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.

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.

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.

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.

Current Status of Trachoma Among Underserved Population of India: Results from the National Trachoma Rapid Assessment Survey 2014-17.

PURPOSE: To determine the burden of trachoma and its related risk factors among the underserved population of sixteen states/union territories (UTs) in India. METHODS: Trachoma rapid assessment (TRA) was conducted in seventeen Enumeration Units (EUs) spanning sixteen states/UTs in India according to standard WHO guidelines. A total of ten clusters were selected in each EU and 50 children aged 1-9 years were assessed clinically for signs of active trachoma and facial cleanliness in each cluster. Additionally, all adults aged 15 years and above in the same households were examined for evidence of trachomatous trichiasis (TT) and corneal opacity. Environmental risk factors contributing to trachoma were also noted in all households. RESULTS: Out of 766 districts in India, seventeen EUs were selected for TRA depending on evidence of socio-developmental indicators like poverty and suboptimal access to water, sanitation, and healthcare facilities. The total population of the selected clusters was 21,774 in the 17 EUs. Overall, 104 of 8807 children (1.2%; CI: 0.9-1.4) had evidence of follicular or inflammatory stages of trachoma. Nearly 16.6% (CI:15.8-17.4) children were noted to have unclean faces in the 170 clusters. Trichiasis was noted in 19 adults (2.1 per 1000; CI:1.2-3.2 per 1000). Environmental sanitation was found to be unsatisfactory in two-thirds (67.8%) of the surveyed households in the clusters mainly due to improper garbage disposal. CONCLUSION: Active trachoma was not a public health problem in any of the EUs surveyed. However, burden of TT among adults was found to be above 0.2% in two EUs; hence, further public health interventions like trichiasis surgery were recommended.

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.

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.

ISP good clinical practice recommendations for gum care.

Oral health is vital for the general well-being, overall body health and the quality of life throughout our lifetime. Most of the oral diseases and conditions are largely related to the maintenance of oral hygiene, lacking that people suffer from diverse oral diseases at different times in their life. With greater life expectancy, the individuals have teeth involved with periodontal diseases that would not only require professional care but also home gum care for them to last a lifetime. Indian Society of Periodontology (ISP) has recognized the need for systematic documents to update everyday clinical practice of general dental practitioners and have provided evidence-based consensus documents, namely good clinical practice recommendations from time to time to raise the oral health-related awareness and standards of oral healthcare delivery across the country. The current set of clinical practice recommendations focused to "Gum Care for All", is aimed at emphasizing and enhancing the awareness regarding oral health promotion, maintenance, and disease prevention. Twenty-five subject matter experts from across the nation, prepared these recommendations after a thorough literature review and group discussions. The document has been prepared in three distinct sections, namely pretherapeutic, therapeutic, and post therapeutic, to provide guidance during the respective phases of patient management and may serve as a quick and concise reference to the readers. The guidelines shall provide the distinct definitions, signs and symptoms, treatment required; recall visit specifications for plausible clinical case situations, home care advice regarding maintenance of oral hygiene including information on brushing technique, care and change of brush, use of interdental aids, and mouthwashes, etc. The document should advocate and guide the combined efforts of general dentists, and the population at large toward an empowered, evidence based, integrated, and comprehensive oral health care, which shall enhance the healthful functioning and longevity of the dentition and general health of the individual.

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively.

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

Chloroplasts evolved an additional layer of translational regulation based on non-AUG start codons for proteins with different turnover rates.

Chloroplasts have evolved from photosynthetic cyanobacteria-like progenitors through endosymbiosis. The chloroplasts of present-day land plants have their own transcription and translation systems that show several similarities with prokaryotic organisms. A remarkable feature of the chloroplast translation system is the use of non-AUG start codons in the protein synthesis of certain genes that are evolutionarily conserved from Algae to angiosperms. However, the biological significance of such use of non-AUG codons is not fully understood. The present study was undertaken to unravel the significance of non-AUG start codons in vivo using the chloroplast genetic engineering approach. For this purpose, stable transplastomic tobacco plants expressing a reporter gene i.e. uidA (GUS) under four different start codons (AUG/UUG/GUG/CUG) were generated and ß-glucuronidase (GUS) expression was compared. To investigate further the role of promoter sequences proximal to the start codon, uidA was expressed under two different chloroplast gene promoters psbA and psbC that use AUG and a non-AUG (GUG) start codons, respectively, and also showed significant differences in the DNA sequence surrounding the start codon. Further, to delineate the role of RNA editing that creates AUG start codon by editing non-AUG codons, if any, which is another important feature of the chloroplast transcription and translation system, transcripts were sequenced. In addition, a proteomic approach was used to identify the translation initiation site(s) of GUS and the N-terminal amino acid encoded when expressed under different non-AUG start codons. The results showed that chloroplasts use non-AUG start codons in combination with the translation initiation site as an additional layer of gene regulation to over-express proteins that are required at high levels due to their high rates of turnover.

Single-virus tracking reveals variant SARS-CoV-2 spike proteins induce ACE2-independent membrane interactions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a global health crisis after its emergence in 2019. Replication of the virus is initiated by binding of the viral spike (S) protein to human angiotensin-converting enzyme 2 (ACE2) on the target cell surface. Mutations acquired by SARS-CoV-2 S variants likely influence virus-target cell interaction. Here, using single-virus tracking to capture these initial steps, we observe how viruses carrying variant S interact with target cells. Specificity for ACE2 occurs for viruses with the reference sequence or D614G mutation. Analysis of the Alpha, Beta, and Delta SARS-CoV-2 variant S proteins revealed a progressive altered cell interaction with a reduced dependence on ACE2. Notably, the Delta variant S affinity was independent of ACE2. These enhanced interactions may account for the increased transmissibility of variants. Knowledge of how mutations influence cell interaction is essential for vaccine development against emerging variants of SARS-CoV-2.

COVID tongue.

Since the advent of the coronavirus disease (COVID-19) infection, this highly infectious virus has spread worldwide infecting millions of people. Not only it has affected the pulmonary function of the body, leading to difficulty in breathing, but at the same time, an array of other systemic infections which may or may not be directly due to coronavirus infection, due to an absent established relationship. The mucocutaneous manifestations seen in COVID-19 infection include depapillation of the tongue, lesions seen on alveolar mucosa, gingiva, buccal mucosa, dysgeusia, and dry mouth. This case report highlights the effect of COVID-19 on the tongue also known as COVID tongue seen as depapillation of the tongue surface. Due to the absence of long-term studies and time-limited research, a direct relationship between COVID-19 and the systemic manifestation is not yet established. More research has to be done in this direction, to chart out the exact etiology of these systemic infections.

Study Protocol: IMPETUS: Implementing a Uniform Stroke Care Pathway in Medical Colleges of India: IMPETUS Stroke.

Introduction: In India, a national program for stroke (national programme for the control of cardiovascular diseases, diabetes, cancer, and stroke) and stroke management guidelines exist. Its successful implementation would need an organized system of stroke care in practice. However, many challenges exist including lack of awareness, prehospital notification systems, stroke ready hospitals, infrastructural weaknesses, and rehabilitation. We present here a protocol to investigate the feasibility and fidelity of implementing a uniform stroke care pathway in medical colleges of India. Methods and Analysis: This is a multicentric, prospective, multiphase, mixed-method, quasi-experimental implementation study intended to examine the changes in a select set of stroke care-related indicators over time within the sites exposed to the same implementation strategy. We shall conduct process evaluation of the implementation process as well as evaluate the effect of the implementation strategy using the interrupted time series design. During implementation phase, education and training about standard stroke care pathway will be provided to all stakeholders of implementing sites. Patient-level outcomes in the form of modified Rankin Scale score will be collected for all consecutive patients throughout the study. Process evaluation outcomes will be collected and reported in the form of various stroke care indicators. We will report level and trend changes in various indicators during the three study phases. Discussion: Acute stroke requires timely detection, management, and secondary prevention. Implementation of the uniform stroke care pathway is a unique opportunity to promote the requirements of homogenous stroke care in medical colleges of India.

A two-step mechanism governing PARP1-DNA retention by PARP inhibitors.

PARP inhibitors (PARPi) have emerged as promising cancer therapeutics capable of targeting specific DNA repair pathways, but their mechanism of action with respect to PARP1-DNA retention remains unclear. Here, we developed single-molecule assays to directly monitor the retention of PARP1 on DNA lesions in real time. Our study reveals a two-step mechanism by which PARPi modulate the retention of PARP1 on DNA lesions, consisting of a primary step of catalytic inhibition via binding competition with NAD+ followed by an allosteric modulation of bound PARPi. While clinically relevant PARPi exhibit distinct allosteric modulation activities that can either increase retention of PARP1 on DNA or induce its release, their retention potencies are predominantly determined by their ability to outcompete NAD+ binding. These findings provide a mechanistic basis for improved PARPi selection according to their characteristic activities and enable further development of more potent inhibitors.

Current status of trachoma in India: Results from the National Trachoma Prevalence Survey.

Purpose: In the mid-twentieth century, trachoma was endemic in the northwestern states of India. We aimed to generate recent estimates of prevalence of trachomatous inflammation, follicular (TF) and trachomatous trichiasis (TT) in ten suspected-endemic districts across seven previously hyper-endemic states and union territories for trachoma in India including Delhi, Rajasthan, Haryana, Punjab, Gujarat, Uttarakhand and the Andaman and Nicobar Islands. Methods: Population-based prevalence surveys were undertaken in 10 districts. In each of those districts, two-stage cluster sampling was used to select a sample of 2000 children aged 1-9 years and all adults aged ≥15 years in the enumerated households from a total of 20 clusters per district. Consenting eligible participants were examined for trachoma by trained ophthalmologists using the World Health Organization's simplified grading system. Data were analyzed at the district level. Results: A total of 13,802 households were surveyed in which 19,662 children were examined for TF and 44,135 adults aged ≥15 years were examined for TT. District-level TF prevalence in 1-9-year-olds ranged from 0.1% in Bikaner (95% CI: 0.01-0.3) to 2.1% in Dholpur (95% CI: 1.6-2.8) and that of trichiasis ranged from 0.7 per 1000 in Pauri Garhwal (95% CI: 0.01-1.4) to 22.1 per 1000 (95% CI: 15.8-28.4) in Car Nicobar. In four districts (Car Nicobar, Dholpur, Hoshiarpur, Tonk), trichiasis prevalence in adults aged ≥15 years was ≥0.2%. Conclusion: TF was not a public health problem in any of the districts surveyed; thus, antibiotic mass drug administration is not needed. However, TT among adults was found to be above 0.2% in four districts; thus, further trichiasis surgery interventions at the public health level are warranted to achieve elimination. These findings will facilitate planning for elimination of trachoma as a public health problem in India.