Biological Reference Ranges for Healthy Indian Blood Donors: Experience of a Tertiary Care Center Vis-à-Vis International Literature.

INTRODUCTION: Complete blood count is the most common, basic test requisitioned in hematology. The normal reference ranges of hematological parameters are required owing to variable socioeconomic, environmental, and genetic factors in populations. The current study determines the reference ranges of the healthy Indian donor population of a high socioeconomic group. METHODS: The study was conducted in the Department of Transfusion Medicine at a tertiary care hospital in India and included 4098 individuals, aged 18-65 years coming for voluntary blood donation from July 2021 to October 2022. Blood samples were collected in K2EDTA, analyzed on the Sysmex XN-31 hematology analyzer, and using statistical tools, the normal reference ranges were calculated. RESULTS: The reference ranges for hemoglobin (HB) (137-185 g/L), WBC (5.1-1.7 × 109/L), platelet count (115.6-370.0 × 109/L) were noted. No statistically significant changes were observed in different age groups. There were gender-wise differences noted in nearly all parameters. The HB and hematocrit (HCT) range was slightly higher in other Indian and other Asian populations with comparable values with the Chinese, Korean populations, and Western populations; RBC parameters were overall comparable with minor differences; the WBC count was higher than the other Indian and Asian populations particularly the upper limit of lymphocyte and monocyte; and the range of platelet counts had a comparable upper limit with all populations and had the lowest lower value in males in our study, which was comparable to only the Chinese population. CONCLUSIONS: It is concluded that reference ranges of common parameters were calculated with minor changes noted in all hematological parameters on comparing with other Indian, Asian population, and Western data.

Emphasizing Patient-Centricity Through a Tailored Training Program to Empower Patients, Advocates, and Ethics Committees in Good Clinical Practice.

OBJECTIVES: Good Clinical Practices (GCP) are essential for patient-centric research. The standard bioethics and GCP training emphasizing a "one-size-fits-all" approach may not adequately equip ethics committee members, especially the lay and social scientist members, towards their critical role in reviewing clinical trials and related documentation. This article explores a patient-centered, patient advocates-driven training program focused on raising awareness about research ethics and GCP among patients, advocates and ethics committee members. METHODS: A patient advocates-driven program called Patient Advocates for Clinical Research (PACER) conducted trainings focused on GCP for patient-centric research for patients, advocates and ethics committee members. Pre- and post-workshop questionnaires were used to assess the participants' knowledge of GCP. RESULTS: The workshop was attended by 116 participants. Of these 91 consented to participate in questionnaire evaluation that assessed participants' knowledge on ethics committee (EC) functionality, research ethics and data confidentiality. Pre-workshop evaluations highlighted knowledge gaps. Only 16.5% were familiar with the primary ethical consideration for vulnerable populations and 69.2% were knowledgeable about data governance. Post-workshop evaluations demonstrated significant overall response improvement of 5.4% (𝜒2=13.890; p<0.001). The understanding of ethical considerations for vulnerable populations rose by 15.4% (p=0.007), and knowledge of data privacy regulations improved by 11.0% (p=0.041). CONCLUSION: The workshop under PACER initiative highlighted the knowledge gaps in understanding the EC functionality, research ethics and data confidentiality. The workshop effectively fostered participants' understanding of ethical research practices.

Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer.

Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.

Inhibition of high-fat diet-induced miRNA ameliorates tau toxicity in Drosophila.

Alzheimer's disease (AD), caused by amyloid beta (Aß) plaques and Tau tangles, is a neurodegenerative disease characterized by progressive memory impairment and cognitive dysfunction. High-fat diet (HFD), which induces type 2 diabetes, exacerbates Aß plaque deposition in the brain. To investigate the function of HFD in Tau-mediated AD, we fed an HFD to the Drosophila Tau model and found that HFD aggravates Tau-induced neurological phenotypes. Since microRNAs (miRNAs) are biomarkers for diabetes and AD, we evaluated the expression levels of common miRNAs of HFD and AD in HFD-fed Tau model fly brains. Among the common miRNAs, the expression levels of Let-7 and miR-34 were increased. We found that the inhibition of these miRNAs alleviates Tau-mediated AD phenotypes. Our research provides valuable insights into how HFD accelerates tau toxicity. Additionally, our work highlights the therapeutic potential of targeting Let-7 and miR-34 to develop innovative treatment approaches for AD.

Comprehensive Overview of Alzheimer's Disease: Etiological Insights and Degradation Strategies.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD is associated with cognitive decline and memory loss that worsens with aging. A statistical report using U.S. data on AD estimates that approximately 6.9 million individuals suffer from AD, a number projected to surge to 13.8 million by 2060. Thus, there is a critical imperative to pinpoint and address AD and its hallmark tau protein aggregation early to prevent and manage its debilitating effects. Amyloid-ß and tau proteins are primarily associated with the formation of plaques and neurofibril tangles in the brain. Current research efforts focus on degrading amyloid-ß and tau or inhibiting their synthesis, particularly targeting APP processing and tau hyperphosphorylation, aiming to develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies and clinical trials to develop treatments that truly make a difference. Genome-wide association studies (GWASs) across various cohorts identified 40 loci and over 300 genes associated with AD. Despite this wealth of genetic data, much remains to be understood about the functions of these genes and their role in the disease process, prompting continued investigation. By delving deeper into these genetic associations, novel targets such as kinases, proteases, cytokines, and degradation pathways, offer new directions for drug discovery and therapeutic intervention in AD. This review delves into the intricate biological pathways disrupted in AD and identifies how genetic variations within these pathways could serve as potential targets for drug discovery and treatment strategies. Through a comprehensive understanding of the molecular underpinnings of AD, researchers aim to pave the way for more effective therapies that can alleviate the burden of this devastating disease.

Patient Advocates for Clinical Research (PACER): A Step Toward Ethical, Relevant, and Truly Participatory Clinical Research in India.

Background Clinical research presents a promising path for improving healthcare in contemporary India. Yet, researchers identify gaps in trust, awareness, as well as misconceptions about being a '"guinea pig." We proposed building the capacity of training patient advocacy groups (PAGs) in patient-centered clinical research and through them creating aware patients as research partners. Methodology Patient Advocates for Clinical Research (PACER) is a tiered program to share information and education about clinical research with PAGs. Tier one is a self-paced online learning course, followed by workshops on clinical research, Good Clinical Practice, research consent, case studies, and group discussions. Results A total of 20 PAGs represented by 48 participants, active in areas of pediatric cancer, breast cancer, multiple myeloma, type I diabetes, spinal muscular atrophy, sickle cell disease, and inflammatory bowel diseases, participated. Among 48 participants 30 successfully completed the online course (multiple-choice question evaluation score cut-off >70%), attaining an average score of 23.9 ± 2.1 out of 30. Overall, 48 participants attended workshop 1 and 45 workshop 2, with 140 participants joining the focus group discussion (FGD). An overall improvement of 9.4% (𝜒2 = 46.173; p < 0.001) for workshop 1 and 8.2% (𝜒2 = 25.412; p < 0.001) for workshop 2 was seen in knowledge gain about clinical research. The FGD raised issues such as misleading information from research teams, unethical recruitment, incomprehensible information sheets, and limited trial-related knowledge fostering fear of participation in clinical research. Conclusions Multimodal and tiered learning of clinical research such as that used by PACER has a good participatory and learning response from PAGs and may be further explored.

Molecular Chaperonin HSP60: Current Understanding and Future Prospects.

Molecular chaperones are highly conserved across evolution and play a crucial role in preserving protein homeostasis. The 60 kDa heat shock protein (HSP60), also referred to as chaperonin 60 (Cpn60), resides within mitochondria and is involved in maintaining the organelle's proteome integrity and homeostasis. The HSP60 family, encompassing Cpn60, plays diverse roles in cellular processes, including protein folding, cell signaling, and managing high-temperature stress. In prokaryotes, HSP60 is well understood as a GroEL/GroES complex, which forms a double-ring cavity and aids in protein folding. In eukaryotes, HSP60 is implicated in numerous biological functions, like facilitating the folding of native proteins and influencing disease and development processes. Notably, research highlights its critical involvement in sustaining oxidative stress and preserving mitochondrial integrity. HSP60 perturbation results in the loss of the mitochondria integrity and activates apoptosis. Currently, numerous clinical investigations are in progress to explore targeting HSP60 both in vivo and in vitro across various disease models. These studies aim to enhance our comprehension of disease mechanisms and potentially harness HSP60 as a therapeutic target for various conditions, including cancer, inflammatory disorders, and neurodegenerative diseases. This review delves into the diverse functions of HSP60 in regulating proteo-homeostasis, oxidative stress, ROS, apoptosis, and its implications in diseases like cancer and neurodegeneration.

Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases.

The heat shock response is an evolutionarily conserved mechanism that protects cells or organisms from the harmful effects of various stressors such as heat, chemicals toxins, UV radiation, and oxidizing agents. The heat shock response triggers the expression of a specific set of genes and proteins known as heat shock genes/proteins or molecular chaperones, including HSP100, HSP90, HSP70, HSP60, and small HSPs. Heat shock proteins (HSPs) play a crucial role in thermotolerance and aiding in protecting cells from harmful insults of stressors. HSPs are involved in essential cellular functions such as protein folding, eliminating misfolded proteins, apoptosis, and modulating cell signaling. The stress response to various environmental insults has been extensively studied in organisms from prokaryotes to higher organisms. The responses of organisms to various environmental stressors rely on the intensity and threshold of the stress stimuli, which vary among organisms and cellular contexts. Studies on heat shock proteins have primarily focused on HSP70, HSP90, HSP60, small HSPs, and ubiquitin, along with their applications in human biology. The current review highlighted a comprehensive mechanism of heat shock response and explores the function of heat shock proteins in stress management, as well as their potential as therapeutic agents and diagnostic markers for various diseases.

Correlation Between Volume and Pressure of Intracranial Space With Craniectomy Surface Area and Brain Herniation: A Phantom-Based Study.

There are proponents of decompressive craniectomy (DC) and its various modifications who claim reasonable clinical outcomes for each of them. Clinical outcome in cases of traumatic brain injury, managed conservatively or aided by different surgical techniques, depends on multiple factors, which vary widely among patients and have complex interplay, making it difficult to compare one case with another in absolute terms. This forms the basis of the perceived necessity to have a standard model to study, compare, and strategize in this field. We designed a phantom-based model and present the findings of the study aimed at establishing a correlation of the volume of intracranial space and changes in intracranial pressure (ICP) with surface area of the craniectomy defect created during DC and brain herniation volume. A roughly hemispherical radio-opaque container was scanned on a 128-slice computed tomography scanner. Craniectomies of different sizes and shapes were marked on the walls of the phantom. Two spherical sacs of stretchable materials were subsequently placed inside the phantom, fixed to three-way connectors, filled with water, and connected with transducers. The terminals of the transducer cables were coupled with the display monitor through a signal amplifier and processor module. Parts of the wall of the phantom were removed to let portions of the sac herniate through the defect, simulating a DC. Volume measurements using AW volume share 7® software were done. Resection of a 12.7 × 11.5 cm part of the wall resulted in a 10-cm-diameter defect in the wall. Volume differential of 35 mL created a midline shift of 5 mm to the side with lesser volume. When measuring pressure in two stretchable sacs contained inside the phantom, there always remained a pressure differential ranging from 1 to 2 mm Hg in different recordings, even with sacs on both sides containing an equal volume of fluids. Creating a circular wall defect of 10 cm in diameter with an intracavitary pressure of 35 mm Hg on the ipsilateral sac and 33 mm on the contralateral sac recorded with intact walls, resulted in a true volume expansion of 48.411 cm3. The herniation resulted in a reduction of pressure in both sacs, with the pressure recorded as 25 mm in the ipsilateral sac and 24 mm in the contralateral sac. The findings closely matched those of the other model-based studies. Refinement of the materials used is likely to provide a valid platform to study cranial volume, ICP, craniectomy size, and brain prolapse volume in real time. The model will help in pre-operatively choosing the most appropriate technique between a classical DC, a hinge craniotomy, and an expansive cranioplasty technique in cases of refractory raised ICP.

A numerical model for the prediction of radon flux from uranium mill tailings at Jaduguda, India.

Solid process fine waste or tailings of a uranium mill is a potential source of release of radiologically significant gaseous radon (222Rn). A number of variables such as radium (226Ra) content, porosity, moisture content, and tailings density can affect the extent of emanation from the tailings. Further, if a cover material is used for remediation purposes, additional challenges due to changes in the matrix characteristics in predicting the radon flux can be anticipated. The uranium mill tailings impoundment systems at Jaduguda have been in use for the long-term storage of fine process waste (tailings). A pilot-scale remediation exercise of one of the tailings ponds has been undertaken with 30 cm soil as a cover material. For the prediction of the radon flux, a numerical model has been developed to account for the radon exhalation process at the remediated site. The model can effectively be used to accommodate both the continuous and discrete variable inputs. Depth profiling and physicochemical characterization for the remediated site have been done for the required input variables of the proposed numerical model. The predicted flux worked out is well below the reference level of 0.74 Bq m-2 s-1 IAEA (2004).

Nanocavity-Mediated Purcell Enhancement of Er in TiO2 Thin Films Grown via Atomic Layer Deposition.

The use of trivalent erbium (Er3+), typically embedded as an atomic defect in the solid-state, has widespread adoption as a dopant in telecommunication devices and shows promise as a spin-based quantum memory for quantum communication. In particular, its natural telecom C-band optical transition and spin-photon interface make it an ideal candidate for integration into existing optical fiber networks without the need for quantum frequency conversion. However, successful scaling requires a host material with few intrinsic nuclear spins, compatibility with semiconductor foundry processes, and straightforward integration with silicon photonics. Here, we present Er-doped titanium dioxide (TiO2) thin film growth on silicon substrates using a foundry-scalable atomic layer deposition process with a wide range of doping controls over the Er concentration. Even though the as-grown films are amorphous after oxygen annealing, they exhibit relatively large crystalline grains, and the embedded Er ions exhibit the characteristic optical emission spectrum from anatase TiO2. Critically, this growth and annealing process maintains the low surface roughness required for nanophotonic integration. Finally, we interface Er ensembles with high quality factor Si nanophotonic cavities via evanescent coupling and demonstrate a large Purcell enhancement (≈300) of their optical lifetime. Our findings demonstrate a low-temperature, nondestructive, and substrate-independent process for integrating Er-doped materials with silicon photonics. At high doping densities this platform can enable integrated photonic components such as on-chip amplifiers and lasers, while dilute concentrations can realize single ion quantum memories.

KLF2 enhancer variant rs4808485 increases lupus risk by modulating inflammasome machinery and cellular homoeostasis.

OBJECTIVE: A recent genome-wide association study linked KLF2 as a novel Asian-specific locus for systemic lupus erythematosus (SLE) susceptibility. However, the underlying causal functional variant(s), cognate target gene(s) and genetic mechanisms associated with SLE risk are unknown. METHODS: We used bioinformatics to prioritise likely functional variants and validated the best candidate with diverse experimental techniques, including genome editing. Gene expression was compared between healthy controls (HCs) and patients with SLE with or without lupus nephritis (LN+, LN-). RESULTS: Through bioinformatics and expression quantitative trait locus analyses, we prioritised rs4808485 in active chromatin, predicted to modulate KLF2 expression. Luciferase reporter assays and chromatin immunoprecipitation-qPCR demonstrated differential allele-specific enhancer activity and binding of active histone marks (H3K27ac, H3K4me3 and H3K4me1), Pol II, CTCF, P300 and the transcription factor PARP1. Chromosome conformation capture-qPCR revealed long-range chromatin interactions between rs4808485 and the KLF2 promoter. These were directly validated by CRISPR-based genetic and epigenetic editing in Jurkat and lymphoblastoid cells. Deleting the rs4808485 enhancer in Jurkat (KO) cells disrupted NLRP3 inflammasome machinery by reducing KLF2 and increasing CASPASE1, IL-1ß and GSDMD levels. Knockout cells also exhibited higher proliferation and cell-cycle progression than wild type. RNA-seq validated interplay between KLF2 and inflammasome machinery in HC, LN+ and LN-. CONCLUSIONS: We demonstrate how rs4808485 modulates the inflammasome and cellular homoeostasis through regulating KLF2 expression. This establishes mechanistic connections between rs4808485 and SLE susceptibility.

Clinical Outcomes of Autologous Hematopoietic Stem Cell Transplant in Multiple Myeloma Patients: A 5-year Experience from a Single Centre in North India.

Swati PabbiIntroduction Multiple myeloma (MM) forms a significant proportion of hematological malignancies. Autologous transplantation continues to be an effective consolidation strategy in resource-restricted settings such as India. Objectives The main objective of the study was to analyze the clinical outcomes of autologous hematopoietic stem cell transplant (HSCT) in MM patients in a single tertiary care center in north India over a period of 5 years. Materials and Methods This retrospective observational study was conducted in a tertiary care center in north India. Data of all MM patients who underwent HSCT between January 2014, and December 2018, were analyzed. The outcome of HSCT was investigated in terms of transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and relapse. PFS and OS were calculated by Kaplan-Meier method and differences between the groups were tested for statistical significance using the two-tailed log-rank test. Life-table method was used for the estimation of survival rate at 1, 3, 5, and 6 years. Results Patient characteristics and survival post-transplant was similar to other published Indian studies. In total, 378 patients were diagnosed with MM in our hospital between 2014 and 2018. One hundred ninety-three patients were found to be eligible for autologous HSCT, out of which 52 ended up having a transplant giving us a high percentage (26.9%) of patients receiving a transplant in our setting. Transplant-related mortality (TRM) was nil in the present study. The mean PFS and OS were 62.8 and 70.1 months, respectively. The mean PFS and OS rates at 5 years were 75.3% and 84.2%, respectively. The average cost estimate of HSCT in our setting was 7.2 lakh Indian national rupees. Conclusion Autologous HSCT is a safe procedure with nil 100-day mortality in present series. Moreover, considering the cost of novel agents, autologous transplant remains a cost-effective way for prolonging remission and time-to-next treatment in India.

Sheehan's Syndrome in India: Clinical Characteristics and Laboratory Evaluation.

Background: Sheehan's Syndrome (SS) is an important cause of hypopituitarism especially in developing countries though it remains underdiagnosed to a great extent. Torrential bleeding after delivery followed by lactation failure and amenorrhoea gives a clue to the diagnosis which is usually made after several years of delivery. Materials and Methods: It was a retrospective observational study conducted by reviewing the case records of 38 cases of SS. The age, anthropometric measurements, signs and symptoms, biochemical parameters, hormone levels and imaging reports were examined and analyzed. Results: The mean age at presentation was 36.5 years because there was a delay of 8.4 years from last delivery before diagnosis could be made. Ninety percent patients presented with lactation failure. Anaemia, hypotension, hypogonadism, hypothyroidism, and altered lipid profile were the most common findings. The mean systolic blood pressure (BP) was 80.95 mm and diastolic BP was 51.6 mm of Hg at the time of presentation. Hyponatremia was the most common electrolyte abnormality noted and low HDL was the commonest lipid abnormality. Conclusion: A large percentage of patients presented with amenorrhea, lactation failure, and decreased or absent axillary/pubic hair. Shock, anemia, and hyponatremia were also common symptoms among the patients studied. The diagnosis of SS rests upon a thorough history taking of the postpartum events in cases presenting with hypopituitarism irrespective of the age at presentation. Proper antenatal care with exclusive institutional deliveries can reduce the prevalence of SS in developing countries.

Political competition and environment quality: a study of India.

The focus of sustainable development goals (SDGs) is to promote the use of renewable energy so that countries can achieve better environmental quality. However, the progression is plodding, and still, 80% of energy comes mainly from conventional sources in developing countries. The implementation of procedures depends on the political attitudes, political stability, and quality of institutions. India has a diverse political structure ranging from central government to state government to local governments. In the late '80 s, India witnessed a stiff rise in regional and national political parties, which leads more political competition. This paper tries to explain the possible relationship between political competition and CO2 emission in India. With the application of the time series non-linear ARDL (NARDL) model, this study tries to find the asymmetric relationship between political competition and CO2 emission. In our empirical model, we also include other important elements of environmental quality like innovation and fossil fuel consumption. Empirical results show that political competition is asymmetrically related to CO2 emissions in the long run. Fossil fuel consumption and innovation also have a significant relationship with emissions. Based on the results, a few policy recommendations have been discussed.

Impact of various detergent-based immersion and perfusion decellularization strategies on the novel caprine pancreas derived extracellular matrix scaffold.

Limited availability of the organs donors has facilitated the establishment of xenogeneic organ sources for transplantation. Numerous studies have decellularized several organs and assessed their implantability in order to provide such organs. Among all the decellularized organs studies for xenotransplantation, the pancreas has garnered very limited amount of research. The presently offered alternatives for pancreas transplantation are unable to liberate patients from donor dependence. The rat and mice pancreas are not of an accurate size for transplantation but can only be used for in-vitro studies mimicking in-vivo immune response in humans, while the porcine pancreas can cause zoonotic diseases as it carries porcine endogenous retrovirus (PERV- A/B/C). Therefore, we propose caprine pancreas as a substitute for these organs, which not only reduces donor dependence but also poses no risk of zoonosis. Upon decellularization the extracellular matrix (ECM) of different tissues responds differently to the detergents used for decellularization at physical and physiological level; this necessitates a comprehensive analysis of each tissue independently. This study investigates the impact of decellularization by ionic (SDS and SDC), non-ionic (Triton X-100 and Tween-20), and zwitterionic detergents (CHAPS). All these five detergents have been used to decellularize caprine pancreas via immersion (ID) and perfusion (PD) set-up. In this study, an extensive comparison of these two configurations (ID and PD) with regard to each detergent has been conducted. The final obtained scaffold with each set-up has been evaluated for the left-over cytosolic content, ECM components like sGAG, collagen, and fibronectin were estimated via Prussian blue and Immunohistochemical staining respectively, and finally for the tensile strength and antimicrobial activity. All the detergents performed consistently superior in PD than in ID. Conclusively, PD with SDS, SDC, and TX-100 successfully decellularizes caprine pancreatic tissue while retaining ECM architecture and mechanical properties. This research demonstrates the viability of caprine pancreatic tissue as a substitute scaffold for porcine organs and provides optimal decellularization protocol for this xenogeneic tissue. This research aims to establish a foundation for further investigations into potential regenerative strategies using this ECM in combination with other factors.

Cost-effectiveness of population-based screening for oral cancer in India: an economic modelling study.

Background: Oral cancer screening reduces mortality associated with oral cancer. The current study evaluated the cost-effectiveness of commonly used screening techniques, namely conventional oral examination (COE), toluidine blue staining (TBS), oral cytology (OC), and light-based detection (LBD) in the Indian scenario. Methods: The study used a Markov modelling approach to estimate the cost and health outcomes of four different approaches (COE, TBS, OC, and LBD) for screening oral cancer over time from a societal perspective. The discount rate was assumed as 3%. The outcomes estimated were oral cancer incident cases, deaths averted, and quality-adjusted life years (QALYs). To address the high burden of risk factors (tobacco and/or alcohol) in India, two Markov models were developed: Model A adopted a mass-screening strategy, whereas Model B adopted a high-risk screening strategy versus no screening. Probabilistic sensitivity analysis (PSA) was undertaken to address any parameter uncertainty. Findings: Mass-screening using LBD at three years had the least incident cases (3271.68) and averted the maximum number of oral cancer deaths (459.76). High-risk screening using COE at ten years interval incurred the least lifetime cost of 2,292,816.21 US$ (182,794,468.26 INR). The high-risk strategies (US$/QALY), namely COE 5 years (-29.21), COE 10 years (-90.68), TBS 10 years (-60.54), and LBD 10 years (-13.51), were dominant over no-screening. Interpretation: The most cost-saving approach was the conventional oral examination at an interval of 10 years for oral screening in high-risk populations above 30 years of age. Funding: Department of Health Research, Ministry of Health & Family Welfare, Government of India.

Detection of the ß-lactoglobulin genotype in zebu cattle (Gangatiri) milk using high-resolution accurate mass spectroscopy.

We studied the genetic polymorphism of beta-lactoglobulin (ß-Lg) whey protein in Gangatiri zebu cows for this Research Communication. The polymorphic nature of milk protein fractions and their association with milk production traits, composition and quality has attracted several efforts in evaluating the allelic distribution of protein locus as a potential dairy trait marker. Genetic variants of ß-Lg have highly significant effects on casein number (B > A) and protein recovery (B > A) and also determine the yield of cheese dry matter (B > A). Molecular techniques of polyacrylamide gel electrophoresis and high-resolution accurate mass-spectroscopy were applied to characterize the ß-Lg protein obtained from the Gangatiri breed milk. Sequence analysis of ß-Lg showed the presence of variant B having UniProt database accession number P02754, coded on the PAEP gene. Our study can provide reference and guidance for the selection of superior milk (having ß-LgB) from this indigenous breed that could potentially give a good yield of ß-Lg for industrial applications.

A Non-Coding Variant in SLC15A4 Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic basis. Despite the identification of several single nucleotide polymorphisms (SNPs) near the SLC15A4 gene that are significantly associated with SLE across multiple populations, specific causal SNP(s) and molecular mechanisms responsible for disease susceptibility are unknown. To address this gap, we employed bioinformatics, expression quantitative trait loci (eQTLs), and 3D chromatin interaction analysis to nominate a likely functional variant, rs35907548, in an active intronic enhancer of SLC15A4 . Through luciferase reporter assays followed by chromatin immunoprecipitation (ChIP)-qPCR, we observed significant allele-specific enhancer effects of rs35907548 in diverse cell lines. The rs35907548 risk allele T is associated with increased regulatory activity and target gene expression, as shown by eQTLs and chromosome conformation capture (3C)-qPCR. The latter revealed long-range chromatin interactions between the rs35907548 enhancer and the promoters of SLC15A4, GLTLD1 , and an uncharacterized lncRNA. The enhancer-promoter interactions and expression effects were validated by CRISPR/Cas9 knock-out (KO) of the locus in HL60 promyeloblast cells. KO cells also displayed dramatically dysregulated endolysosomal pH regulation. Together, our data show that the rs35907548 risk allele affects multiple aspects of cellular physiology and may directly contribute to SLE.

PCL retention demonstrates better functional scores and gait patterns in total knee arthroplasty using a medial congruent insert-a prospective study.

PURPOSE: Despite Total Knee Arthroplasty (TKA) being one of the most successful procedures for end stage arthritis, nearly 20% of patients undergoing this procedure remain dissatisfied. Various design options have been introduced to reduce this cohort of patients. One such option has been the introduction of the medial congruent (MC) polyethylene design. This study was undertaken to evaluate outcome measures and gait analysis in patients undergoing bilateral single stage TKA where the posterior cruciate ligament (PCL) was retained or excised in contralateral knees. METHODS: 60 bilateral TKA's were performed by a single surgeon using a MC design option from July to Sep 2021. The study lots included patients between the ages of 55 and 70 years with fixed varus deformity of degenerative aetiology, and Kellgren Lawrence Grade 3 and 4 radiological changes. Exclusion criteria were previous surgery to the lower extremities, sero positive arthropathies, post traumatic arthritis, valgus deformity, flexion contractures > 20°, and any pre-existing pathology impacting gait, e.g., poliomyelitis, or neuromuscular disorders. The PCL was retained or sacrificed on contralateral sides for the purpose of this study. Functional scores, outcomes and gait analysis on level and gradient walking were evaluated at a follow-up of 18 months. RESULTS: At 18, months the Range of Motion (ROM) improved from a preoperative value of 97.3 ± 11.5 to 110.3 ± 6.1 on the PCL retained side (MC-PCL) and from 96.5 ± 10.8 to 113 ± 5.8 on the PCL excised side (MC-PCLX). Knee Society Score (KSS-2011) improved from a preoperative value of 21.2 ± 4.5 to 89.8 ± 3.4 at 18 months postoperatively on the MC-PCL side and from 21.5 ± 4 to 88.2 ± 3.7 on the MC-PCLX side. Forgotten Joint Score (FJS-12) was 8.8 ± 0.7 on the MC-PCL side and 8.1 ± 0.9 on the MC-PCLX side 18 months after surgery. Our gait analysis evaluation demonstrated a lower forefoot pressure in the MC-PCL group in comparison to the MC-PCLX group when subjects were made to walk on a 30° upward incline. This difference was found to be statistically significant. CONCLUSION: In this study, while ROM was greater in the MC-PCLX study lot, patient satisfaction was higher in the MC-PCL study lot. Gait assessment demonstrated lower forefoot pressure while ascending an incline of 30° in the MC-PCL study lot as compared to the MC-PCLX study lot approximating normal gait patterns. LEVEL OF EVIDENCE: II.