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OBJECTIVES/GOALS: Tumor PDL1 signals to immune cells for tumor immune evasion but has cell-intrinsic signals that promote tumor virulence. We identify novel tumor PDL1 depleting drugs (PDDs) to interrupt tumor-intrinsic PDL1 signals and sensitize tumors to targeted therapy in vitro and in vivo. METHODS/STUDY POPULATION: We screened the Prestwick and LOPAC libraries for FDA-approved drugs reducing B16 melanoma PDL1 > 2.6-fold. ?-lactam antibiotics were used at 80 ?M and Chk1 inhibitor rabusertib as indicated in T24 human bladder cancer, and murine ID8agg ovarian cancer, 4T1 breast cancer and B16. Genetic PDL1 KO was by CRISPR or shRNA and re-expression by lentivirus. Viability was by MTT and protein by immunoblot. We challenged 5 NSG mice/group with 2x106 T24 (SQ) cells and 5 BALB/c mice/group with 5x105 4T1 cells (mammary fat pad) and treated with cefepime (200 mg/kg), rabusertib (2.5 mg/kg), vehicle, or combo daily from day 3. RESULTS/ANTICIPATED RESULTS: Structurally-related ?-lactam antibiotics cefepime and ceftazidime are tumor PDDs. Cefepime or ceftazidime reduced tumor PD-L1 and thus its cell-intrinsic signals to deplete the DNA damage sensing Chk2 protein and promote rabusertib synthetic lethality in vitro and in vivo in a tumor PDL1-dependent manner independent of immunity. Structurally distinct ?-lactam antibiotics did not sensitize tumor cells to rabusertib, suggesting ?-lactam antimicrobial functions did not promote PDL1 depletion or rabusertib treatment effects in vivo. Although rabusertib effects were immune-independent, both PDDs induced immunogenic tumor STING signaling, suggesting they can improve tumor immunotherapy. DISCUSSION/SIGNIFICANCE: We show a rapidly translatable way to deplete detrimental tumor-intrinsic PDL1 signals, and sensitize tumors to rabusertib. We are testing PDD structure activity relationships to improve PDD effects and testing PDD effects on other treatments, e.g., PARP inhibitors, immunotherapy.
Uttar Pradesh (UP), with more than 220 million people, is the most populous state in India. Despite a high unmet need for modern family planning methods, the state has experienced a substantial decline in fertility. India has also seen a decline during this period which can be attributed to the increased prevalence of modern methods of family planning, particularly female sterilisation, but in UP, the corresponding increase was marginal. At the same time, Traditional Family Planning Methods (TMs) increased significantly in UP in contrast to India, where it was marginal. The trends in UP raise questions about the drivers in fertility decline and question the conventional wisdom that fertility declines are driven by modern methods, and the paper aims to understand this paradox. Fertility trends and family planning practices in UP were analysed using data from different rounds of National Family Health Surveys (NFHS) and the two UP Family Planning Surveys conducted by the UP Technical Support Unit to understand whether the use of TMs played a role in the fertility decline. As per NFHS-4, the prevalence of TM in India (6%) was less than half that of UP (13%). The UP Family Planning Survey in 25 High Priority Districts estimated that 22% of women used TMs. The analysis also suggested that availability and accessibiility of modern contraceptives might have played a role in the increased use of TMs in UP. If there are still couples who make a choice in favour of TMs, they should be well informed about the risks associated with the use of traditional methods as higher failure rate is observed among TMs users.
This paper describes a multiple-input multiple-output (MIMO) antenna for low millimeter (mm)-wave applications based on dielectric resonators. This is the first time that a filtering response is used in conjunction with an MIMO antenna operating at a low mm-wave frequency. The antenna is simulated using an asymmetrical U-shaped aperture and a microstrip line feed. The suggested filtenna has two distinguishing characteristics: (i) the diversity parameters of the proposed MIMO are increased by including pattern and spatial diversity, and (ii) the proposed feed mechanism of a dielectric resonator provides the filtering response. Between the two ports, a metallic plate tilts the radiation pattern by 45°. The anti-parallel locations of the ports increase the isolation value by >30 dB. To validate the performance of the suggested antenna, the proposed filtenna was built and confirmed. The proposed antenna operates between the frequencies 27.9 and 28.5 GHz. Within the operating frequency range, the observed gain is ~4.5 dBi. On the contrary, the gain suppression level beyond the operational frequency range is ~15 dB. The stable radiation properties and high diversity parameter values of the suggested filtenna make it an effective solution for 5G Internet of Things sensing applications.
Health Technology Assessment (HTA) is an important but time-consuming process to inform decision-making. Following requests from stakeholders in Scotland to provide advice on technologies that had recently undergone HTA in other jurisdictions, SHTG recognized a gap in their ‘product menu’. Colleagues within the SHTG team devised a mechanism through which an original HTA could be adapted for Scotland, taking into account local contextual factors.
SHTG Adaptations comprise the following: i) assessment of the original HTA using the EUnetHTA HTA Adaptation Toolkit and checklist; ii) draft Adaptation using the outcome of the assessment and contextual information for Scotland; iii) consultation group of relevant Scottish clinicians is provided with the original HTA and draft SHTG Adaptation; iv) modified Delphi approach (max. three rounds of questioning) is used to ascertain the relevance of the original HTA to Scotland; v) the Adaptation is submitted to SHTG Council for endorsement.
SHTG Adaptations have a timeline of 2–3 months, three have been published since this product was launched. The process has run smoothly with excellent clinical engagement from across NHS Scotland. Key learning focusses on the role of the SHTG Council (i.e. appraisal committee) in this process and in handling of expert opinion of evidence which has already been appraised by another agency.
The SHTG Adaptation is a new product which offers a timely assessment and utilization of an HTA from another agency.
The Evidence Directorate produced eighteen rapid responses during the early stages of the COVID-19 pandemic. To address this need while retaining methodological integrity a three-tiered system for rapid responses was developed.
All rapid responses answer specific research questions rather than broad health system issues. The appropriate level varies depending on the time and resource available, and the requester's need:
• Level 1 – Reference List (turnaround 4–8hrs, delivered by an information scientist): a quick search for best available evidence, and results presented as a reference list.
• Level 2 – Summary of evidence (turnaround 1–2 days, delivered by an information scientist): a quick search and brief summary of the best available evidence.
• Level 3 – Synthesis of evidence (turnaround 3–7 days, delivered by a Health Services Researcher or Health Economist): a quick search and then a narrative summary and synthesis of the best available evidence, with a brief appraisal of validity, reliability and generalizability.
Since the launch of the three-tiered model in September 2020 there have been five rapid responses. Two were Level 2 products and three were Level 3 products.
The Evidence Directorate of Healthcare Improvement Scotland now has an agile rapid response product which can be applied to a variety of settings and needs. This was borne out of a need for a rapid turnaround and evidence synthesis during the COVID-19 pandemic.
We studied the fine histological structures of pecten oculi of the Eurasian tree sparrow using various microscopy techniques. The pecten of the tree sparrow was found to be of a pleated type comprising of pleats, bridges, and base. The light microscopic study revealed further that the pleats consist of capillaries of varying sizes, blood vessels, and numerous pigmented cells that give them a black color. Histochemical studies of pecten showed a large deposition of lipid droplets, which were more abundant in the basal area. The transmission electron microscopy displayed capillaries and blood vessels that remain surrounded by a thick fibrous basal membrane. They are formed of endothelial cells having a large lumen and abluminal area with microfolds. Interstitial spaces were found filled with rounded melanocytes, electron-dense pigment granules, and mitochondria. Observations under the scanning electron microscope revealed the presence of a dense vascular network of capillaries and vessels. In addition, large hyalocytes were also observed on the surface of the pleats. The above observations suggest that the histological structure of the pecten of the tree sparrow resembles those present in the pecten of other diurnal birds. However, further investigation is required to ascertain its functional role in birds.
Isolated ventricular inversion with situs solitus is a severe and rare congenital cardiac malformation characterised by an atrioventricular discordance but with ventriculo-arterial concordance. Here, we present the rare case of an adolescent with isolated ventricular inversion and hypoplasia of the left-sided morphological right ventricle and pulmonary stenosis, a first of its kind to be reported in the literature.
To investigate the relative contributions of cerebral cortex and basal ganglia to movement stopping, we tested the optimum combination Stop Signal Reaction Time (ocSSRT) and median visual reaction time (RT) in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD) and compared values with data from healthy controls.
Thirty-five PD patients, 22 AD patients, and 29 healthy controls were recruited to this study. RT and ocSSRT were measured using a hand-held battery-operated electronic box through a stop signal paradigm.
The mean ocSSRT was found to be 309 ms, 368 ms, and 265 ms in AD, PD, and healthy controls, respectively, and significantly prolonged in PD compared to healthy controls (p = 0.001). The ocSSRT but not RT could separate AD from PD patients (p = 0.022).
Our data suggest that subcortical networks encompassing dopaminergic pathways in the basal ganglia play a more important role than cortical networks in movement-stopping. Combining ocSSRT with other putative indices or biomarkers of AD (and other dementias) could increase the accuracy of early diagnosis.
Start-ups tend to form with a central idea that differentiates them from their competitors in the market. It is crucial for them to efficiently transform the idea into a marketable product. Prototyping helps to iteratively achieve a minimum viable product and plays a crucial role by enabling teams to test their ideas with limited resources early on. However, the prototyping process may have wrong focus leading to a suboptimal allocation of resources. Previously, we proposed role-based prototyping for fuzzy front-end development in small teams. It supports (1) resource allocation, (2) the definition of responsibilities, and (3) structuring the development process with milestones. In recent research this was a promising yet incomplete approach. We extend the previous work by refining the prototyping process by adding a prototyping matrix with two dimensions (purpose and lens), a prototyping cycle (plan, execute, test, reflect, assimilate), and a modified Kanban board (Protoban) for planning, managing, and reflecting cycles. This process, named PETRA was tested with a start-up developing an autonomous trash picking robot. The extended approach supported the team significantly in providing a clear idea of what to do at what time.
In 1700 the Mughals controlled much of the Indian subcontinent. By 1858 the British Crown ruled. Why did this transition occur? How did the relationship between the state and economic activity change? And how did the economy perform? This chapter provides an overview, discussing competing perspectives on the breakdown of the Mughal Empire, the rise of the East India Company, the increasing commercialization of the economy, and changes in the economic structure. The literature suggests that the East India Company’s political and military success partly came from more successful fiscal administration compared to its Indian rivals. After consolidating its rule, British policy favoured the export of Indian primary products and the import of manufactured goods, contributing to deindustrialization. In agriculture, the area cultivated increased with population, but technology stagnated. Per capita income, which was already low, may have fallen slightly. Conflicts between the state and local users of forests and other resources emerged, especially in conjunction with the introduction of a major technological innovation, the railways. Our period ends with the Mutiny, a formidable challenge to British rule, following which British policy became conservative, seeking to preserve the existing social order.
To present a case of a near-miss, where an unexpected Pulmonary Embolism (PE) was identified in a patient with psychotic depression and catatonia, who almost had Electroconvulsive Therapy (ECT). Our aim is to highlight the importance of Venous-Thrombo Embolism (VTE) risk assessment in all psychiatric inpatients, particularly those with catatonia, and those about to undergo ECT.
A 53-year-old female admitted with her first presentation of psychotic depression, catatonia, poor oral intake, and significant weight loss in the community for months prior to admission. She was recommended for emergency ECT as the severity of her self-neglect was becoming life threatening. Her first ECT session was cancelled due to low potassium levels prior to ECT, which proved to be a fortunate event. She developed sudden onset chest pain the next day, and following further medical investigations; was diagnosed to have a bilateral PE, and subsequently treated with Apixaban. Due to the potential risk of ECT dislodging the clots, treatment was done by optimising medication alone; Venlafaxine 300 mg, Mirtazapine 45 mg, Haloperidol 6 mg. She made a slow but successful recovery, and was discharged home, with ongoing support from Early Intervention in Psychosis services.
We conducted a literature search, and it is well known that there is an increased risk of VTE in catatonic patients, as well as other psychiatric inpatients; due to anti-psychotic medication. Furthermore, cases have been reported where ECT was associated with increased risk of death in patients with known VTE/PE.
On retrospective review of the patient's risks of developing VTE in the community, it was clear, that she was at very high risk of developing VTE. It was also noted that she should have had a VTE risk assessment on admission, in accordance with NICE guidelines; where all acute psychiatric inpatients should have this assessed as soon as possible.
Through a process of assessment and treatment, VTE is often preventable. Identification of high-risk patients on admission to hospital is therefore crucial. It is thus, imperative that a comprehensive VTE risk assessment is completed on admission and regularly reviewed.
This case highlights the risk of missing VTE assessments in WAA Inpatients, particularly those with catatonia, about to undergo ECT, which could have been fatal. As such, VTE/PE risk assessment in such patients, about to undergo ECT, is particularly crucial.
Clinicians need to have a high index of suspicion of VTE/PE, particularly in patients with catatonia.
Developing countries experience both household air pollution resulting from the use of biomass fuels for cooking and industrial air pollution. We conceptualise and estimate simultaneous exposure to both outdoor and household air pollution by adapting the Total Exposure Assessment model from environmental health sciences. To study the relationship between total exposure and health, we collected comprehensive data from a region (Goa) in India that had extensive mining activity. Our data allowed us to apportion individuals’ exposure to pollution in micro-environments: indoor, outdoor, kitchen, and at work. We find that higher cumulative exposure to air pollution is positively associated with both self-reported and clinically- diagnosed respiratory health issues. Households in regions with higher economic (mining) activity had higher incomes and had switched to cleaner cooking fuels. In other words, household air pollution due to higher biomass use had been substituted away for outdoor air pollution in regions with economic activity.
In August 2019, public health surveillance systems in Scotland and England identified seven, geographically dispersed cases infected with the same strain (defined as isolates that fell within the same five single nucleotide polymorphism single linage cluster) of Shiga toxin-producing Escherichia coli O157:H7. Epidemiological analysis of enhanced surveillance questionnaire data identified handling raw beef and shopping from the same national retailer (retailer A) as the common exposure. Concurrently, a microbiological survey of minced beef at retail identified the same strain in a sample of minced beef sold by retailer A, providing microbiological evidence of the link. Between September and November 2019, a further four primary and two secondary cases infected with the same strain were identified; two cases developed haemolytic uraemic syndrome. None of the four primary cases reported consumption of beef from retailer A and the transmission route of these subsequent cases was not identified, although all four primary cases visited the same petting farm. Generally, outbreaks of STEC O157:H7 in the UK appear to be distinct, short-lived events; however, on-going transmission linked to contaminated food, animals or environmental exposures and person-to-person contact do occur. Although outbreaks of STEC caused by contaminated fresh produce are increasingly common, undercooked meat products remain a risk of infection.
In this study, we examine disparities in financial development at the regional level in India. The major research questions of the study are: how do we measure the level of financial development at the sub-national level? How unequal is financial development across the states? Does it vary by ownership of financial institutions? To explore these research questions, our study develops a composite banking development index at the sub-national level for three different bank groups – public, private and foreign for 25 Indian states covering 1996–2015. Our findings suggest that despite reforms, banking development is significantly higher in the leading high income and more developed regions compared to lagging ones. Furthermore, we find that all bank groups including public banks are concentrated more in the developed regions. Overall, over the years the position of top three and bottom three states in the aggregate banking index have remained unchanged reflecting lop-sidedness of regional development. We also note improvement in the ranking of some north-eastern states during the period 2009–15.
Climate change presents a particularly complex challenge in the context of flyway scale conservation of migratory bird species as it requires coordinated action by multiple countries along these species’ migratory routes. Coordinating conservation responses requires understanding the vulnerability of species and their habitats to climate change at the flyway scale throughout each species’ annual cycle. To contribute to such understanding, we used species distribution models to assess the exposure to climate change of waterbird species that are the focus of the Agreement on the Conservation of African-Eurasian Migratory Waterbirds (AEWA). We found that the species with the smallest proportion of their current range projected to be climatically suitable by 2050 (those whose distributions respond to changes in water availability but that do not perform synchronised migration) are dispersive species in the Afrotropical biogeographic realm, and migratory species in their breeding season, particularly Arctic breeding waders. These species also have the most limited availability of newly suitable areas. Projections for most other Palearctic migratory waterbird species suggest that losses of suitable areas in their current passage and wintering ranges may be largely offset by new areas becoming climatically suitable. The majority of migratory Palearctic waterbirds in the breeding season and Afrotropical waterbirds are widely dispersed with only a small proportion of their populations currently supported by ‘Critical Sites’ (i.e. sites that are either important for Globally Threatened Species or support 1% of the bioregional population of any waterbird species). This makes it unlikely that climate change adaptation measures focusing only on key sites will be sufficient to counter the predicted range losses. Therefore, climate change adaptation responses should also be implemented at the landscape scale for Afrotropical waterbirds and for breeding populations of Palearctic migrant waterbirds.
Aortopulmonary window is a rare congenital heart defect. Left main coronary artery extrinsic compression by an enlarged pulmonary artery is a rare complication and a potential cause for chest pain and sudden cardiac death in patients with pulmonary hypertension. Here, we present the case of a 14-year-old boy with a large aortopulmonary window who was planned for a device closure, but during the procedure, he developed ST-T segment changes while the device was being deployed, and hence the procedure was abandoned. The boy subsequently underwent a successful surgical closure thereafter.
Dictionary learning has emerged as a powerful method for data-driven extraction of features from data. The initial focus was from an algorithmic perspective, but recently there has been increasing interest in the theoretical underpinnings. These rely on information-theoretic analytic tools and help us understand the fundamental limitations of dictionary-learning algorithms. We focus on theoretical aspects and summarize results on dictionary learning from vector- and tensor-valued data. Results are stated in terms of lower and upper bounds on sample complexity of dictionary learning, defined as the number of samples needed to identify or reconstruct the true dictionary underlying data from noiseless or noisy samples, respectively. Many analytic tools that help yield these results come from information theory, including restating the dictionary-learning problem as a channel-coding problem and connecting analysis of minimax risk in statistical estimation to Fano’s inequality. In addition to highlighting effects of parameters on the sample complexity of dictionary learning, we show the potential advantages of dictionary learning from tensor data and present unaddressed problems.
The current investigation was conducted with the objective to develop an epidemiological case definition of possible severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) re-infection and assess its magnitude in India. The epidemiological case definition for SARS-CoV-2 re-infection was developed from literature review of data on viral kinetics. For achieving second objective, the individuals who satisfied the developed case definition for SARS-CoV-2 re-infection were contacted telephonically. Taking available evidence into consideration, re-infection with SARS-CoV-2 in our study was defined as any individual who tested positive for SARS-CoV-2 on two separate occasions by either molecular tests or rapid antigen test at an interval of at least 102 days with one negative molecular test in between. In this archive based, telephonic survey, 58 out of 1300 individuals (4.5%) fulfilled the above-mentioned definition; 38 individuals could be contacted with healthcare workers (HCWs) accounting for 31.6% of the cases. A large proportion of participants was asymptomatic and had higher Ct value during the first episode. While SARS-CoV-2 re-infection is still a rare phenomenon, there is a need for epidemiological definition of re-infection for establishing surveillance systems and this study contributes to such a goal.
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) re-infection is an emerging concern and there is a need to define it. Therefore, working epidemiological case definition for re-infection was developed and its magnitude was explored via archive-based, telephonic survey. Re-infection with SARS-CoV-2 was defined as two positive tests at an interval of at least 102 days with one interim negative test. Thirty-eight of the 58 eligible patients could be contacted with 12 (31.6%) being HCWs. Majority of the participants were asymptomatic and had higher Ct value during their first episode. To conclude, a working epidemiological case definition of SARS-CoV-2 re-infection is important to strengthen surveillance. The present investigation contributes to this goal and records reinfection in 4.5% of SARS-CoV-2 infected individuals in India.