Prevalence of Chronic Kidney Disease in a High-Risk Population in Urban Lahore, Pakistan: A Cross-sectional Study.

Background Chronic kidney disease (CKD) is a globally increasing health concern, and there is a growing focus on early screening and prevention efforts. However, the availability of data on CKD prevalence in Pakistan, particularly in the urban area of Lahore district, is limited. The objective of the Kidney Early Evaluation Program (KEEP) Lahore was to assess the prevalence of CKD in a high-risk population residing in the urban area of Lahore, Pakistan. Methods A cross-sectional study was conducted involving 254 participants, who were over 18 years old and belonged to a high-risk population according to the pre-defined operational definitions. The participants were randomly selected from various towns in Lahore. Screening camps were set up to measure serum creatinine levels and urinary albumin to creatinine ratio (UACR), and then the estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration 2021 (CKD EPI) equation. Results Out of the total 254 participants, a diagnosis of CKD was made in 62 (24.2%) individuals. Significant associations were found between CKD and risk factors including hypertension, diabetes, family history of CKD, ischemic heart disease (IHD) or congestive heart failure (CHF), intake of painkillers, and herbal medicines. However, no association was found between obesity (BMI ≥ 30) and CKD. Participants diagnosed with CKD had a mean age of 49.9 years and a mean serum creatinine level of 1.2 mg/dL, while non-CKD participants had a mean age of 43.7 years and a mean serum creatinine level of 0.7 mg/dL. Conclusion Our study revealed that CKD was prevalent in about one-fourth of the participants from the high-risk population of Lahore, indicating a high prevalence of the disease within society. Moreover, hypertension, diabetes, family history of CKD, heart disease, painkillers, and the use of herbal medicines were all significantly linked to CKD in the surveyed sample population.

What are the experiences and psychosocial needs of female survivors of domestic violence in Afghanistan? A qualitative interview study in three Afghan provinces.

OBJECTIVES: This study aimed to qualitatively explore (1) the experiences of female survivors of domestic abuse and mental health problems in Afghanistan; (2) how female survivors of violence and abuse, male members of the community and service providers perceive and respond to mental health and domestic violence in Afghanistan and (3) the provision of mental health services for female survivors of violence and abuse in Afghanistan, including the barriers and challenges faced around accessing mental health services. DESIGN: Qualitative interviews and framework thematic analysis. SETTING: Kabul, Bamyan and Nangarhar in Afghanistan. PARTICIPANTS: 60 female survivors of domestic abuse, 60 male community members and 30 service providers who work with female survivors of domestic abuse. RESULTS: Experiences of multiple and compounding traumatic experiences of violence, armed conflict, and complex and competing psychosocial concerns were common among the female survivor participants. All female survivor participants reported experiencing negative mental health outcomes in relation to their experiences of violence and abuse, which were further precipitated by widespread social stigma and gender norms. Support and service provision for female survivors was deemed by participants to be insufficient in comparison to the amount of people who need to access them. CONCLUSIONS: There are many risks and barriers women face to disclosing their experiences of violence and mental health problems which restrict women's access to psychological support. Culturally relevant services and trauma-informed interventions are necessary to respond to these issues. Service providers should be trained to effectively recognise and respond to survivors' mental health needs.

Metabolic Profile of Offspring of Mothers with Gestational Diabetes Mellitus.

Introduction: Gestational diabetes mellitus (GDM) is defined as diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes before gestation. Unrecognized and untreated GDM confers significantly greater maternal and fetal risk, which is largely related to the degree of hyperglycemia. The specific risks of diabetes in pregnancy include but are not limited to, spontaneous abortion, pre-eclampsia, fetal anomalies, macrosomia, neonatal hypoglycemia, hyperbilirubinemia, and respiratory distress syndrome. Additionally, GDM is also implicated in long-term metabolic derangements in the offspring in the form of obesity/overweight, hypertension, dysglycemia, insulin resistance, and dyslipidemias later in life. To determine the prevalence of anthropometric and metabolic derangements in children between 1 and 5 years of age, born to women with GDM. Methods: This hospital-based cross-sectional study was conducted between November 2019 and November 2021 at our Pediatric Endocrine Clinic. Women were diagnosed as having GDM based on the American Diabetes Association Criteria (2019). History regarding the treatment of the GDM (diet only/diet and medical treatment) and detailed physical examination, including anthropometry and blood pressure, were recorded. Blood samples were collected from children for the estimation of their metabolic profile. Results: Overweight, obesity, and severe obesity were present in 18 (11.3%), 2 (1.3%), and 2 (1.3%) children, respectively. Hypertension was found in 21 (19.4%) children. Elevated LDL, triglyceride, and total cholesterol were seen in 3 (1.9%), 84 (52.5%), and 1 (0.6%) children, respectively. Impaired fasting glucose (IFG) was found in 6 (3.8%) children, while 27 (16.9%) subjects were found to be having impaired glucose tolerance after OGTT. Insulin resistance was found in 30 (18.8%) children. GDM mothers with a higher BMI tended to have children with a higher BMI (correlation coefficient, r = .414, P < .001). Higher serum triglyceride levels (r = -0.034, P = 0.672) were recorded in children, irrespective of the BMI of their mothers. There was no significant correlation of maternal BMI with blood pressure (r = -0.134, P = 0.091) or with HOMA-IR (r = 0.00, P = 0.996) in children. However, mothers with a higher BMI had children with statistically higher fasting blood glucose (r = +0.339, P = <0.001) as well as blood glucose 2 hours after OGTT (r = +0.297, P = <0.001). This positive correlation of maternal BMI with the glucose metabolism of their offspring was observed for both male and female genders. Conclusion: Children of women with GDM had a higher BMI, and the mode of treatment for GDM did not lead to differences in childhood BMI. The higher BMI of a GDM mother is associated with altered glucose metabolism in their offspring. Deranged levels of triglyceride across the gender were not found to be statistically significant. This has implications for future metabolic and cardiovascular risks in targeting this group for intervention studies to prevent obesity and disorders of glucose metabolism as one potential strategy to prevent adverse metabolic health outcomes.

Exploring the association between early childhood caries, malnutrition, and anemia by machine learning algorithm.

OBJECTIVE: The objective of this study was to determine the prevalence of early childhood caries in children with severe acute malnutrition (SAM) and also the hierarchy of association if any with malnutrition, anemia, and other risk factors with ECC using machine learning algorithms. METHODS: A hospital-based preventive and interventional study was conducted on SAM children (age = 2 to <6 years) who were admitted to the malnutrition treatment unit (MTU). An oral examination for early childhood caries status was done using the deft index. The anthropometric measurements and blood examination reports were recorded. Oral health education and preventive dental treatments were given to the admitted children. Three machine learning algorithms (Random Tree, CART, and Neural Network) were applied to assess the relationship between early childhood caries, malnutrition, anemia, and the risk factors. RESULTS: The Random Tree model showed that age was the most significant factor in predicting ECC with predictor importance of 98.75%, followed by maternal education (29.20%), hemoglobin level (16.67%), frequency of snack intake (9.17%), deft score (8.75%), consumption of snacks (7.1%), breastfeeding (6.25%), severe acute malnutrition (5.42%), frequency of sugar intake (3.75%), and religion at the minimum predictor importance of 2.08%. CONCLUSION: Anemia and malnutrition play a significant role in the prediction, hence in the causation of ECC. Pediatricians should also keep in mind that anemia and malnutrition have a negative impact on children's dental health. Hence, Pediatricians and Pediatric dentist should work together in treating this health problem.

How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a functional assessment.

BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic disorders. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs remain key challenges to study human nociception in vitro. Here, we report a detailed functional characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Anatomic's commercially available RealDRG™ were further characterized for both functional and expression phenotyping of key nociceptor markers. METHODS: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Manual patch clamp was used to functionally characterize both control and patient-derived neurons. High throughput techniques were further used to demonstrate that RealDRGs™ derived from the Anatomic protocol are amenable to high throughput technologies for disease modelling. RESULTS: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. Chambers protocol results in predominantly tonic firing when compared to Anatomic protocol. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. RealDRG™ sensory neurons show heterogeneity of nociceptive markers indicating that the cells may be useful as a humanized model system for translational studies. CONCLUSIONS: We validated the efficiency of two differentiation protocols and their potential application for functional assessment and thus understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Multiomic profiling of human clonal hematopoiesis reveals genotype and cell-specific inflammatory pathway activation.

ABSTRACT: Clonal hematopoiesis (CH) is an age-associated phenomenon that increases the risk of hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood.1 Here, we profile peripheral blood gene expression in 66 968 single cells from a cohort of 17 patients with CH and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant Tet methylcytosine dioxygenase 2 (TET2) and DNA methyltransferase 3A (DNMT3A) cells with nonmutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a proinflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage inhibitory factor. We also found that T cells from patients with CH, although mostly unmutated, had decreased expression of GTPase of the immunity associated protein genes, which are critical to T-cell development, suggesting that CH impairs T-cell function.

Rhythmic motor behavior explains individual differences in grammar skills in adults.

A growing body of literature has reported the relationship between music and language, particularly between individual differences in perceptual rhythm skill and grammar competency in children. Here, we investigated whether motoric aspects of rhythm processing-as measured by rhythmic finger tapping tasks-also explain the rhythm-grammar connection in 150 healthy young adults. We found that all expressive rhythm skills (spontaneous, synchronized, and continued tapping) along with rhythm discrimination skill significantly predicted receptive grammar skills on either auditory sentence comprehension or grammaticality well-formedness judgment (e.g., singular/plural, past/present), even after controlling for verbal working memory and music experience. Among these, synchronized tapping and rhythm discrimination explained unique variance of sentence comprehension and grammaticality judgment, respectively, indicating differential associations between different rhythm and grammar skills. Together, we demonstrate that even simple and repetitive motor behavior can account for seemingly high-order grammar skills in the adult population, suggesting that the sensorimotor system continue to support syntactic operations.

IgA Vasculitis following AstraZeneca/Oxford COVID-19, case report.

Immunoglobulin A (IgA) vasculitis, also known as Henoch-Schönlein purpura, is an immune-mediated vasculitis that affects small vessels. IgA vasculitis could be triggered by numerous conditions including infectious and non-infectious conditions. So far, few reported cases of Covid-19 vaccines related vasculitis. We report a case of IgA vasculitis after AstraZeneca/Oxford COVID-19 vaccine. A 29-year-old healthy man who developed purpuric skin lesions one week after his second AstraZeneca/Oxford COVID-19 vaccine which complicated by glomerulonephritis and gastrointestinal involvement. Skin biopsy revealed fibrinoid necrosis and leukocytoclasia consistent with small vessel vasculitis. Due to the temporal association, AstraZeneca/Oxford COVID-19 vaccine-related IgA vasculitis would be the most likely explanation.

Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

Introducing Birth Companion in Labour: A Quality Improvement Initiative.

Background: Birth companion (BC) has been globally recognised as an essential component of childbirth care. As our institution did not allow BC in labour, this study was planned as a quality improvement (QI) project to introduce the concept. We aimed to achieve birth companionship from existing 0 to 100% over a period of six months. Intervention: QI team was constituted, and an initial brainstorming session conducted. A fishbone diagram was drawn to analyse issues that need addressal before implementation of the initiative. The framework was defined, and team members assigned their roles and responsibilities. A series of five successive Plan-Do-Study-Act (PDSA) cycles were carried out over a period of six months, which included introduction of the concept, dissemination of information, infrastructural changes in labour room and introducing column for documentation in birth register. To achieve sustainability, comprehensive group counselling sessions were started for women during antenatal period, and sensitisation classes were regularly conducted for newly inducted trainees and faculty. Result: Birth companionship was achieved in 98% of cases. Conclusion: The QI tools helped in preparation and planning of changes by breaking down a large problem into smaller sections and covering all aspects of challenges in a systematic manner using team-based approach. National directives and recommendations, sensitisation of leadership and training of stakeholders were found to be important facilitators. Robust systems of monitoring and successive PDSA cycles were needed for continuous improvement and sustainability of the idea.

How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a comparison of two protocols.

Background: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic symptoms. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs for disease modelling remain key challenges to study human nociception in vitro. Here, we report a detailed characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Methods: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Expression profiling of sensory neurons was performed with Immunocytochemistry and in situ hybridization techniques. Manual patch clamp and high throughput cellular screening systems (Fluorescence imaging plate reader, automated patch clamp and multi-well microelectrode arrays recordings) were applied to functionally characterize the generated sensory neurons. Results: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. High throughput systems confirmed functional expression of Na+ and K+ ion channels. Multi-well microelectrode recordings display spontaneously active neurons with sensitivity to increased temperature indicating expression of heat sensitive ion channels. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. Conclusions: We validated the efficiency of two differentiation protocols and their potential application for understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Assessment of Acute Side Effects Among 3D-Concurrent Radiotherapy With Cisplatin-Treated Head and Neck Cancer Patients.

INTRODUCTION: Three-dimensional conformal radiation therapy has become one of the basic components of multidisciplinary treatment for head and neck cancer. Generally, patients with squamous-cell carcinoma of the head and neck receive cisplatin-based chemoradiation. AIMS: In the current project, the goal was to assess 3D-CRT with cisplatin-induced acute side effects (dermatitis plus xerostomia) among head and neck cancer patients. METHODOLOGY: This descriptive case series was held at the Institute of Nuclear Medicine and Oncology, Lahore, Pakistan, with an enrollment of 106 head and neck cancer patients following the hospital's ethical approval. All patients received 3D-CRT with concurrent cisplatin chemotherapy according to the oncology treatment protocol at the Institute of Nuclear Medicine and Oncology. The evaluation of enrolled patients was done during treatment at a weekly interval and at one-month post-radiation. Stage 3 patients (17.9%) received chemo-radiation therapy with 40 mg/m2 cisplatin once weekly for seven weeks. All patients received 70 grays in 35 fractions with two grays per fraction over the course of seven weeks following a standard protocol. All enrolled cases had biopsy-proven squamous cell carcinoma of the head and neck. IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. analyzed the data. Chi-square and Fisher's exact tests were applied, while a p-value ≤ 0.05 was taken as statistically significant. RESULTS: All patients developed acute skin changes (dermatitis plus xerostomia) as a side effect of radiation therapy, with cisplatin having different grades during treatment until seven weeks. However, these changes improved and became less severe in terms of grade after one month of post-treatment among all patients. CONCLUSION: It was concluded that 3D-CRT was associated with dermatitis and xerostomia during and immediately after follow-up, even though the treatment response was good. However, clinical signs and symptoms improved, indicating that radiation therapy is a relatively safe treatment modality among cancer patients. Moreover, 40 mg/m2 cisplatin once weekly for seven weeks resulted in better loco-regional control and survival among advanced-stage head and neck cancer patients as a part of treatment. Although, higher doses of cisplatin (100 mg/m2 ) every three weeks have more harmful acute side effects and delay treatment for patients due to poor compliance.

Protease-Activated Receptor 2 (PAR2) Expressed in Sensory Neurons Contributes to Signs of Pain and Neuropathy in Paclitaxel Treated Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of cancer therapy. Protease-activated receptor 2 (PAR2) is implicated in a variety of pathologies, including CIPN. In this study, we demonstrate the role of PAR2 expressed in sensory neurons in a paclitaxel (PTX)-induced model of CIPN in mice. PAR2 knockout/wildtype (WT) mice and mice with PAR2 ablated in sensory neurons were treated with PTX administered via intraperitoneal injection. In vivo behavioral studies were done in mice using von Frey filaments and the Mouse Grimace Scale. We then examined immunohistochemical staining of dorsal root ganglion (DRG) and hind paw skin samples from CIPN mice to measure satellite cell gliosis and intra-epidermal nerve fiber (IENF) density. The pharmacological reversal of CIPN pain was tested with the PAR2 antagonist C781. Mechanical allodynia caused by PTX treatment was alleviated in PAR2 knockout mice of both sexes. In the PAR2 sensory neuronal conditional knockout (cKO) mice, both mechanical allodynia and facial grimacing were attenuated in mice of both sexes. In the DRG of the PTX-treated PAR2 cKO mice, satellite glial cell activation was reduced compared to control mice. IENF density analysis of the skin showed that the PTX-treated control mice had a reduction in nerve fiber density while the PAR2 cKO mice had a comparable skin innervation as the vehicle-treated animals. Similar results were seen with satellite cell gliosis in the DRG, where gliosis induced by PTX was absent in PAR cKO mice. Finally, C781 was able to transiently reverse established PTX-evoked mechanical allodynia. PERSPECTIVE: Our work demonstrates that PAR2 expressed in sensory neurons plays a key role in PTX-induced mechanical allodynia, spontaneous pain, and signs of neuropathy, suggesting PAR2 as a possible therapeutic target in multiple aspects of PTX CIPN.

Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response.

The Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice for Tmem97, we find that a new σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.