed. RESULTS: The health policy research workforce (N = 19 955) was characterized by gender segregation: 74% women, compared with 58% women among non-health policy research occupations (N = 102 555). Women health policy researchers earned on average 4.8% (95% CI 1.5‒8.0%) less than men after adjusting for other professional and personal variables. This gap was wider than among education policy researchers with similar gender composition (75% women; adjusted wage gap of 2.6%). Wages among health policy researchers were 21.1% (95% CI 19.4‒22.8%) lower than their counterparts in the male-dominated economics policy domain, all else being equal. Overall, women's earnings averaged 3.2% lower than men's due to factors that remained unexplained by policy domain or other measured predictors. CONCLUSIONS: This investigation found that the gender inequalities already widely seen among clinical practitioners are replicated among health policy researchers, potentially hindering the competitiveness of the health sector for attracting and retaining talent. Our findings suggest intersectoral actions are necessary to tackle wage gaps and devaluation of female-dominated health professions. Accountability for gender equity in health must extend to the professionals tasked with conducting equity-informative health policy research.

A case report of sciatic hernia as a cause of sciatica and lower back pain: Diagnostic dilemma for family physicians.

Degenerative changes in lumbosacral spine or disc bulges impinging on the thecal sac are the usual causes of sciatica. However peripheral compression of sciatic nerve in pelvis or lower limb presenting as sciatica is an uncommon entity. The sciatic hernia is a rare type of hernia. Due to the deep location of this pathology, the clinical examination would add little and imaging plays a pivotal role in diagnosis. We present a case of sciatica diagnosed with giant gluteal lipoma presenting as sciatic notch hernia and compressing sciatic nerve in the greater sciatic notch. Less than 100 cases are reported in the literature so far. The possibility of this rare diagnosis should be kept in mind by family physicians while evaluating patients of sciatica with no significant imaging findings in lumbosacral spine.

Time trends in tuberculosis mortality across the BRICS: an age-period-cohort analysis for the GBD 2019.

Background: Tuberculosis is the leading cause of death from a single infectious agent among the HIV-negative population and ranks first among the HIV-positive population. However, few studies have assessed tuberculosis trends in Brazil, Russia, India, China and South Africa (BRICS) or with an emphasis on HIV status. This study assesses the time trends of tuberculosis mortality across the BRICS with an emphasis on HIV status from 1990 to 2019. Methods: We obtained tuberculosis data from the Global Burden of Disease 2019 study (GBD 2019). We calculated the relative proportion of tuberculosis to all communicable, maternal, neonatal, and nutritional diseases by HIV status across the BRICS. We used age-period-cohort modelling to estimate cohort and period effects in tuberculosis from 1990 to 2019, and calculated net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks. Findings: There were 549,522 tuberculosis deaths across the BRICS in 2019, accounting for 39.3% of global deaths. Among HIV-negative populations, the age-standardised mortality rate (ASMR) of tuberculosis in BRICS remained far higher than that of high-income Asia Pacific countries, especially in India (36.1 per 100 000 in 2019, 95% UI [30.7, 42.6]) and South Africa (40.1 per 100 000 in 2019, 95% UI [36.8, 43.7]). China had the fastest ASMR reduction across the BRICS, while India maintained the largest tuberculosis death numbers with an annual decrease much slower than China's (-4.1 vs -8.0%). Among HIV-positive populations, the ASMR in BRICS surged from 0.24 per 100 000 in 1990 to 5.63 per 100 000 in 2005, and then dropped quickly to 1.70 per 100 000 in 2019. Brazil was the first country to reverse the upward trend of HIV/AIDS-tuberculosis (HIV-TB) mortality in 1995, and achieved the most significant reduction (-3.32% per year). The HIV-TB mortality in South Africa has realised much progress since 2006, but still has the heaviest HIV-TB burden across the BRICS (ASMR: 70.0 per 100 000 in 2019). We also found unfavourable trends among HIV-negative middle-aged (35-55) adults of India, men over 50 in the HIV-negative population and whole HIV-positive population of South Africa, and women aged 45-55 years of Russia. China had little progress in its HIV-positive population with worsening period risks from 2010 to 2019, and higher risks in the younger cohorts born after 1980. Interpretation: BRICS' actions on controlling tuberculosis achieved positive results, but the overall improvements were less than those in high-income Asia Pacific countries. BRICS and other high-burden countries should strengthen specified public health approaches and policies targeted at different priority groups in each country. Funding: National Natural Science Foundation of China (82073573; 72074009), Peking University Global Health and Infectious Diseases Group.

Differential molecular mechanistic behavior of HDACs in cancer progression.

Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs' role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.

Necrotic mediastinal lymphadenopathy: Tuberculosis or Sarcoidosis, a diagnostic conundrum - A case report and review of the literature.

Sarcoidosis is an uncommon disease involving pulmonary parenchyma and lymph nodes. Non-necrotizing, bilaterally symmetric hilar, and right paratracheal lymph nodes are the pathognomonic imaging features of sarcoidosis. Rarely, atypical radiological findings of sarcoidosis may mimic mycobacterial infections, posing a diagnostic dilemma, especially in tuberculosis endemic countries. In this report, we have discussed the case of a 61-year-old female presenting with multiple conglomerated necrotic mediastinal lymph nodes on computed tomography that looked tubercular but eventually turned out to be sarcoidosis. It is important for primary care physicians, who are the first point of contact for patients, to keep in mind the atypical radiologic manifestations of sarcoidosis, in order to reach a timely diagnosis and help reduce the associated morbidity and mortality.