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The prognosis of root-filled teeth depends not only on a successful root canal treatment but also on the restorative prognosis. This critical review discusses the advantages and limitations of various methodologies used to assess the load capacity or clinical survivability of root-filled teeth and restorations. These methods include static loading, cyclic loading, finite element analysis and randomized clinical trials. In vitro research is valuable for preclinical screening of new dental materials or restorative modalities. It also can assist investigators or industry to decide whether further clinical trials are justified. It is important that these models present high precision and accuracy, be reproducible, and present adequate outcomes. Although in vitro models can reduce confounding by controlling important variables, the lack of clinical validation (accuracy) is a downside that has not been properly addressed. Most importantly, many in vitro studies did not explore the mechanisms of failure and their results are limited to rank different materials or treatment modalities according to the maximum load capacity. An extensive number of randomized clinical trials have also been published in the last years. These trials have provided valuable insight on the survivability of the root-filled tooth answering numerous clinical questions. However, trials can also be affected by the selected outcome and by intrinsic and extrinsic biases. For example, selection bias, loss to follow-up and confounding. In the clinical scenario, hypothesis-based studies are preferred over observational and retrospective studies. It is recommended that hypothesis-based studies minimize error and bias during the design phase.

Objective. To assess trends in incident cases, and case fatality rate between first and second waves, we analyzed programmatic COVID-19 data from Pune city, an epicenter of COVID-19 cases in India. Method. The trends of incident cases, time-to-death, and case fatality rate (CFR) were analysed. In addition, Poisson regression models adjusted for age and gender were used to determine the independent effect of pandemic waves on mortality. Results. Of 465,192 COVID-19 cases, 162,182 (35%) were reported in the first wave, and 4,146 (2.5%) died among them; second wave reported 275,493 (59%) cases and 3184 (1.1%) deaths (p

Similar to other dental specialties, there are many clinical procedures in restorative dentistry that may or may not be supported by good evidence. Thus, the effectiveness of these procedures is uncertain. The aim of this paper is to reduce this knowledge gap by critically inspecting selective procedures in restorative dentistry and exploring if these well-established or widely advocated treatment modalities are necessary for improving treatment outcomes based on the best available evidence.A MEDLINE search was conducted to identify research on selective procedures while focusing on clinical trials and systematic reviews. Due to their practical relevance in the decision-making process, cost-effectiveness analyses were also included.Mixed results were identified regarding the included interventions. Some procedures had adequate evidence supporting them while others were mostly based on beliefs.A critical review of the available literature indicates that some common restorative procedures lack adequate support from high-quality research evidence.This paper attempts to highlight the need to critically examine the scientific validity of traditional knowledge and techniques through the context of current research evidence. This will not only help generate consensus between educators, clinicians, and researchers regarding restorative procedures but will also lead to improved patient care and outcomes.

PurposeBreast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25%) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are however predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in IndiaMethodsUsing a multi-gene NGS (next-generation sequencing) panel of 26 ACMG recommended genes associated with inherited cancers.ResultsIn our study cohort of 193 TNBC patients, we identified 57 pathogenic mutations of which BRCA1 (71.93%) and BRCA2 (14.03%) were most commonly mutated. Additionally, 8 pathogenic mutations were identified in non-BRCA genes associated with the HR pathway. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100K indicated that the novel mutations were unique. Furthermore, we identified 48 variants of uncertain significance (VUS) (24.9%).ConclusionsOur study confirms the major proportion of mutations in BRCA1/2 genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Additionally, large scale studies are also warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.

Promoter proximal pausing (PPP) of RNA polymerase II has emerged as a crucial rate-limiting step in the regulation of gene expression. Regulation of PPP is brought about by complexes 7SK snRNP, P-TEFb (Cdk9/cycT), and the negative elongation factor (NELF), which are highly conserved from Drosophila to humans. Here, we show that RNAi-mediated depletion of bin3 or Hexim of the 7SK snRNP complex or depletion of individual components of the NELF complex enhances Yki-driven growth, leading to neoplastic transformation of Drosophila wing imaginal discs. We also show that increased CDK9 expression cooperates with Yki in driving neoplastic growth. Interestingly, overexpression of CDK9 on its own or in the background of depletion of one of the components of 7SK snRNP or the NELF complex necessarily, and specifically, needed Yki overexpression to cause tumorous growth. Genome-wide gene expression analyses suggested that deregulation of protein homeostasis is associated with tumorous growth of wing imaginal discs. As both Fat/Hippo/Yki pathway and PPP are highly conserved, our observations may provide insights into mechanisms of oncogenic function of YAP—the ortholog of Yki in humans.

Genetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: the Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth during development and cancer in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR. Resources reported here are available freely for anyone to use.

BackgroundPrecise prediction of residual tumour size following neoadjuvant systemic therapy for breast cancer is crucial in assessing response and surgical decision making. Our study is aimed at assessing the performance of conventional imaging modalities like ultrasound and mammography in predicting the residual tumour size after neoadjuvant systemic therapy and in evaluating the impact of imaging on the surgical outcomes.MethodsWe retrospectively compared the tumour size measured by ultrasonography and mammography and the residual tumour size on final histopathology in 109 patients. Concordance was defined as a size difference within 25% of the histopathology size. We also looked at the distribution of concordance between different T status and molecular subtypes, accuracy of USG in predicting pathological complete response and axillary lymph nodal metastasis and also surgical outcomes in the discordant cases.ResultsThe concordance rates of mammography and ultrasonography were 68.2% and 52.3% respectively without statistically significant difference between the two modalities (p = 0.081). Combination of both the modalities had a concordance rate of 57.8%. Ultrasonography had accuracy of 81.7% for predicting pathological complete response and 79.8% for predicting axillary nodal metastasis. We did not identify any influence of histologic subtype on the associations between preoperative measurements and pathology size or the accuracy for detecting pathological complete response (p values 0.43 and 0.46 respectively). In 12 cases, the radiology-pathology discordance could have led to large excision volume surgeries. In the overall cohort, recurrence free survival and overall survival rates at median follow up of 19.1 month were 87.2% and 95.4% respectively.ConclusionsUltrasound and mammography showed moderate concordance with pathology for estimation of the residual tumour size without any significant difference in the performance between the two. Despite the moderate concordance, surgical outcomes were fairly well managed in the discordant cases with the oncoplastic surgical techniques. Our study highlights the usefulness of the cheaper and widely available conventional imaging modalities in the developing countries where the cost of treatment is to be contained.

IntroductionTherapeutic mammoplasty (TM) is a type of oncoplastic breast surgery (OBS) well suited to breast cancers in medium-large sized breasts with ptosis, and in some cases of large or multifocal/Multicentric (MF/MC) tumors. It includes contralateral symmetrisation. This report describes our experiences and outcomes of TM in breast cancer patients in a single institutional cohort in India.MethodsWe present data for 207 cases (194 breast cancer, 13 benign disease) who underwent TM as part of their primary treatment. All patients underwent surgery after careful analysis of feasibility by a multidisciplanary tumor board and patient counselling. We report the clinicopathological profiles, surgical and oncological outcomes, and patient related outcome measures (PROMs) with different TM surgical procedures.ResultsPatients were relatively young at a median age of 49 years with moderate-large breasts and grade II-III ptosis. Patients underwent simple (n=96), complex (n=79) or extreme TM (n=46). Low post-operative complication rates and good-excellent cosmetic scores were observed. With median follow-up of 26 months, 148 patients completed more than 1 year follow-up. The 1-year BREAST-Q PROMs revealed good-to-excellent scores for all types of therapeutic mammoplasty.ConclusionWe conclude that in a country where women present with large and locally advanced tumours, TM safely expands the indications for breast conservation surgery. PROMs scores show that this surgery is perceived to be physically and mentally satisfactory. With the popularization of this procedure, it is possible that more Indian patients with breast cancer will receive the benefits of breast conservation while maintaining their quality of life.

BackgroundThe recent second wave in India in April-May 2021 placed an unprecedented burden on the Indian health systems. However, limited data exist on the epidemiology of the COVID-19 pandemic from the first wave through the second wave in India. With detailed epidemiologic data, we aimed to assess trends in incident cases and case fatality, its risk between pandemic waves in Pune, an epicenter of COVID-19 cases in India, a country with the second-largest absolute burden worldwide.MethodsProgrammatic COVID-19 data from Pune city between the first wave (March 09th 2020-October 31st, 2020), maintenance phase (November 01st 2020-February 14th, 2021), the second wave (February 15th, 2021-May 31st, 2021) were assessed for trends of incident cases, time-to-death, and case fatality rate (CFR). In addition, Poisson regression models adjusted for age and gender were used to determine the independent effect of pandemic waves on mortality.ResultsOf 465,192 COVID-19 cases, 162,182 (35%) were reported in the first wave, and 4,146 (2.5%) died among them; Maintenance period registered 27,517 (6%) cases with 590 (2.1%) deaths; Second wave reported 275,493 (59%) cases and 3184 (1.1%) deaths (pInterpretationThe absolute burden of COVID-19 cases and deaths were more significant in the second wave in Pune, India; however, the CFR declined as the pandemic progressed. Nevertheless, investigating newer therapies and implementing mass vaccinations against COVID-19 are urgently needed.

Background: The recent second wave in India in April-May 2021 placed an unprecedented burden on the Indian health systems. With detailed epidemiologic data, we aimed to assess trends in incident cases and case fatality, its risk between pandemic waves in Pune, an epicenter of COVID-19 cases in India, a country with the second-largest absolute burden worldwide. Methods: Programmatic COVID-19 data from Pune city between the first wave (March 09th 2020-October 31st 2020), maintenance phase (November 01st 2020-February 14th 2021), the second wave (February 15th 2021-May 31st 2021) were assessed for trends of incident cases, time-to-death, and case fatality rate (CFR). In addition, Poisson regression models adjusted for age and gender were used to determine the independent effect of pandemic waves on mortality. Findings: Of 465,192 COVID-19 cases, 162,182 (35%) were reported in the first wave, and 4,146 (2.5%) died among them; Maintenance period registered 27,517 (6%) cases with 590 (2.1%) deaths; Second wave reported 275,493 (59%) cases and 3184 (1.1%) deaths (p

High resolution images and supplement information, images and tables of the MS: GENETICS-2020-303419

Promoter proximal pausing (PPP) of RNA Polymerase II has emerged as a crucial rate-limiting-step in the regulation of gene expression. Regulation of PPP is brought about by complexes 7SK snRNP, P-TEFb (Cdk9/cycT) and the Negative Elongation Factor (NELF) which are highly conserved from Drosophila to humans. Here we show that RNAi-mediated depletion of bin3 or Hexim of the 7SK snRNP complex or depletion of individual components of the NELF complex enhance Yki-driven growth leading to neoplastic transformation of Drosophila wing imaginal discs. We also show that increased CDK9 expression cooperates with Yki, in driving neoplastic growth. Interestingly, over-expression of CDK9 on its own or in the background of depletion of one of the components of 7SK snRNP or the NELF complex necessarily and specifically needed Yki over-expression to cause tumorous growth. Genome-wide gene expression analyses suggested that deregulation of protein homeostasis is associated with tumorous growth of wing imaginal discs. As both Fat/Hippo/Yki pathway and PPP are highly conserved, our observations may provide insights into mechanisms of oncogenic function of YAP, the orthologue of Yki in human.

Genetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: The Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR.

BACKGROUND: A suspicious occlusal caries lesion (SOCL) can be defined as a lesion with no cavitation and no radiographic radiolucency, but where caries is suspected. This study evaluated whether using a device changed: (1) the percentage of SOCLs that were opened surgically; and (2) among those SOCLs that were opened, the proportion that had penetrated into dentin. METHODS: Eighty-two dentists participated. In phase 1 of the study, dentists identified approximately 20 SOCLs, obtained patient consent, and recorded information about the lesion, treatment(s), and depth, if opened. Dentists were then randomized into one of three groups: no device, DIAGNOdent(®), and Spectra(®). In phase 2, dentists enrolled approximately 20 additional patients, and recorded the same phase 1 information, while using the assigned device to help make their treatment decisions. A mixed-model logistic regression was used to determine any differences after randomization in the proportion of lesions opened and, if opened, the proportion of lesions that penetrated into dentin. RESULTS: 1500 SOCLs were enrolled in each phase. There was no statistically significant difference in the change in proportion of lesions receiving invasive treatment from phase 1 to phase 2 across the three groups (p=0.33) or in the change in proportion of percent of opened lesions that extended into dentin (p=0.31). CONCLUSION: Caries detecting devices in the study did not change significantly dentists’ decisions to intervene or the accuracy of the intervention decision in predicting lesion penetration into dentin. PRACTICAL IMPLICATIONS: The caries detecting devices tested may not improve dentists’ clinical decision-making for SOCLs.