Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.

Optimizing the White Light Emission of Pr3+ Activated SrCeO3 Perovskite by Controlling the Excitation Wavelength for High CRI wLED Applications.

The current research illustrates excitation energy-triggered photoluminescent characteristics of Pr3+ions in SrCeO3 providing a practical approach for developing high CRI wLED and its applications. SrCeO3: xPr3+ (x = 0, 0.005, 0.01, 0.02, 0.03 wt) perovskites synthesized by fuel excess gel combustion method generate high CRI (~98) for wLED applications. Crystalline phosphors with orthorhombic structures having space group Pnma were confirmed by XRD. The unit cell volume expansion occurred with an increase in Pr3+ concentration was verified through the Rietveld refinement technique. Surface morphology, particle distribution, and size were observed via FE-SEM imaging, and detected a well-defined regular distorted spherical structure with average grain size 0.826 µm for Pr3+ doped SrCeO3. Elemental mapping and EDS analysis identified the uniform distribution and elemental purity of SrCeO3: 0.01 Pr3+. Further, the molecular vibrations and modes were analyzed from the Raman spectrum. Moreover, the average particle size assessed via TEM analysis was found to be ~83.2 nm, consistent with XRD analysis. UV-visible absorption spectra for optical energy-band gap analysis showed a decrease in band gap energy with an increase in Pr3+ concentration, realizing an effective energy transfer from Ce4+ to Pr3+. PL measurements showed a huge variety of emission transitions, corresponding to excitations 290 nm, 321 nm, 373 nm, and 449 nm. The critical dopant concentration instigated by concentration quenching was 1 wt% Pr3+, ascribed to dipole-dipole interaction. The fluorescence lifetime of the optimal sample was 4.835 µs. Commission International de I'Eclairage (CIE) diagram exposes the white light emanation of SrCeO3: Pr3+. Among which white light with high CRI (~98) and comparably low CCT (~6311 K) was obtained for SrCeO3: 0.01 Pr3+ at 373 nm excitation. The obtained results recommend that SrCeO3: Pr3+ perovskite as an efficient white phosphor for fabricating high-performance wLEDs.

Development and Evaluation of I-PASS-to-PICU: A Standard Electronic Template to Improve Referral Communication for Interfacility Transfers to the Pediatric ICU.

BACKGROUND: Miscommunication during interfacility handoffs to a higher level of care can harm critically ill children. Adapting evidence-based handoff interventions to interfacility referral communication may prevent adverse events. The objective of this project was to develop and evaluate a standard electronic referral template (I-PASS-to-PICU) to improve communication for interfacility pediatric ICU (PICU) transfers. METHODS: I-PASS-to-PICU was iteratively developed in a single PICU. A core PICU stakeholder group collaboratively designed an electronic health record (EHR)-supported clinical note template by adapting elements from I-PASS, an evidence-based handoff program, to support information exchange between referring clinicians and receiving PICU physicians. I-PASS-to-PICU is a receiver-driven tool used by PICU physicians to guide verbal communication and electronic documentation during PICU transfer calls. The template underwent three cycles of iterative evaluation and redesign informed by individual and group interviews of multidisciplinary PICU staff, usability testing using simulated and actual referral calls, and debriefing with PICU physicians. RESULTS: Individual and group interviews with 21 PICU staff members revealed that relevant, accurate, and concise information was needed for adequate admission preparedness. Time constraints and secondhand information transmission were identified as barriers. Usability testing with six receiving PICU physicians using simulated and actual calls revealed good usability on the validated System Usability Scale (SUS), with a mean score of 77.5 (standard deviation 10.9). Fellows indicated that most fields were relevant and that the template was feasible to use. CONCLUSION: I-PASS-to-PICU was technically feasible, usable, and relevant. The authors plan to further evaluate its effectiveness in improving information exchange during real-time PICU practice.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease.

BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association of women-specific health factors in the severity of Parkinson's disease.

Parkinson's disease (PD) is an age-related neurological disorder known for the observational differences in its risk, progression, and severity between men and women. While estrogen has been considered to be a protective factor in the development of PD, there is little known about the role that fluctuations in hormones and immune responses from sex-specific health experiences have in the disease's development and severity. We sought to identify women-specific health experiences associated with PD severity, after adjusting for known PD factors, by developing and distributing a women-specific questionnaire across the United States and creating multivariable models for PD severity. We created a questionnaire that addresses women's specific experiences and their PD clinical history and deployed it through The Parkinson's Foundation: PD Generation. To determine the association between women-specific health factors and PD severity, we constructed multivariable logistic regression models based on the MDS-UPDRS scale and the participants' questionnaire responses, genetics, and clinical data. For our initial launch in November 2021, we had 304 complete responses from PD GENEration. Univariate and multivariate logistic modeling found significant associations between major depressive disorder, perinatal depression, natural childbirth, LRRK2 genotype, B12 deficiency, total hysterectomy, and increased PD severity. This study is a nationally available questionnaire for women's health and PD. It shifts the paradigm in understanding PD etiology and acknowledging how sex-specific experiences may contribute to PD severity. In addition, the work in this study sets the foundation for future research to investigate the factors behind sex differences in PD.

The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson's disease data.

Open science and collaboration are necessary to facilitate the advancement of Parkinson's disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.

Gender Differences in the Prevalence of Parkinson's Disease.

Background: Parkinson's disease (PD) affects males more than females. The reasons for the gender differences in PD prevalence remain unclear. Objective: The objective of this systematic review and meta-analysis was to update the overall male/female prevalence ratios (OPR). Methods: We updated previous work by searching MEDLINE, SCOPUS, and OVID for articles reporting PD prevalence for both genders between 2011 and 2021. We calculated OPRs and investigated heterogeneity in effect estimates. Results: We included 19 new articles and 13 articles from a previously published meta-analysis. The OPR was 1.18, 95% CI, [1.03, 1.36]. The OPR was lowest in Asia and appeared to be decreasing over time. Study design, national wealth, and participant age did not explain OPR heterogeneity. Conclusion: Gender differences in PD prevalence may not be as stark as previously thought. Studies are needed to understand the role of other determinants of gender differences in PD prevalence.

Killer cell immunoglobulin-like receptor (KIR) gene contents: Are they associated with cervical cancer?

Killer cell immunoglobulin-like receptors (KIRs) are required for natural killer cell function against virus-infected cells or tumor cells. KIR gene content polymorphisms in Indian women with cervical cancer (CaCx) remain unexplored. Hence, we analyzed the frequencies of KIR genes, KIR haplotypes, and Bx subsets to draw their association with CaCx. The polymerase chain reaction-sequence-specific primer method was used for KIR genotyping in three groups of women: healthy controls (n = 114), women with human papillomavirus (HPV) infection (n = 70), and women with CaCx (n = 120). The results showed that the frequency of KIR2DS5 was significantly higher in women with CaCx compared to women with HPV infection (p = 0.02) and healthy controls (p = 0.01). Whereas the frequency of KIR2DL5B was significantly higher in healthy controls than in women with HPV infection (p = 0.02). The total number of activating KIR genes was higher in women with CaCx than in healthy controls (p = 0.006), indicating their positive association with CaCx. Moreover, the C4T4 subset was higher in women with CaCx than in women with HPV infection, though not significant. In conclusion, our findings highlight KIR2DS5, the C4T4 subset, and activating KIR genes are susceptible factors or positively associated with CaCx. Besides KIR2DL5B, this study also reported for the first time significantly high frequency of KIR2DL1 in healthy controls, indicating its possible protective association against CaCx. Further, significantly high frequency of KIR2DL3 observed in HPV-infected women might be also a promising biomarker for viral infections. Thus, the study confirms the association of KIR genes with cervical cancer in women with HPV infection.

Underrepresented Populations in Parkinson's Genetics Research: Current Landscape and Future Directions.

BACKGROUND: Human genetics research lacks diversity; over 80% of genome-wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. OBJECTIVE: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations. METHODS: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non-European populations. Two levels of independent reviewers identified and extracted information. RESULTS: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome-wide approach published up to 2021, including URPs. CONCLUSION: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society.

Microbubbles Contrast Agents: General Overview as Diagnostics and Therapeutic Agent.

Recent discoveries have unfolded many powerful emerging applications in the field of drug delivery science. For the past few years, ultrasound mediated microbubble contrast agents have been an emerging modality for diagnostic and drug delivery applications. Microbubbles are small spherical bubbles composed of a gas core encapsulated by a shell with different materials. The composition of the microbubble determines its stiffness, encapsulation efficiency, stability, and clearance from the system. A gas-filled microbubble, when activated by an acoustic pulse, can produce large volumetric oscillations and, once administered intravenously, can act as a cavitating nuclei, allowing for a wide range of ultrasound-assisted drug delivery applications. Microbubbles offer a fantastic approach to ultrasound triggered drug delivery with various drug loading techniques and targeting strategies for the uptake of bioactive substances such as polynucleotides, proteins, genes, and small-molecule drugs. Microbubbles can be used for several diagnostic and therapeutic purposes for accurate detection and treatment of various life-threatening diseases.

Human Papillomavirus E6/E7 oncogene transcripts as biomarkers for the early detection of cervical cancer.

Cancer of the cervix uteri is the fourth most common cancer worldwide with a high mortality rate. Due to limitations of the existing methods, alternative methods for triage are needed for early detection of cervical cancer precursors before progression to high-grade disease. The aim of this study was to evaluate human papillomavirus (HPV) E6/E7 oncogene expression as markers for early identification of cervical cancer risk in women with minor cytological abnormalities and in those with negative cytology. The detection of HPV was done using PCR and confirmed by southern hybridization. The high-risk (HR) and low-risk HPV types were identified by HPV typing. HPV DNA-positive patients were further tested for markers of oncogene expression by real-time PCR. Out of the women screened, 54/512 (10.54%) women tested positive for HPV infection. HR HPV DNA was found in 32/485 (6.60%) women with normal cytology (Pap negative) and 22/27 (81.5%) atypical squamous cells of undetermined significance/low-grade intraepithelial lesion cases. HR HPV E6/E7 oncogene transcripts were detected in 36/512 (7.03%) patients. The positivity rate of E6/E7 messenger RNA (mRNA) was 2.48% (12/485) in normal cervical cytology group and 88.9% (24/27) in abnormal cervical cytology group. The HPV E6/E7 mRNA test sensitivity was found to be 88.89% and specificity was 97.53%. In comparison, the sensitivity of the HPV DNA test was found to be 81.48% and specificity was 93.40%. In conclusion, E6 and E7 transcripts could provide a sensitive, early predictor of cervical cancer risk in women with normal cytology and minor cytological alterations.

Invasive Aspergillosis of Nose and Paranasal Sinus in COVID-19 Convalescents: Mold Goes Viral?

Invasive Aspergillosis of the paranasal sinus is an aggressive illness, particularly affecting the immunocompromised and rarely, the immunocompetent. COVID-19 has been shown to cause a derangement of immune parameters both during active infection and the convalescent period. A retrospective study was done from June 10th 2021 to September 10th 2021 on patients who underwent endoscopic debridement of the involved sinuses for post COVID fungal rhinosinusitis. This study included the patients who had Aspergillus infection from the isolated nasal tissue samples. Patient's information, complaints, history of COVID infection, clinical findings, investigations and treatment details were obtained from the records. 13 patients with post-COVID Invasive Fungal Sinusitis were identified. Symptom onset usually occurred within 1 month of COVID 19 diagnosis in all the patients. Nasal obstruction (84%) and headache (61%) were the most common symptoms. Computerized tomography imaging showed maxillary sinus involvement in all patients followed by ethmoid sinus in 76% of patients. Microbiological diagnosis and histopathological confirmation of Aspergillus species was done. All 13 patients underwent endoscopic debridement of the involved sinuses followed by anti-fungal therapy with Posaconazole. All responded well to the treatment with no recurrence till date. Admist an infinite number of Mucormycosis cases in this era of COVID-19 pandemic, we experienced a surge of Aspergillus infection during this second wave. Presentation at a young age, with no known co-morbidities, with minimal symptoms and history of COVID-19 infection are some of the important aspects to be considered in this series. A better morbidity outcome is expected when early detection and treatment is made in patients with post Covid-19 viral illness with Aspergillosis of nose and paranasal sinus.

Study of Association of Sensory Neural Hearing Loss with Iron Deficiency Anaemia.

Hearing loss is an ignored community health problem. Along with various mental and motor developmental impairments, iron deficiency anemia (IDA) may cause hearing abnormalities. Study aimed to correlate the Sensorineural hearing loss with iron deficiency anemia in adults. This case control study conducted. Total of 200 participants fulfilling the inclusion criteria were included in present study and grouped into group 1 as cases and group 2 as controls. The participants included in present study after obtaining the consent and evaluated for the iron profile, PTA, OAE for sensory neural hearing loss. They were followed up for 3 months and 6 months. The mean age of case was 41.9 ± 10.77 and there was female preponderance in present study with 120 female and 80 males. Among 100 participants with iron deficiency anemia, twenty among them had the SNHL. The hearing impairment improved with the treatment of the IDA in patients in follow-up. There is a significant association between the SNHL and the Iron deficiency anemia in the patient. The treatment of IDA improves the hearing loss among the adults. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-021-02619-4.

Academic Crisis During COVID 19: Online Classes, a Panacea for Imminent Doctors.

Introduction: COVID 19 made a serious impact on many aspects of everyday life. The world saw a paradigm shift in the education system favouring online learning during the constrains of pandemic. Methodology: To assess the attitude of the students towards online learning in subject of ENT, we conducted an observational study among 170 third year MBBS undergraduate students of our institute attending online classes through the student portal of our university website. Results: Our survey revealed students favoured online learning to sustain their academic interest and development during this pandemic. Yet, they perceived many challenges during online learning like lack of face-to-face interactions, lack of socialization, distraction by social media, technology related issues etc. Students also opted for a combined approach of learning in the post pandemic period. Conclusion: This article reflects the challenges faced during online learning and added the innovative methods that can be included to overcome the obstacles of online learning. During this period of COVID, one must embrace the alternative to classroom learning to keep up with one's academic development and can consider an integrated approach of learning after the pandemic.

Simulation to Train Pediatric ICU Teams in Endotracheal Intubation of Patients with COVID-19.

To prevent transmission of severe acute respiratory syndrome coronavirus 2 to healthcare workers, we must quickly implement workflow modifications in the pediatric intensive care unit (PICU). Our objective was to rapidly train interdisciplinary PICU teams to safely perform endotracheal intubations in children with suspected or confirmed coronavirus disease 2019 using a structured simulation education program. METHODS: We conducted a quality improvement study in a tertiary referral PICU. After developing stakeholder-driven guidelines for modified intubation in this population, we implemented a structured simulation program to train PICU physicians, nurses, and respiratory therapists. We directly observed PICU teams' adherence to the modified intubation process before and after simulation sessions and compared participants' confidence using the Simulation Effectiveness Tool-Modified (SET-M, Likert scale range 0: do not agree to 2: strongly agree regarding statements of confidence). RESULTS: Fifty unique PICU staff members participated in 9 simulation sessions. Observed intubation performance improved, with teams executing a mean of 7.3-8.4 out of 9 recommended practices between simulation attempts (P = 0.024). Before undergoing simulation, PICU staff indicated that overall they did not feel prepared to intubate patients with suspected or confirmed SARS-CoV-2 (mean SET-M score 0.9). After the simulation program, PICU staff confidence improved (mean SET-M score increased from 0.9 to 2, P < 0.001). CONCLUSION: PICU teams' performance and confidence in safely executing a modified endotracheal intubation process for children with suspected or confirmed SARS-CoV-2 infection improved using a rapidly deployed structured simulation education program.