Experiences, Challenges, and Lessons Learned During Implementation of a Remote Monitoring Program for Home-Isolated COVID-19 Patients in Chennai, India.

During the early months of the COVID-19 pandemic in 2020, the majority of the identified COVID-19 patients in Chennai, a southern metropolitan city of India, presented as asymptomatic or with mild clinical illness. Providing facility-based care for these patients was not feasible in an overburdened health system. Thus, providing home-based clinical care for patients who were asymptomatic or with mild clinical illnesses was a viable solution. Because of the imminent possibility of worsening clinical conditions in home-isolated COVID-19 patients, continuous monitoring for red flag signs was essential. With growing evidence of the effectiveness of remote monitoring of patients, the Greater Chennai Corporation in partnership with the National Institute of Epidemiology conceptualized and implemented a remote monitoring program for home-isolated COVID-19 patients. The key steps used to develop the program were to (1) decentralize triage systems and establish a home-isolation protocol, (2) develop a remote monitoring platform and remote health care workforce, and (3) onboard patients and conduct remote hybrid monitoring. In this article, we share the pragmatic solutions, critical components of the systems and processes, lessons, and experiences in implementing a remote monitoring program for home-isolated COVID-19 patients in a large metropolitan setting.

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.

Discovery and pre-clinical characterization of a selective PI3Kδ inhibitor, LL-00071210 in rheumatoid arthritis.

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.

Epidemiology of COVID-19 and effect of public health interventions, Chennai, India, March-October 2020: an analysis of COVID-19 surveillance system.

OBJECTIVES: To describe the public health strategies and their effect in controlling the COVID-19 pandemic from March to October 2020 in Chennai, India. SETTING: Chennai, a densely populated metropolitan city in Southern India, was one of the five cities which contributed to more than half of the COVID-19 cases in India from March to May 2020. A comprehensive community-centric public health strategy was implemented for controlling COVID-19, including surveillance, testing, contact tracing, isolation and quarantine. In addition, there were different levels of restrictions between March and October 2020. PARTICIPANTS: We collected the deidentified line list of all the 192 450 COVID-19 cases reported from 17 March to 31 October 2020 in Chennai and their contacts for the analysis. We defined a COVID-19 case based on the real-time reverse transcriptase-PCR (RT-PCR) positive test conducted in one of the government-approved labs. OUTCOME MEASURES: The primary outcomes of interest were incidence of COVID-19 per million population, case fatality ratio (CFR), deaths per million, and the effective reproduction number (Rt). We also analysed the surveillance, testing, contact tracing and isolation indicators. RESULTS: Of the 192 450 RT-PCR confirmed COVID-19 cases reported in Chennai from 17 March to 31 October 2020, 114 889 (60%) were males. The highest incidence was 41 064 per million population among those 61-80 years. The incidence peaked during June 2020 at 5239 per million and declined to 3627 per million in October 2020. The city reported 3543 deaths, with a case fatality ratio of 1.8%. In March, Rt was 4.2, dropped below one in July and remained so until October, even with the relaxation of restrictions. CONCLUSION: The combination of public health strategies might have contributed to controlling the COVID-19 epidemic in a large, densely populated city in India. We recommend continuing the test-trace-isolate strategy and appropriate restrictions to prevent resurgence.

Secondary attack rate of COVID-19 among contacts and risk factors, Tamil Nadu, March-May 2020: a retrospective cohort study.

OBJECTIVE: To describe the characteristics of contacts of patients with COVID-19 case in terms of time, place and person, to calculate the secondary attack rate (SAR) and factors associated with COVID-19 infection among contacts. DESIGN: A retrospective cohort study SETTING AND PARTICIPANTS: Contacts of cases identified by the health department from 14 March 2020to 30 May 2020, in 9 of 38 administrative districts of Tamil Nadu. Significant proportion of cases attended a religious congregation. OUTCOME MEASURE: Attack rate among the contacts and factors associated with COVID-19 positivity. RESULTS: We listed 15 702 contacts of 931 primary cases. Of the contacts, 89% (n: 14 002) were tested for COVID-19. The overall SAR was 4% (599/14 002), with higher among the household contacts (13%) than the community contacts (1%). SAR among the contacts of primary cases with congregation exposure were 5 times higher than the contacts of non-congregation primary cases (10% vs 2%). Being a household contact of a primary case with congregation exposure had a fourfold increased risk of getting COVID-19 (relative risk (RR): 16.4; 95% CI: 13 to 20) than contact of primary case without congregation exposure. Among the symptomatic primary cases, household contacts of congregation primaries had higher RR than household contacts of other cases ((RR: 25.3; 95% CI: 10.2 to 63) vs (RR: 14.6; 95% CI: 5.7 to 37.7)). Among asymptomatic primary case, RR was increased among household contacts (RR: 16.5; 95% CI: 13.2 to 20.7) of congregation primaries compared with others. CONCLUSION: Our study showed an increase in disease transmission among household contacts than community contacts. Also, symptomatic primary cases and primary cases with exposure to the congregation had more secondary cases than others.

Surveillance for face mask compliance, Chennai, Tamil Nadu, India, October-December, 2020.

PURPOSE: Government of Tamil Nadu, India, mandated the face mask wearing in public places as one of the mitigation measures of COVID-19. We established a surveillance system for monitoring the face mask usage. This study aimed to estimate the proportion of the population who wear face masks appropriately (covering nose, mouth, and chin) in the slums and non-slums of Chennai at different time points. METHODS: We conducted cross-sectional surveys among the residents of Chennai at two-time points of October and December 2020. The sample size for outdoor mask compliance for the first and second rounds of the survey was 1800 and 1600, respectively, for each of the two subgroups-slums and non-slums. In the second round, we included 640 individuals each in the slums and non-slums indoor public places and 1650 individuals in eleven shopping malls. We calculated the proportions and 95% confidence interval (95%CI) for the mask compliance outdoors and indoors by age, gender, region, and setting (slum and non-slum). RESULTS: We observed 3600 and 3200 individuals in the first and second surveys, respectively, for outdoor mask compliance. In both rounds, the prevalence of appropriate mask use outdoors was significantly lower in the slums (28%-29%) than non-slum areas (36%-35%) of Chennai (p<0.01). Outdoor mask compliance was similar within slum and non-slum subgroups across the two surveys. Lack of mask use was higher in the non-slums in the second round (50%) than in the first round of the survey (43%) (p<0.05). In the indoor settings in the 2nd survey, 10%-11% among 1280 individuals wore masks appropriately. Of the 1650 observed in the malls, 947 (57%) wore masks appropriately. CONCLUSION: Nearly one-third of residents of Chennai, India, correctly wore masks in public places. We recommend periodic surveys, enforcement of mask compliance in public places, and mass media campaigns to promote appropriate mask use.

Epidemiology of COVID-19 and effect of public health interventions, Chennai, India, March - October 2020

ObjectivesTo describe the public health strategies and their effect in controlling the COVID-19 pandemic from March to October 2020 in Chennai, India. SettingChennai, a densely populated metropolitan city in Southern India, was one of the five cities which contributed to more than half of the COVID-19 cases in India. ParticipantsWe collected the de-identified line list of all the 192,450 COVID-19 case-patients reported from 17 March to 31 October 2020 in Chennai and their contacts for the analysis. We defined a COVID-19 case-patient based on the RT-PCR positive test in one of the Government approved labs. Outcome measuresThe primary outcomes of interest were incidence of COVID-19 per million population, case fatality ratio, deaths per million and the effective reproduction number (Rt). We also analysed the indicators for surveillance, testing, contact tracing and isolation. ResultsOf the 192,450 RT-PCR confirmed COVID-19 case-patients reported in Chennai from 17 March-31 October 2020, 114,889 (60%) were males. The highest incidence was 41,064 per million population among the 61-80 years. The incidence peaked during June 2020 at 5239 per million and declined to 3,627 per million in October 2020. The city reported 3,543 deaths, with a case fatality ratio (CFR) of 1.8% and the crude death rate was 431 per million. When lockdown began, Rt was high (4.2) in March and fluctuated from April to June 2020. The Rt dropped below one by the first week of July and remained so until October 2020, even with the relaxation of restrictions ConclusionThe combination of public health strategies controlled the COVID-19 epidemic in a large, densely populated city in India. We recommend continuing the interventions to prevent resurgence, even as vaccination is being rolled out. StrengthsO_LIWe did a comprehensive analysis of COVID-19 strategies and outcome in a large, densely populated metropolitan city in India. C_LIO_LIWe documented that the community-centric public health strategies were feasible and effective in controlling the COVID-19 outbreak even in a large, thickly populated city C_LIO_LIThe lessons learnt are relevant to similar settings in low-and middle-income countries. Given the ongoing multiple waves of COVID-19 and the difficulty in controlling the transmission, our experience and lessons learnt will be valuable for policymakers and scientific advisors globally C_LI LimitationsO_LIWe analysed the data available from the GCC database and not from the hospitals where patients with moderate to severe illness were admitted. Hence, we could not report the severity of illness among admitted patients. C_LIO_LISecond, the COVID-19 incidence might have been underestimated while testing was low during the early phase of the epidemic C_LI

Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Ameloblastic fibro-odontoma in a 14 year old girl: A case report.

Ameloblastic fibro-odontoma (AFO) is a benign, epithelial odontogenic tumor with odontogenic mesenchyme having the histologic characteristics of both ameloblastic fibroma and complex odontoma. This report describes the case of a 14-year-old girl with AFO on the right posterior mandibular region that mimics complex odontoma on incisional biopsy due to the presence of atypical dentin- and cementum-like areas. On histological examination, sections of excisional biopsy showed odontogenic epithelial islands with embryonic connective tissue and decalcified sections showed atypical dentin with dentinal tubules and islands of cementum. These features led to the diagnosis of AFO.

Squamous Papilloma on Hard Palate: Case Report and Literature Review.

Most of the lesions in the oral cavity have papillary appearance. Oral squamous papilloma (SP) is one such type, which is a benign proliferation of the stratified squamous epithelium and presents as papillary or verrucous exophytic mass induced by human papillomavirus (HPV). Most of the oral mucosal lesions are often asymptomatic and have small progression. The common sites of occurrence include tongue, soft palate, and uvula. Squamous papilloma arising on hard palate is described in this article. Surgical excision of the lesion was done and sent for histopathological analyses that confirmed the clinical diagnosis. In larynx and trachea, malignant transformation of papillomas has been reported. The potentially malignant nature of SP if present needs to be explored. How to cite this article: Chaitanya P, Martha S, Punithvathy R, Reddy M. Squamous Papilloma on Hard Palate: Case Report and Literature Review. Int J Clin Pediatr Dent 2018;11(3):244-246.

Mucocele on Lower Lip: A Case Series.

Mucocele is a common salivary gland disorder that can appear in the lacrimal sac, paranasal sinuses, oral cavity, appendix, or gall bladder. These lesions occur due to mucous accumulation resulting from the alteration of minor salivary glands. Lower lip is the most common site of occurrence of these lesions in the oral cavity and most probable cause is trauma or habit of lip biting. Diagnosis is mainly clinical due to its pathognomonic presentation. We report a case series of mucocele in children treated by conventional surgical excision of the lesion.

Is intracranial pressure monitoring useful in children with severe traumatic brain injury?

BACKGROUND: Intracranial pressure monitoring (ICP) is considered as optional for management of severe traumatic brain injury (TBI) in children. AIMS: This study was performed to determine whether ICP monitoring is beneficial in the managing severe TBI in children. SETTINGS AND DESIGN: Neurosurgical intensive care unit (ICU) of a tertiary care referral center; prospective observational study. MATERIALS AND METHODS: Children aged 16 years or less with severe TBI defined as "postresuscitation Glasgow Coma Scale (GCS) score of 8 or less admitted to an ICU" were enrolled. All children underwent standard treatment for TBI as indicated. ICP monitoring was done in 30 cases and was not done in 20 cases. The outcome in both the groups was assessed using Glasgow outcome scale. STATISTICAL ANALYSIS: The characteristics of the patients in the two groups were compared using independent sample T test for continuous variables and chi-square and Mann-Whitney test for nonparametric variables. RESULTS: The children who did not undergo ICP monitoring required more number of doses of hyperosmolar agents. However, the duration of ventilation and length of ICU stay were significantly shorter in children who did not undergo ICP monitoring. The outcome was unfavorable in 16.7% of children who underwent ICP monitoring as compared with 55% of children who did not undergo ICP monitoring; this difference was significant. CONCLUSIONS: ICP-targeted therapy results in significantly better outcome in children with severe TBI.

Developing an in vitro screening assay platform for evaluation of antifibrotic drugs using precision-cut liver slices.

BACKGROUND: Precision-cut liver slices present different cell types of liver in a physiological context, and they have been explored as effective in vitro model systems to study liver fibrosis. Inducing fibrosis in the liver slices using toxicants like carbon tetrachloride is of less relevance to human disease conditions. Our aim for this study was to establish physiologically relevant conditions in vitro to induce fibrotic phenotypes in the liver slices. RESULTS: Precision-cut liver slices of 150 µm thickness were obtained from female C57BL/6 J mice. The slices were cultured for 24 hours in media containing a cocktail of 10 nM each of TGF-ß, PDGF, 5 µM each of lysophosphatidic acid and sphingosine 1 phosphate and 0.2 µg/ml of lipopolysaccharide along with 500 µM of palmitate and were analyzed for triglyceride accumulation, stress and inflammation, myofibroblast activation and extracellular matrix (ECM) accumulation. Incubation with the cocktail resulted in increased triglyceride accumulation, a hallmark of steatosis. The levels of Acta2, a hallmark of myofibroblast activation and the levels of inflammatory genes (IL-6, TNF-α and C-reactive protein) were significantly elevated. In addition, this treatment resulted in increased levels of ECM markers - collagen, lumican and fibronectin. CONCLUSIONS: This study reports the experimental conditions required to induce fibrosis associated with steatohepatitis using physiologically relevant inducers. The system presented here captures various aspects of the fibrosis process like steatosis, inflammation, stellate cell activation and ECM accumulation and serves as a platform to study the liver fibrosis in vitro and to screen small molecules for their antifibrotic activity.

Activation of GPR40 attenuates chronic inflammation induced impact on pancreatic ß-cells health and function.

BACKGROUND: Chronic inflammation-mediated ß-cell apoptosis is known to decrease ß-cell mass in diabetes leading to reduced insulin secretion. Exposure to pro-inflammatory cytokines can stimulate apoptosis in pancreatic ß-cells. The G protein coupled receptor 40 (GPR40) is implicated for glucose induced insulin secretion. We hypothesized that GPR40 activation can protect ß-cells from inflammation-induced apoptosis and restore glucose stimulated insulin secretion. RESULTS: By exposing NIT1 insulinoma cells and rat islets to a cocktail of pro-inflammatory cytokines (TNFα and IL1ß), we mimicked inflammatory signaling as seen by JNK and NFκB activation and increased mRNA levels of TNFα, IL1ß and NOS2a. These changes were reversed by pharmacological activation of GPR40 by a specific, small molecule, CNX-011-67. Further, GPR40 activation reduced inflammation-mediated oxidative and endoplasmic reticulum (ER) stresses. Importantly, GPR40 activation decreased inflammation-induced apoptosis as measured by key markers. These impacts of GPR40 were mediated through activation of PLC, CaMKII, calcineurin and cAMP. Cell survival was also enhanced by GPR40 activation as seen from the increased phosphorylation of Akt/PKB and enhanced expression of BCL2 and PDX1 genes. Interestingly, GPR40 activation restored both, inflammation-mediated inhibition on insulin secretion and intracellular insulin content. CONCLUSIONS: In this study, we provide evidences that CNX-011-67, a GPR40 agonist, reduces inflammatory signaling and apoptosis in pancreatic ß-cells while promoting insulin secretion and synthesis. Activation of GPR40 leads to attenuation of ß-cell dysfunction caused by chronic inflammation and thus could be of immense clinical value to improve insulin secretion and ß-cell survival.

Integrated analysis of chronic lipotoxicity on muscle metabolism and stress and its reversal by antioxidants.

Apart from elevated glucose, triglyceride and cholesterol, elevated levels of serum free-fatty acid (FFA) are observed in diabetic patients. Increased FFA load can cause multiple dysregulation which are collectively known as lipotoxicity. Impacts of FFA induced lipotoxicity were evaluated on various cellular responses of metabolism and stress in skeletal muscle myotubes. Under lipotoxicity, oxidative capacity of C2C12 myotubes was reduced and decreased levels ATP and NAD were observed. Lipotoxicity augmented non-oxidative disposal of metabolites in terms of lactate release, IMTG and ceramide synthesis. Concomitantly, insulin resistance was also observed. These impacts were in conjunction with increased cellular stress, inflammation, proteolysis and apoptosis. Quenching of lipotoxicity mediated oxidative stress by antioxidant reverted its deleterious impacts and restored insulin stimulated glucose uptake. In conclusion, the in vitro lipotoxicity makes a system which resembles in vivo pathology of muscle as seen in diabetic patients and represents an integrated perspective of lipotoxicity on various parameters of metabolism and stress.

Accurate grading of 3 synchronous liposarcomas assessed by PET-CT in a single patient.

Positron emission tomography (PET) with 2-fluoro-deoxyglucose (FDG) has become an established imaging modality that can accurately and noninvasively differentiate malignant neoplasms from benign masses. It is increasingly being used to grade malignant neoplasms as well and has almost replaced other studies like gallium 67-citrate scans for metabolic imaging. We describe an interesting case of 3 synchronous liposarcomas with different radio-opacifications on computed tomography (CT). The more aggressive lesion with more opacity on CT showed intense FDG activity and was found to be a high-grade liposarcoma on pathology. The well-differentiated lesion with more fat content appearing less radio-opaque on CT showed almost no FDG activity and an intermediate grade lesion with intermediate radio-opacity on CT showed mildly increased FDG activity. Dual modality imaging with integrated PET/CT systems have strengthened the confidence of classifying these lesions even before knowing the pathology as depicted in this case.