ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

Treatment for osteoporosis in people with beta-thalassaemia.

BACKGROUND: Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with beta-thalassaemia, osteoporosis represents an important cause of morbidity and is due to a number of factors. First, ineffective erythropoiesis causes bone marrow expansion, leading to reduced trabecular bone tissue with cortical thinning. Second, excessive iron loading causes endocrine dysfunction, leading to increased bone turnover. Lastly, disease complications can result in physical inactivity, with a subsequent reduction in optimal bone mineralization. Treatments for osteoporosis in people with beta-thalassaemia include bisphosphonates (e.g. clodronate, pamidronate, alendronate; with or without hormone replacement therapy (HRT)), calcitonin, calcium, zinc supplementation, hydroxyurea, and HRT alone (for preventing hypogonadism). Denosumab, a fully human monoclonal antibody, inhibits bone resorption and increases bone mineral density (BMD). Finally, strontium ranelate simultaneously promotes bone formation and inhibits bone resorption, thus contributing to a net gain in BMD, increased bone strength, and reduced fracture risk. This is an update of a previously published Cochrane Review. OBJECTIVES: To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which includes references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of most recent search: 4 August 2022. SELECTION CRITERIA: Randomized controlled trials (RCTs) in people with beta-thalassaemia with: a BMD Z score below -2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and premenopausal females aged over 15 years; or a BMD T score below -2.5 SDs for postmenopausal females and males aged over 50 years. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and risk of bias of the included RCTs, and extracted and analysed data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included six RCTs (298 participants). Active interventions included bisphosphonates (3 trials, 169 participants), zinc supplementation (1 trial, 42 participants), denosumab (1 trial, 63 participants), and strontium ranelate (1 trial, 24 participants). The certainty of the evidence ranged from moderate to very low and was downgraded mainly due to concerns surrounding imprecision (low participant numbers), but also risk of bias issues related to randomization, allocation concealment, and blinding. Bisphosphonates versus placebo or no treatment Two RCTs compared bisphosphonates to placebo or no treatment. After two years, one trial (25 participants) found that alendronate and clodronate may increase BMD Z score compared to placebo at the femoral neck (mean difference (MD) 0.40, 95% confidence interval (CI) 0.22 to 0.58) and the lumbar spine (MD 0.14, 95% CI 0.05 to 0.23). One trial (118 participants) reported that neridronate compared to no treatment may increase BMD at the lumbar spine and total hip at six and 12 months; for the femoral neck, the study found increased BMD in the neridronate group at 12 months only. All results were of very low-certainty. There were no major adverse effects of treatment. Participants in the neridronate group reported less back pain; we considered this representative of improved quality of life (QoL), though the certainty of the evidence was very low. One participant in the neridronate trial (116 participants) sustained multiple fractures as a result of a traffic accident. No trials reported BMD at the wrist or mobility. Different doses of bisphosphonate compared One 12-month trial (26 participants) assessed different doses of pamidronate (60 mg versus 30 mg) and found a difference in BMD Z score favouring the 60 mg dose at the lumbar spine (MD 0.43, 95% CI 0.10 to 0.76) and forearm (MD 0.87, 95% CI 0.23 to 1.51), but no difference at the femoral neck (very low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment. Zinc versus placebo One trial (42 participants) showed zinc supplementation probably increased BMD Z score compared to placebo at the lumbar spine after 12 months (MD 0.15, 95% CI 0.10 to 0.20; 37 participants) and 18 months (MD 0.34, 95% CI 0.28 to 0.40; 32 participants); the same was true for BMD at the hip after 12 months (MD 0.15, 95% CI 0.11 to 0.19; 37 participants) and 18 months (MD 0.26, 95% CI 0.21 to 0.31; 32 participants). The evidence for these results was of moderate certainty. The trial did not report BMD at the wrist, fracture incidence, mobility, QoL, or adverse effects of treatment. Denosumab versus placebo Based on one trial (63 participants), we are unsure about the effect of denosumab on BMD Z score at the lumbar spine, femoral neck, and wrist joint after 12 months compared to placebo (low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment, but the investigators reported a reduction in bone pain measured on a visual analogue scale in the denosumab group after 12 months of treatment compared to placebo (MD -2.40 cm, 95% CI -3.80 to -1.00). Strontium ranelate One trial (24 participants) only narratively reported an increase in BMD Z score at the lumbar spine in the intervention group and no corresponding change in the control group (very low-certainty evidence). This trial also found a reduction in back pain measured on a visual analogue scale after 24 months in the strontium ranelate group compared to the placebo group (MD -0.70 cm (95% CI -1.30 to -0.10); we considered this measure representative of improved quality of life. AUTHORS' CONCLUSIONS: Bisphosphonates may increase BMD at the femoral neck, lumbar spine, and forearm compared to placebo after two years' therapy. Zinc supplementation probably increases BMD at the lumbar spine and hip after 12 months. Denosumab may make little or no difference to BMD, and we are uncertain about the effect of strontium on BMD. We recommend further long-term RCTs on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia-associated osteoporosis.

Spectacle Coverage among Urban Schoolchildren with Refractive Error Provided Subsidized Spectacles in North India.

SIGNIFICANCE: Provision of subsidized spectacles to schoolchildren with refractive error in Delhi was associated with increased spectacle coverage. PURPOSE: Studies involving free spectacle distribution and self-purchase of spectacles often report poor compliance. We assessed 1-year spectacle coverage among schoolchildren with refractive error who were provided subsidized spectacles. METHODS: This was a study of a prospective cohort of 10,114 students from 20 randomly selected schools of Delhi. Children were presumed to have refractive error when unaided visual acuity was worse than or equal to 6/12 in either eye and a best-corrected visual acuity better than or equal to 6/9.5 in both eyes (n = 1503). Children with unmet need of spectacles (presenting with a visual acuity worse than 6/9.5 in the worse eye) were provided subsidized spectacles (n = 1191). Coverage was established by direct observation at baseline and after 1 year through unannounced visits. RESULTS: Mean age of cohort was 12.0 ± 2.0 years, and 566 (37.7%) were girls. Baseline spectacle coverage was 29.3% (95% confidence interval [CI], 27.1 to 31.7%), which improved to 65.9% (95% CI, 56.0 to 61.6%) among all children (n = 1470) and 58.8% (95% CI, 56.0 to 61.6%) among children with unmet need (n = 1163) at 1 year. Uptake of the subsidized spectacles was 98.6%. On multivariate regression, the odds of spectacle use were greatest when unaided vision was poor: 55.5% when visual acuity was better than or equal to 6/9.5, 74.8% when visual acuity was 6/19 to 6/60 (adjusted odds ratio, 2.5; 95% CI, 1.7 to 3.5), and 91.5% when visual acuity was worse than 6/60 (adjusted odds ratio, 3.1; 95% CI, 1.0 to 9.5). Sex (boys, 66.3%; girls, 65.3%) and socioeconomic status (lower, 58.6%; middle, 61.8%; upper middle, 70.7%) were not associated with coverage. Increasing maternal education and baseline spectacle use were associated with coverage. However, 38.0% were wearing spectacles prescribed by the project, and 61.9% of the spectacles being used at 1 year were purchased in the open market. CONCLUSIONS: Spectacle coverage after 1 year increased through a subsidized spectacle scheme, particularly for children with poor uncorrected vision.

Diabetic retinopathy screening programme utilising non-mydriatic fundus imaging in slum populations of New Delhi, India.

OBJECTIVES: To develop and implement a community-based programme for screening of diabetic retinopathy (DR) in urban populations of Delhi. METHODS: Known diabetics (KDs) aged 40 years and older were identified through house-to-house surveys, volunteers and publicity. All KDs were referred to DR screening camps organised locally where procedures included brief medical history, ocular examination and non-mydriatic fundus photography using portable handheld camera. Fundal images were graded on the spot by trained optometrists for DR. Patients with DR were referred to tertiary centre for management. RESULTS: A total of 11 566 KDs were identified, of whom 9435 (81.6%) visited DR screening camps and 8432 (89.4%) had DR gradable images. DR was identified in 13.5% of subjects; 351 cases were mild NPDR, 567 moderate, 92 severe. Seventy-seven had PDR, and 49 had DME, and 2.7% of participants were blind (presenting visual acuity <3/60 in better eye). Non-use of lifestyle management, presence of systemic complications, BMI <18.5 kg/m2 , disease duration of >5 years and uncontrolled diabetes were associated with increased odds of DR. All cases with DR were referred, and 420 (37%) successful referrals to base hospital were observed. CONCLUSION: The programme of creating awareness about DR, identifying KDs and optometrist-led DR screening using non-mydriatic fundus camera based in slums was successful.

A Successful Pharmacist-Based Quality Initiative to Reduce Inappropriate Stress Ulcer Prophylaxis Use in an Academic Medical Intensive Care Unit.

Stress ulcer prophylaxis (SUP) is often inappropriately utilized, particularly in critically ill patients. The objective of this study is to find an effective way of reducing inappropriate SUP use in an academic medical intensive care unit (ICU). Medical ICU patients receiving SUP were identified over a 1-month period, and their charts were reviewed to determine whether American Society of Health-System Pharmacists guidelines were followed. Inappropriate usage was calculated as inappropriate patient-days and converted to incidence per 100 patient-days. Two interventions were implemented: (1) Pharmacists reviewed indications for SUP on each patient during daily team rounds and daily medication reconciliation and (2) residents rotating on ICU services were educated on a bimonthly basis. Postintervention data were obtained in a similar fashion. Prior to intervention, the incidence of inappropriate SUP usage was calculated to be 26.75 per 100 patient-days (n = 1099 total patient-days). Total cost attributable to the inappropriate use was $2433. Post intervention, we were able to decrease the inappropriate incidence of SUP usage to 7.14 per 100 patient-days (n = 1149 total patient-days). In addition, total cost of inappropriate use was reduced to $239.80. Our study highlights an effective multidisciplinary approach to reduce the inappropriate use of SUP in an academic medical ICU. We were able to reduce the incidence of inappropriate use of SUP by 73.31% ( P < .001). Furthermore, we were able to decrease the costs by approximately $2200/month.

Treatment for osteoporosis in people with ß-thalassaemia.

BACKGROUND: Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis represents an important cause of morbidity in people with beta-thalassaemia and its pathogenesis is multifactorial. Factors include bone marrow expansion due to ineffective erythropoiesis, resulting in reduced trabecular bone tissue with cortical thinning; endocrine dysfunction secondary to excessive iron loading, leading to increased bone turnover; and lastly, a predisposition to physical inactivity due to disease complications with a subsequent reduction in optimal bone mineralization.A number of therapeutic strategies have been applied to treat osteoporosis in people with beta-thalassaemia, which include bisphosphonates, with or without, hormone replacement therapy. There are various forms of bisphosphonates, such as clodronate, pamidronate, alendronate and zoledronic acid. Other treatments include calcitonin, calcium, zinc supplementation, hydroxyurea and hormone replacement therapy for preventing hypogonadism. OBJECTIVES: To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 04 February 2016. SELECTION CRITERIA: Randomised, placebo-controlled trials in people with thalassaemia with a bone mineral density z score of less than -2 standard deviations for: children less than 15 years old; adult males (15 to 50 years old); and all pre-menopausal females above 15 years and a bone mineral density t score of less than -2.5 standard deviations for post-menopausal females and males above 50 years old. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and completed the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate. MAIN RESULTS: Four trials (with 211 participants) were included; three trials investigated the effect of bisphosphonate therapies and one trial investigated the effect of zinc supplementation. Only one trial was judged to be of good quality (low risk of bias); the remaining trials had a high or unclear risk of bias in at least one key domain.One trial (data not available for analysis) assessing the effect of neridronate (118 participants) reported significant increases in favour of the bisphosphonate group for bone mineral density at the lumbar spine and hip at both six and 12 months. For the femoral neck, a significant difference was noted at 12 months only. A further trial (25 participants) assessed the effect of alendronate and clodronate and found that after two years, bone mineral density increased significantly in the alendronate and clodronate groups as compared to placebo at the lumbar spine, mean difference 0.14 g/cm(2) (95% confidence interval 0.05 to 0.22) and at the femoral neck, mean difference 0.40 g/cm(2) (95% confidence interval 0.22 to 0.57). One 12-month trial (26 participants) assessed the effects of different doses of pamidronate (30 mg versus 60 mg) and found a significant difference in bone mineral density in favour of the 60 mg dose at the lumbar spine and forearm, mean difference 0.43 g/cm(2) (95% CI 0.10 to 0.76), mean difference 0.87 g/cm(2) (95% CI 0.23 to 1.51), respectively, but not at the femoral neck.In a zinc sulphate supplementation trial (42 participants), bone mineral density increased significantly compared to placebo at the lumbar spine after 12 months (37 participants), mean difference 0.15 g/cm(2) (95% confidence interval 0.10 to 0.20) and after 18 months (32 participants), mean difference 0.34 g/cm(2) (95% confidence interval 0.28 to 0.40). The same was true for bone mineral density at the hip after 12 months, mean difference 0.15 g/cm(2) (95% confidence interval 0.11 to 0.19) and after 18 months, mean difference 0.26 g/cm(2) (95% confidence interval 0.21 to 0.31).Fractures were not observed in one trial and not reported in three trials. There were no major adverse effects reported in two of the bisphosphonate trials; in the neridronate trial there was a reduction noted in the use of analgesic drugs and in the reported back pain score in favour of bisphosphonate treatment. Adverse effects were not reported in the trial of different doses of pamidronate or the zinc supplementation trial. AUTHORS' CONCLUSIONS: There is evidence to indicate an increase in bone mineral density at the femoral neck, lumbar spine and forearm after administration of bisphosphonates and at the lumbar spine and hip after zinc sulphate supplementation. The authors recommend that further long-term randomised control trials on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia and osteoporosis are undertaken.

Telestroke in resource-poor developing country model.

CONTEXT: Telemedicine is a major effort to tackle the uneven availability of facilities for thrombolysis in acute ischemic stroke. We present a telestroke model introduced in a small hilly state of Himachal Pradesh in India. AIMS: To provide acute ischemic stroke treatment with tissue plasminogen activator in all district hospitals of Himachal Pradesh with computerized axial tomographic scan facility through Telemedicine. SETTINGS AND DESIGN: Smartphone-based hub and spoke telestroke model was used with two tertiary care hospitals (with neurologists) as hub and 17 district hospitals (without onsite neurologists) as spokes. SUBJECT AND METHODS: The telestroke project was launched in the state of Himachal Pradesh in April 2014. Medical officers in district hospitals (Medicine graduates and Internal Medicine postgraduates) were trained in the treatment of stroke through workshops. Tissue plasminogen activator was made available at all these centers, free of cost through hospital pharmacies. Four neurologists at two tertiary care centers were made available for consultation on phone. RESULTS: Between June 2014 and May 2015, a total of 26 patients received thrombolysis under the telestroke project at nine district hospitals without onsite presence of a neurologist. Eight patients were females and 18 males. The age of patients ranged from 26 to 80 years. Only 2 patients developed an intracranial bleed following thrombolysis, and both were nonfatal. CONCLUSIONS: Smartphone-based telestroke services may be a much cheaper alternative to video-conferencing-based telestroke services and are more portable with less technical glitches. To the best of our knowledge, this is the first telestroke model being reported from India. It seems to be the way forward in providing timely treatment in acute ischemic stroke in underserved and resource poor settings.

Characterizing TDP-43 interaction with its RNA targets.

One of the most important functional features of nuclear factor TDP-43 is its ability to bind UG-repeats with high efficiency. Several cross-linking and immunoprecipitation (CLIP) and RNA immunoprecipitation-sequencing (RIP-seq) analyses have indicated that TDP-43 in vivo can also specifically bind loosely conserved UG/GU-rich repeats interspersed by other nucleotides. These sequences are predominantly localized within long introns and in the 3'UTR of various genes. Most importantly, some of these sequences have been found to exist in the 3'UTR region of TDP-43 itself. In the TDP-43 3'UTR context, the presence of these UG-like sequences is essential for TDP-43 to autoregulate its own levels through a negative feedback loop. In this work, we have compared the binding of TDP-43 with these types of sequences as opposed to perfect UG-stretches. We show that the binding affinity to the UG-like sequences has a dissociation constant (Kd) of ∼110 nM compared with a Kd of 8 nM for straight UGs, and have mapped the region of contact between protein and RNA. In addition, our results indicate that the local concentration of UG dinucleotides in the CLIP sequences is one of the major factors influencing the interaction of these RNA sequences with TDP-43.

Revisiting rubisco as a protein substrate for insect midgut proteases.

Gene fragments encoding the large subunit (LS) of Rubisco (RBCL) were cloned from various species of host plants of phytophagous Lepidoptera and expressed as recombinant proteins in Escherichia coli. Recombinant RBCLs were compared among each other along with casein and native Rubisco as proteinaceous substrates for measuring total midgut protease activities of fourth instar larvae of Helicoverpa armigera feeding on casein, Pieris brassicae feeding on cauliflower, and Antheraea assamensis feeding on Litsea monopetala and Persea bombycina. Cognate rRBCL (from the pertinent host plant species) substrates performed similar to noncognate rRBCL reflecting the conserved nature of encoding genes and the versatile use of these recombinant proteins. Casein and recombinant RBCL generally outperformed native Rubisco as substrates, except where inclusion of a reducing agent in the enzyme assay likely unfolded the plant proteins. Levels of total midgut protease activities detected in A. assamensis larvae feeding on two primary host species were similar, suggesting that the suite(s) of digestive enzymes in these insects could hydrolyze a plant protein efficiently. Protease activities detected in the presence of protease inhibitors and the reducing agent dithiothreitol (DTT) suggested that recombinant RBCL was a suitable protein substrate for studying insect proteases using in vitro enzyme assays and substrate zymography.

Musculoskeletal symptoms and orthopaedic complications in pregnancy: pathophysiology, diagnostic approaches and modern management.

Low back pain is a common musculoskeletal symptom in pregnancy that can present as lumbar pain or pelvic girdle pain, with significant physical and psychosocial implications. Pelvic girdle pain is more prevalent and results in greater disability than lumbar pain. It is possible to distinguish between these two conditions from a detailed history based on the site of the pain, its intensity, disability and pain provocation tests. Management of low back pain in pregnancy is conservative, with physical exercise for lumbar pain and minimising activities that exacerbate pain, analgesics and bed rest for pelvic girdle pain, as well as avoiding abduction beyond the pain-free zone in labour. There is evidence that stabilising exercises in patients with pelvic girdle pain postpartum have a beneficial effect. Other treatment modalities that have been shown to be safe and effective include pelvic belts, transcutaneous electrical nerve stimulation, spinal manipulative therapy, acupuncture and complementary therapy with yoga. Other orthopaedic complications in pregnancy such as carpal tunnel syndrome, pubic symphysis rupture, transient osteoporosis and osteonecrosis are usually self-limiting with a satisfactory outcome. However, a lack of awareness and failure to recognise these complications can result in long-term morbidity. Knowledge of the preoperative diagnostic investigations, surgical approaches and intraoperative positioning of the mother to avoid gravid uterus compression is vital in orthopaedic emergencies such as lumbar disc herniation, cauda equina syndrome, fractures and acute compartment syndrome of the lower limb to ensure a safe maternal and fetal outcome and to prevent serious disability. Pregnancy is not contraindicated in women with pre-existing orthopaedic complications such as kyphoscoliosis and total hip arthroplasty as there is no evidence to suggest increased maternal or fetal risks.

Comparative Evaluation and Correlation of Periodontal Status With Inflammatory Markers in Pregnant Women With or Without Chronic Periodontitis: A Clinico-Hematological Study.

Background The research delves into the intricate relationship between periodontal health and specific blood biomarkers in pregnant women during their second trimester. It specifically focuses on the levels of interleukin-6 (IL-6), lactate dehydrogenase (LDH), and C-reactive protein (CRP) in those suffering from chronic periodontitis compared to healthy controls. Methodology A detailed approach was taken involving 60 pregnant women categorized into two groups based on the presence or absence of chronic periodontitis. Out of 60 pregnant women, 30 had chronic periodontitis, while the other 30 served as controls selected from the regular patient population of the college. The study utilized blood sample analysis and advanced statistical tools for data analysis, ensuring precise and reliable results. Levels of IL-6, LDH, and CRP in those suffering from chronic periodontitis compared to healthy controls were checked. Results The findings revealed a notable variance in IL-6, LDH, and CRP levels between the two groups. Women with chronic periodontitis exhibited significantly higher levels of these biomarkers. The statistical analysis reinforced the validity of these differences, highlighting their significance. Conclusions The study underscored a clear link between higher levels of IL-6, LDH, and CRP and the presence of chronic periodontitis in pregnant women. These biomarkers emerge as potential indicators for early detection and monitoring of periodontal health in this demographic.

Reinforcement of Teeth Having Reenacted Perforating Internal Resorption Cavities After Repair Using Different Calcium Silicate-based Cements and Backfilling Materials: An In vitro Study.

To evaluate the fracture resistance (FR) of the teeth having reenacted perforating internal resorption cavities repaired by distinctive calcium silicate-based cements (CSCs) specifically: Endocem MTA, Biodentine, NeoMTA Plus, and backfilling materials. Ninety-six freshly extracted human mandibular premolar teeth were selected. Twelve roots were used as the negative control group. Rotary files were used to complete the final irrigation and root canal preparation on the remaining teeth. Following that, burs were used to make standardized internal resorption chambers in the middle part of the roots. Twelve of these samples were used as positive control samples. The remaining 72 root canals were obturated in the apical 4 mm using a single-cone approach, and they were separated into 6 groups based on the CSCs used to fill voids and the materials used as backfilling. Group 1: Endocem MTA (resorption) + Endocem MTA (coronal), Group 2: Endocem MTA (resorption) + Gutta-percha/sealer (coronal), Group 3: Biodentine (resorption) + Biodentine (coronal), Group 4: Biodentine (resorption) + Gutta-percha/sealer (coronal), Group 5: NeoMTA Plus (resorption) + NeoMTA Plus (coronal), and Group 6: NeoMTA Plus (resorption) + Gutta-percha/sealer (coronal). Specimens were inserted in acrylic resin and then subjected to fracture testing. Fracture strength tests were performed using a Universal Testing Machine. The force was employed vertically with a consistent speed of 1 mm/minute. The results were analyzed with Variance and Bonferrini tests at P < 0.005. The mean force of fracture values were 447.00, 201.25, 318.75, 187.50, 596.58, 258.75, 347.50, and 298.75 N for Group 1, 2, 3, 4, 5, 6, 7, and 8, respectively. "There was a significant difference (P < 0.001) between the experimental groups and the control group". Group 5 showed the highest FR as compared to other groups. Backfilling with CSCs appears to be a better material than a gutta-percha/sealer combination. Neo MTA plus furthermore appeared the highest fracture-resistant material, while Biodentine + Gutta percha/sealer showed the least FR.

Mechanical Properties of 3D Printed Orthodontic Aligners Produced by Different Commercially Available Printers - An In-Vitro Study.

The aim of this study was to compare the mechanical properties of orthodontic aligners among different commercially available 3D printing devices. Three different 3D printers were included in this study (Formlabs Form 2 3D printer; Moonray S100 printer (Sprintray, Los Angeles, CA, USA); Eden500V Stratasys 3D Printers were used to prepare orthodontic aligners with dental. The central incisors of each aligner were cut, prepared, and evaluated in terms of Martens-Hardness (HM), indentation-modulus (EIT), and elastic-index (ηIT) as per ISO14577-1:2002. Post hoc pairwise comparisons indicated no significant difference in Martens-Hardness (HM), indentation-modulus (EIT), and elastic-index (ηIT) properties in any group. Under the limitations of this study, it may be concluded that the mechanical properties of 3D-printed orthodontic aligners are dependent on the 3D printer used, and thus, differences in their clinical efficacy are anticipated.

Rapid survey for assessing effective cataract surgical coverage (eCSC) and effective refractive error coverage (eREC)-Novel indicators of universal eye health.

PURPOSE: As per the recent World Health Organization estimates, approximately 2.2 billion people have near and distance vision impairment (VI) globally, and out of this almost 50% is avoidable. METHODS: The Rapid Assessment of Avoidable Visual Impairment survey was a cross-sectional study conducted in September 2021, using cluster random sampling in 42 clusters with a cluster size of 140, giving a total of 6000 participants. Two teams comprising of trained optometrists and social workers conducted the ocular examination which included unaided, pinhole, and aided visual acuity assessments followed by examination of the anterior segment and lens. Distance visual acuity was measured using simplified tumbling "E" charts of different sizes for VA of 6/12, 6/18, and 6/60. The lens assessment was done in an un-dilated pupil with torch light by the optometrist. RESULTS: Overall, 6520 individuals aged 6 years and above were enumerated, of whom 5440 (83.4%) were examined. The response rate for examination was better among females (93.1%) than males (73.9%), and it decreased from 93.8% in the age group 6-15 years to 77.1% in the 45+ age group. The prevalence of blindness and VI were 0.18% (95% CI: 0.06-0.29) and 4.19% (95%CI: 3.65-4.72), respectively. The major causes of VI in all age groups were uncorrected refractive error (65.4%), cataract (23.7%), cataract surgical complications (2.6%), corneal opacity (0.4%), and other posterior segment diseases (7.5%). The effective cataract surgical coverage (eCSC) was 61.8%, effective refractive error coverage (eREC) for distance vision was 59.8%, and eREC for near vision was 47.0%. CONCLUSION: The RAAVI methodology is suitable to measure effective coverage in the general population, both for baseline measurement and periodic monitoring. The 2030 targets for the surveyed district are 90% eCSC and 100% eREC. Such exercises need to be conducted in each district of the country to determine the baseline and target values of effective coverage.

A Comparative Evaluation of Prosthetic and Biological Outcome as Influenced by Two Different Implant Restorative Materials (Porcelain Fused to Metal and Monolith Zirconia): A Prospective, Cross-arch Study.

OBJECTIVE: To investigate the prosthetic parameters, clinical indices, crestal bone levels, and inflammatory biomarkers in peri-implant crevicular fluid as influenced by two different implant restorative materials i.e., metal ceramic and monolithic zirconia at baseline, 1 Year and 2 Years. MATERIALS AND METHODS: Twenty patients with bilateral implants placed in the same arch were selected. Monolithic zirconia (4Y-PSZ) crown was placed on one side whereas a metal ceramic (M C) crown was inserted on the contralateral side after randomization. Interproximal marginal bone level (MBL), clinical parameters, MMP-8 levels in PICF, and prosthetic characteristics (as determined by modified USPHS criteria) were evaluated at baseline, 1-year, and 2-year follow-ups. Data were descriptively examined. The results were evaluated using the Chi-Square Test, ANOVA, and student t-test. At p < .05., statistical significance was determined. RESULTS: Twenty MC crowns and twenty Mono-ZrO2 crowns were delivered. A 100% survival of the implants and the prosthetic crowns was achieved across all patients with no instances of failure noted throughout the two-year follow-up period. The periodontal changes observed in the participants were analysed and demonstrated statistically insignificant alterations. Prosthetic alterations were assessed according to USPHS criteria, revealing minor ceramic chippings and instances of screw loosening within the MC group during both the 1- and 2-year follow-up periods. These incidents were collectively categorized as technical issues. Regarding anatomical form and color match to the surrounding dentition, the Mono- ZrO2 crowns obtained much lower evaluations when compared to the M-C crowns. However, when evaluating the loss of marginal bone and level of inflammatory markers there were no discernible variations between the groups. CONCLUSIONS: The null hypothesis that there is no similarity in the survival rates and interactions at the peri-implant interface between the two types of restorations was rejected. Both monolithic zirconia and metal ceramic crowns demonstrated no statistical differences across all parameters examined in the present prospective investigation.

Effective cataract surgical coverage in India: Evidence from 31 districts.

BACKGROUND: Effective Cataract Surgical Coverage (eCSC) is a core outcomes domain indicator to assess accessibility and quality of eye care services with limited available information. PURPOSE: To generate baseline estimates of eCSC for India. METHODS: We performed the analysis of data pooled from Rapid Assessment of Avoidable Blindness surveys conducted in 31 districts of India during 2015-2019 among persons aged 50+ years. eCSC was calculated at various thresholds, the primary being operable cataract at best corrected visual acuity <6/12, good outcome at presenting visual acuity of 6/12. RESULTS: Age-sex standardized and weighed eCSC in India was 36.7% (95% CI: 33.6, 39.9), and cataract surgical coverage (CSC) was 57.3% (95% CI: 53.3, 61.2), a relative quality gap in cataract surgery being 36.0%. eCSC in males was higher at 38.0% than females (35.6%). eCSC increased with education from 31.0% in illiterate participants to 59.7% in class 10 educated. On multivariate analysis, rural setting, increasing age, and residence in eastern or northeastern zones of India continued to be associated with poor/worse eCSC, while female gender was associated with higher eCSC. District-wide variations in eCSC were observed. CONCLUSION: Developmental factors have an important bearing on eCSC in India. Geographical variations point toward the need for targeted, locally relevant strategies.

IMPETUS Stroke: Assessment of hospital infrastructure and workflow for implementation of uniform stroke care pathway in India.

BACKGROUND: India accounts for 13.3% of global disability-adjusted life years (DALYs) lost due to stroke with a relatively younger age of onset compared to the Western population. In India's public healthcare system, many stroke patients seek care at tertiary-level government-funded medical colleges where an optimal level of stroke care is expected. However, there are no studies from India that have assessed the quality of stroke care, including infrastructure, imaging facilities, or the availability of stroke care units in medical colleges. AIM: This study aimed to understand the existing protocols and management of acute stroke care across 22 medical colleges in India, as part of the baseline assessment of the ongoing IMPETUS stroke study. METHODS: A semi-structured quantitative pre-tested questionnaire, developed based on review of literature and expert discussion, was mailed to 22 participating sites of the IMPETUS stroke study. The questionnaire assessed comprehensively all components of stroke care, including human resources, emergency system, in-hospital care, and secondary prevention. A descriptive analysis of their status was undertaken. RESULTS: In the emergency services, limited stroke helpline numbers, 3/22 (14%); prenotification system, 5/22 (23%); and stroke-trained physicians were available, 6/22 (27%). One-third of hospitals did not have on-call neurologists. Although non-contrast computed tomography (NCCT) was always available, 39% of hospitals were not doing computed tomography (CT) angiography and 13/22 (59%) were not doing magnetic resonance imaging (MRI) after routine working hours. Intravenous thrombolysis was being done in 20/22 (91%) hospitals, but 36% of hospitals did not provide it free of cost. Endovascular therapy was available only in 6/22 (27%) hospitals. The study highlighted the scarcity of multidisciplinary stroke teams, 8/22 (36%), and stroke units, 7/22 (32%). Lifesaving surgeries like hematoma evacuation, 11/22 (50%), and decompressive craniectomy, 9/22 (41%), were performed in limited numbers. The availability of occupational therapists, speech therapists, and cognitive rehabilitation was minimal. CONCLUSION: This study highlighted the current status of acute stroke management in publicly funded tertiary care hospitals. Lack of prenotification, limited number of stroke-trained physicians and neurosurgeons, relatively lesser provision of free thrombolytic agents, limited stroke units, and lack of rehabilitation services are areas needing urgent attention by policymakers and creation of sustainable education models for uniform stroke care by medical professionals across the country.

Zinc supplements for treating thalassaemia and sickle cell disease.

BACKGROUND: Haemoglobinopathies, inherited disorders of haemoglobin synthesis (thalassaemia) or structure (sickle cell disease), are responsible for significant morbidity and mortality throughout the world. The WHO estimates that, globally, 5% of adults are carriers of a haemoglobin condition, 2.9% are carriers of thalassaemia and 2.3% are carriers of sickle cell disease. Carriers are found worldwide as a result of migration of various ethnic groups to different regions of the world. Zinc is an easily available supplement and intervention programs have been carried out to prevent deficiency in people with thalassaemia or sickle cell anaemia. It is important to evaluate the role of zinc supplementation in the treatment of thalassaemia and sickle cell anaemia to reduce deaths due to complications. OBJECTIVES: To assess the effect of zinc supplementation in the treatment of thalassaemia and sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 01 February 2013. SELECTION CRITERIA: Randomised, placebo-controlled trials of zinc supplements for treating thalassaemia or sickle cell disease administered at least once a week for at least a month. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and wrote the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate. MAIN RESULTS: We identified nine trials for inclusion with all nine contributing outcome data. Two trials reported on people with thalassaemia (n = 152) and seven on sickle cell anaemia (n = 307).In people with thalassaemia, in one trial, the serum zinc level value showed no difference between the zinc supplemented group and the control group, mean difference 47.40 (95% confidence interval -12.95 to 107.99). Regarding anthropometry, in one trial, height velocity was significantly increased in patients who received zinc supplementation for one to seven years duration, mean difference 3.37 (95% confidence interval 2.36 to 4.38) (total number of participants = 26). In one trial, however, there was no difference in body mass index between treatment groups.Zinc acetate supplementation for three months (in one trial) and one year (in two trials) (total number of participants = 71) was noted to increase the serum zinc level significantly in patients with sickle cell anaemia, mean difference 14.90 (95% confidence interval 6.94 to 22.86) and 20.25 (95% confidence interval 11.73 to 28.77) respectively. There was no significant difference in haemoglobin level between intervention and control groups, at either three months (one trial) or one year (one trial), mean difference 0.06 (95% confidence interval -0.84 to 0.96) and mean difference -0.07 (95% confidence interval -1.40 to 1.26) respectively. Regarding anthropometry, one trial showed no significant changes in body mass index or weight after one year of zinc acetate supplementation. In patients with sickle cell disease, the total number of sickle cell crises at one year were significantly decreased in the zinc sulphate supplemented group as compared to controls, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (total participants 130), but not in zinc acetate group, mean difference 1.54 (95% confidence interval -2.01 to 5.09) (total participants 22). In one trial at three months and another at one year, the total number of clinical infections were significantly decreased in the zinc supplemented group as compared to controls, mean difference 0.05 (95% confidence interval 0.01 - 0.43) (total number of participants = 36), and mean difference -7.64 (95% confidence interval -10.89 to -4.39) (total number of participants = 21) respectively. AUTHORS' CONCLUSIONS: According to the results, there is no evidence from randomised controlled trials to indicate any benefit of zinc supplementation with regards to serum zinc level in patients with thalassaemia. However, height velocity was noted to increase among those who received this intervention.There is mixed evidence on the benefit of using zinc supplementation in people with sickle cell disease. For instance, there is evidence that zinc supplementation for one year increased the serum zinc levels in patients with sickle cell disease. However, though serum zinc level was raised in patients receiving zinc supplementation, haemoglobin level and anthropometry measurements were not significantly different between groups. Evidence of benefit is seen with the reduction in the number of sickle cell crises among sickle cell patients who received one year of zinc sulphate supplementation and with the reduction in the total number of clinical infections among sickle cell patients who received zinc supplementation for both three months and for one year.The conclusion is based on the data from a small group of trials,which were generally of good quality, with a low risk of bias. The authors recommend that more trials on zinc supplementation in thalassaemia and sickle cell disease be conducted given that the literature has shown the benefits of zinc in these types of diseases.

Rapid Assessment of Avoidable Visual Impairment in Two Coastal Districts of Eastern India for Determining Effective Coverage: A Cross-Sectional Study.

Purpose: To measure the prevalence and causes of visual impairment (VI) among the 40+ age population in two coastal districts of India and to determine the levels of effective cataract surgical coverage (eCSC) and effective refractive error coverage (eREC) in the study population. Methods: A cross-sectional study was done on 4200 people chosen using cluster sampling in two coastal districts of Odisha, an eastern state in India. A team consisting of trained optometrists and social workers conducted the ocular examination which included unaided, pinhole, and aided visual acuity assessments followed by examination of the anterior segment and lens. Results: Overall, 3745 (89.2%) participants were examined from 60 study clusters, 30 in each district. Among those examined, 1677 (44.8%) were men, 2554 (68.2%) were educated and number? (17.8%) used distance spectacles during the survey. The prevalence of VI adjusted for age and gender was 12.77% (95% CI 11.85-13.69%). Multiple logistic regression showed that older age (OR 3.1; 95% CI 2.0-4.7) and urban residence (OR 1.2; 95% CI 1.0-1.6) were associated with VI. Being educated (OR 0.4; 95% CI 0.3-0.6) and using glasses (OR 0.3; 95% CI 0.5-0.2) were found to provide protection; therefore, resulting in lower instances of VI. Cataract (62.7%) and uncorrected refractive errors (27.1%) were the two main causes of VI. The eCSC was 35.1%, the eREC for distance was 40.0%, and the eREC for near was 35.7%. Conclusion: VI remains a challenge in Odisha, as the prevalence is high and the surgical coverage is poor. Nearly 90% of VI is avoidable indicating that targeted interventions are required to address this problem.

TERRA R-loops connect and protect sister telomeres in mitosis.

Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase tankyrase to telomeres. In human aged cells, due to insufficient recruitment of TRF1/tankyrase to shortened telomeres, sisters remain cohered in mitosis. This persistent cohesion plays a protective role, but the mechanism by which sisters remain cohered is not well understood. Here we show that telomere repeat-containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43, is required for repression of TERRA R-loops. Persistent telomere cohesion in C19orf43-depleted cells is counteracted by RNaseH1, confirming that RNA-DNA hybrids hold sisters together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduces DNA damage and delays replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop-repressing machinery permits a controlled onset of senescence.