Focal adhesions are controlled by microtubules through local contractility regulation.

Microtubules regulate cell polarity and migration via local activation of focal adhesion turnover, but the mechanism of this process is insufficiently understood. Molecular complexes containing KANK family proteins connect microtubules with talin, the major component of focal adhesions. Here, local optogenetic activation of KANK1-mediated microtubule/talin linkage promoted microtubule targeting to an individual focal adhesion and subsequent withdrawal, resulting in focal adhesion centripetal sliding and rapid disassembly. This sliding is preceded by a local increase of traction force due to accumulation of myosin-II and actin in the proximity of the focal adhesion. Knockdown of the Rho activator GEF-H1 prevented development of traction force and abolished sliding and disassembly of focal adhesions upon KANK1 activation. Other players participating in microtubule-driven, KANK-dependent focal adhesion disassembly include kinases ROCK, PAK, and FAK, as well as microtubules/focal adhesion-associated proteins kinesin-1, APC, and αTAT. Based on these data, we develop a mathematical model for a microtubule-driven focal adhesion disruption involving local GEF-H1/RhoA/ROCK-dependent activation of contractility, which is consistent with experimental data.

Assessing the Burden of COVID-19 among Children Aged 6-14 Years in Karnataka, India: A Cross-sectional Survey.

Background: India experienced three coronavirus disease (COVID-19) waves, with the third attributed to the highly contagious Omicron variant. Before the national vaccination rollout for children above 6, understanding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) positivity in the pediatric population was essential. This study aims to assess the burden of Covid-19 infection and to estimate the seroprevalence in children aged 6 to 14 years in the state of Karnataka. Material and Methods: We surveyed 5,358 children aged 6-14 across Karnataka using 232 health facilities, from June 6 to 14, 2022. We determined the sample size using the PPS (Population Proportional to Size) technique and employed cluster sampling. We tested all participants for SARS-CoV-2 IgG with an enzyme-linked immunosorbent assay (ELISA) kit and SARS-CoV-2 RNA with reverse transcription-polymerase chain reaction (RT-PCR). We sequenced samples with a cycle threshold (CT) value below 25 using whole genomic sequencing (WGS). Result: We found an adjusted seroprevalence of IgG at 75.38% statewide, and we found 0.04% of children RT-PCR positive for COVID-19. We determined a case-to-infection ratio of 1:37 and identified the SARS-CoV-2 strains as Omicron, BA.5, and BA.2.10. Conclusion: The study showed a high seroprevalence of IgG among children with low active infection. Omicron, BA. 5, and BA. 2.10 variants were detected through WGS.

Does non-motorists' safety perception of autonomous vehicles vary across opinion change stemming from crash occurrence? Investigating perceptions using fixed and random parameter ordered logit models.

The perception of non-motorists toward autonomous vehicles (AVs) could change or remain the same after hearing about a fatal AV crash. This study aims to discern the differences between non-motorists whose opinions were influenced and those whose views remained unchanged after hearing about the fatal AV crash. Additionally, this study investigates how the operational competence of AV manufacturers affect non-motorist's safety perception. A fixed parameter ordered logit model was explored to explain non-motorists' safety perception for respondents who changed their opinion after a crash occurrence and those who did not. A random parameter ordered logit model was then explored to address the difference in residual variance. The finding from the random parameter ordered logit model indicates that two factors (i.e., future impact of AVs on traffic injuries and willingness to adopt Pittsburgh's streets as a proving ground) were significant for the respondents with negative change in opinion after the crash. The result also suggests that negative information such as the crash in Arizona may influence non-motorists' safety perception of AVs, but this effect can be mitigated by providing positive information about the AVs. The results also demonstrate that non-motorists who perceive the operational competence of the AV manufacturers to be high have higher safety perception of the AVs, while those who perceive the operational competence of the AV manufacturers to be low have lower safety perception of the AVs. This study offers recommendations for policies and interventions to enhance non-motorists' safety based on the examination of factors associated with safety perception among respondents who changed their opinion following a crash and those who maintained their initial stance.

Impact of interval progression before autologous stem cell transplant in patients with multiple myeloma.

In transplant-eligible patients who undergo upfront autologous stem cell transplant (ASCT) for multiple myeloma (MM), standard practice is to treat with six to eight cycles of induction therapy followed by high-dose chemotherapy with ASCT. A gap between the end of induction and the day of ASCT exists to allow stem cell mobilization and collection. Despite attempts to limit the length of this interval, we noticed that some patients experience interval progression (IP) of disease between the end of induction therapy and the day of ASCT. We analyzed 408 MM patients who underwent ASCT between 2011 and 2016. The median length of the interval between end of induction and ASCT was 38 days. We observed that 26% of patients in the entire cohort and 23.6% of patients who received induction with bortezomib-lenalidomide-dexamethasone (VRD) experienced IP. These patients deepened their responses with ASCT, independently of induction regimen. In the entire cohort, IP was significantly associated with shorter PFS in the univariable analysis (Hazard Ratio, HR = 1.37, P = 0.022) but not in the multivariable analysis (HR = 1.14, P = 0.44). However, analyzing only patients who received VRD as induction, progression-free survival (PFS) remained inferior in both the univariable (HR = 2.02; P = 0.002) and the multivariable analyses (HR = 1.96; P = 0.01). T cells and natural killer (NK) cells are increasingly studied targets of immunomodulatory therapy, as immune dysfunction is known to occur in patients with MM. Peripheral blood from 35 MM patients were analyzed. At time of ASCT, patients with IP had significantly increased percentages of CD3+CD8+CD57+ CD28- (P = 0.05) and CD3+CD4+LAG3+ (P = 0.0022) T-cells, as well as less CD56bright and CD56dim NK cells bearing activated markers such as CD69, NKG2D, and CD226. These data suggest that IP can impact the length of response to ASCT; therefore, further studies on the management of these patients are needed.

CTC service heterogeneity and design of a workforce calculator.

AIM: To determine the level of heterogeneity in delivery of computed tomography (CT) colonography services and develop a workforce calculator that accommodates the variation identified. MATERIALS AND METHODS: A national survey, based on the "WHO workforce indicators of staffing need", established activity standards for essential tasks in delivery of the service. From these data a workforce calculator was designed to guide the required staffing and equipment resource by service size. RESULTS: Activity standards were established as mode responses >70%. Service homogeneity was greater in areas where professional standards and guidance were available. The mean service size was 1,101. Did not attend (DNA) rates were lower where direct booking was available (p<0.0001). Service sizes were larger where radiographer reporting was embedded in reporting paradigms (p<0.024). CONCLUSION: The survey identified benefits of radiographer-led direct booking and reporting. The workforce calculator derived from the survey provides a framework to guide the resourcing of expansion while maintaining standards.

To increase or to decrease the price? Managing public transport queues during COVID-19 in the presence of strategic commuters.

The impact of COVID-19 on urban travel behavior has been unprecedented. It has significantly influenced the travel mode choices of different urban commuters in various countries across the globe. Given that the public transport providers need to tradeoff between minimizing the spread of COVID-19 and providing an affordable travel choice in this environment, we develop a strategic queueing model to analyze the effect of different pricing strategies on the commuter behavior. In particular, we consider a Markovian queue in front of a public transport ticket counter wherein strategic commuters arrive at the service facility and make joining or balking decisions based on their derived utilities. In contrast to conventional wisdom, we suggest that the public transport provider needs to decrease the price to filter out the wealthy commuters who possess feasible alternative travel options from using public transport and promote the commuters with no alternatives in using public transport.

Immediate flapless implant placement in a smoker patient: A challenge for optimum aesthetics and secondary stability: A case report.

The objective of this case report was to restore the young patient with missing teeth and extruded tooth using an immediate implant and synthetic bone graft material for the esthetic and comfort purpose. A 21-year young man reported extrusion of a tooth as well as missing teeth. Clinical examination revealed missing teeth in relation to (irt) 11 and 21, extrusion of tooth in relation to (irt) 12, patient had generalized fluorosis, and localized marginal gingivitis with melanin pigmentation. The patient is a known smoker, and he was advised the cessation of smoking before the treatment. This paper describes a step-by-step approach to different treatment phases, starting with surgical guide fabrication, immediate implant surgical procedures, bone grafting procedure, and later prosthesis fabrication. Follow-up resulted in a satisfactory outcome.

Screening COVID-19 by Swaasa AI Platform using cough sounds: A cross-sectional study

The Advent of Artificial Intelligence (AI) has led to the use of auditory data for detecting various diseases, including COVID-19. SARS-CoV-2 infection has claimed more than 6 million lives till date and hence, needs a robust screening technique to control the disease spread. In the present study we developed and validated the Swaasa AI platform for screening and prioritizing COVID-19 patients based on the signature cough sound and the symptoms presented by the subjects. The cough data records collected from 234 COVID-19 suspects were subjected to validate the convolutional neural network (CNN) architecture and tabular features-based algorithm. The likelihood of the disease was predicted by combining the final output obtained from both the models. In the clinical validation phase, Swaasa was found to be 75.54% accurate in detecting the likely presence of COVID-19 with 95.45% sensitivity and 73.46% specificity. The pilot testing of Swaasa was carried out on 183 presumptive COVID subjects, out of which 82 subjects were found to be positive for the disease by Swaasa. Among them, 58 subjects were truly COVID-19 positive, which corresponds to a Positive Predictive Value of 70.73%. The currently available rapid screening methods are very costly and require technical expertise, therefore a cost effective, remote monitoring tool would be very beneficial for preliminary screening of the potential COVID-19 subject.

Exploring the effect of road network, demographic, and land use characteristics on teen crash frequency using geographically weighted negative binomial regression.

Motor vehicle crashes are one of the leading causes of teen deaths worldwide. It is important to assess the environment and identify the risk factors influencing teen crashes for planning strategies and improving their safety. This research, therefore, focuses on exploring the effect of road network, demographic, and land use characteristics to compute teen crash frequency. Data for 201 spatially distributed road segments in Mecklenburg County, North Carolina, USA were considered for the evaluation. Data related to teen crashes were obtained from the Highway Safety Information System (HSIS). Demographic and land use characteristics were extracted around each selected road segment using two different buffer widths (0.25 miles and 0.5 miles). Teen crash frequency of each road segment was used as the dependent variable. The generalized linear models with the negative binomial distribution (GLM-based NB model) and geographically weighted negative binomial regression models (GWNBR and GWNBRg) were developed and compared. The annual average daily traffic (AADT), light commercial land use, number of household units, and number of pupils enrolled in public or private high schools are significant explanatory variables influencing teen crash frequency. Both methods have good predictive capabilities and can be used to compute teen crash frequency. However, the GWNBR and GWNBRg better capture the spatial dependency and spatial heterogeneity of associated risk factors influencing teen crash frequency.

Pregnant lady with eosinophilia: common cause, uncommon association.

Peripheral eosinophilia can have a myriad of causes and presents a diagnostic challenge in everyday practice. Tropical pulmonary eosinophilia (TPE), seen commonly in tropics, is an immunological reaction to filarial parasites. This disease can present with clinical features that closely mimic asthma, eosinophilic pneumonia, and Loffler's syndrome. Differentiating between these diseases is essential owing to marked differences in treatment. This can be further challenging in pregnancy as any wrong treatment is likely to affect both the mother and the child. We report a case of a pregnant lady who presented with eosinophilia and of how she was worked up to the correct diagnosis. There are only few reported cases of TPE in pregnancy, and there are no reported cases from India. The case also underlines the approach required in these patients to reach the correct diagnosis.

Integration of spatial and single-cell transcriptomic data elucidates mouse organogenesis.

Molecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from tissues, thereby losing the crucial spatial context of regulatory processes. Here, we apply an image-based single-cell transcriptomics method, sequential fluorescence in situ hybridization (seqFISH), to detect mRNAs for 387 target genes in tissue sections of mouse embryos at the 8-12 somite stage. By integrating spatial context and multiplexed transcriptional measurements with two single-cell transcriptome atlases, we characterize cell types across the embryo and demonstrate that spatially resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain-hindbrain boundary (MHB) and the developing gut tube. We uncover axes of cell differentiation that are not apparent from single-cell RNA-sequencing (scRNA-seq) data, such as early dorsal-ventral separation of esophageal and tracheal progenitor populations in the gut tube. Our method provides an approach for studying cell fate decisions in complex tissues and development.

Live Case Demonstrations are Essential for the Success of Pediatric Urology Meetings in India.

PURPOSE: The purpose of the study was to survey the opinion of delegates attending national pediatric urology meeting regarding live case demonstrations (LCDs) to see whether these can be replaced with taped case demonstrations (TCDs) in future. METHODS: A questionnaire-based survey was conducted at the end of the 3-day annual conference and live operative workshop in pediatric urology. Apart from general data such as age of the respondent and type of practice setting, four key questions on LCDs with yes/no responses included: would you have attended this meeting if there were no LCDs? Are unedited videos (TCDs) as effective as LCDs for teaching? Do you think LCDs should be continued? Would you allow your child to be operated in LCD by an expert? For question 3, the outcomes were compared between junior surgeons (<45-year-old) and senior surgeons (>45-year-old). RESULTS: On analysis, 88/140 (62%) respondents (95% confidence interval [CI]: 54%-70%) said that they would not have attended the meeting if there were no LCDs; 70/139 (50%) respondents (95% CI: 42%-58%) felt that TCDs may be an effective alternative to LCDs; 129/144 (90%) respondents (95% CI: 83%-94%) felt that LCDs should be continued. For question 4, 101/129 (79%) said they would allow their child to be operated in LCD by an expert, while 28 (21%) did not agree for their child to be operated in LCD. There was no significant difference between junior and senior surgeons regarding support for LCDs (P = 0.15). CONCLUSIONS: In the Indian scenario, LCDs were favored as an essential part of pediatric urology meeting, attract more participation, and are likely to be important for the success of the meeting.

NE-OBT and TFWT activity concentrations in wild plants in the vicinity of the PHWR nuclear power plant and control regions of the tropical monsoonal climatic region of the Indian subcontinent.

The results of the first detailed study, involving a large number of samples, on water equivalent factor (WEQp), non-exchangeable organically bound tritium (NE-OBT) and tissue free water tritium (TFWT) activity concentrations in predominant plant species of the tropical monsoonal climatic region, are presented. A total of 369 samples from the vicinity of the PHWR nuclear power plant (NPP) at Kaiga, West Coast of India, and 47 samples of the control region (region not affected by local anthropogenic sources) were analysed. The WEQp varied in the range of 0.347-0.666 L kg-1 with an overall mean value of 0.540 ± 0.045 L kg-1. The NE-OBT activity concentration varied in the range of <9.8-60.9 Bq L-1 of combustion water (mean = 24.6 ± 11.5 Bq L-1) and that of TFWT in the range of 9.2-60.5 Bq L-1 (mean = 30.7 ± 10.9 Bq L-1) in the vicinity of the NPP. Rigorous statistical analysis of the data confirmed that (i) the activity concentrations of both forms of tritium decreased with the increase in the distance between the sampling location and NPP, and beyond 10 km, it was similar to that of the control region, (ii) the incorporation of tritium released from the NPP into wild plant leaves is not species-dependent, (iii) the NE-OBT activity concentration in the 5-10 km zone exhibited a dependence on the prevailing wind regime with respect to the NPP, but not in the 2.3-5 km zone which suggests that the transport of tritium, released into the atmosphere as the gaseous effluent, through diffusion is a dominating factor governing its activity concentration in the 2.3-5 km zone. The NE-OBT to TFWT specific activity concentration ratio (R-value) had a mean value of 0.82 ± 0.27 (range: 0.38-1.64) for samples collected from the vicinity of the NPP and 1.93 ± 0.50 (range: 1.35-3.19) for the control region. Recording higher NE-OBT activity concentration and R-value at the control region highlights the necessity of detailed studies to understand the mechanism of NE-OBT partitioning in the terrestrial environment.

Recognition of single-stranded nucleic acids by small-molecule splicing modulators.

Risdiplam is the first approved small-molecule splicing modulator for the treatment of spinal muscular atrophy (SMA). Previous studies demonstrated that risdiplam analogues have two separate binding sites in exon 7 of the SMN2 pre-mRNA: (i) the 5'-splice site and (ii) an upstream purine (GA)-rich binding site. Importantly, the sequence of this GA-rich binding site significantly enhanced the potency of risdiplam analogues. In this report, we unambiguously determined that a known risdiplam analogue, SMN-C2, binds to single-stranded GA-rich RNA in a sequence-specific manner. The minimum required binding sequence for SMN-C2 was identified as GAAGGAAGG. We performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which captured spontaneous binding of a risdiplam analogue to the target nucleic acids. We uncovered, for the first time, a ligand-binding pocket formed by two sequential GAAG loop-like structures. The simulation findings were highly consistent with experimental data obtained from saturation transfer difference (STD) NMR and structure-affinity-relationship studies of the risdiplam analogues. Together, these studies illuminate us to understand the molecular basis of single-stranded purine-rich RNA recognition by small-molecule splicing modulators with an unprecedented binding mode.

Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

Where Does Interventional Radiology Fit in with Trauma Management Algorithm?

Trauma is a major cause of death in the United States, particularly in the younger population. Many traumatic deaths, as well as major morbidity, occur secondary to uncontrolled hemorrhage and eventual exsanguination. Interventional radiology plays a major role in treating these patients, and interventional techniques have evolved to the point where they are an integral part of treatment in these critically ill patients. This article reviews the role of interventional radiology in the treatment algorithms for traumatic injury sponsored by major societies and associations.