Machine learning-guided engineering of genetically encoded fluorescent calcium indicators.

Here we used machine learning to engineer genetically encoded fluorescent indicators, protein-based sensors critical for real-time monitoring of biological activity. We used machine learning to predict the outcomes of sensor mutagenesis by analyzing established libraries that link sensor sequences to functions. Using the GCaMP calcium indicator as a scaffold, we developed an ensemble of three regression models trained on experimentally derived GCaMP mutation libraries. The trained ensemble performed an in silico functional screen on 1,423 novel, uncharacterized GCaMP variants. As a result, we identified the ensemble-derived GCaMP (eGCaMP) variants, eGCaMP and eGCaMP+, which achieve both faster kinetics and larger ∆F/F0 responses upon stimulation than previously published fast variants. Furthermore, we identified a combinatorial mutation with extraordinary dynamic range, eGCaMP2+, which outperforms the tested sixth-, seventh- and eighth-generation GCaMPs. These findings demonstrate the value of machine learning as a tool to facilitate the efficient engineering of proteins for desired biophysical characteristics.

Point-of-Care Ultrasound of a Nasal Septal Abscess.

ABSTRACT: Although nasal septal abscesses (NSA) are rare, complications can be significant and devastating. Thus, timely diagnosis of NSA is critical. In this case report, we describe the use of point-of-care ultrasound in diagnosing NSA in a healthy boy presenting with viral upper respiratory infection symptoms and fever. Point-of-care ultrasound findings resulted in expediting this patient's treatment and transfer to a quaternary care center for definitive treatment.

Development and application of a multiple reaction monitoring method for the simultaneous quantification of sodium channels Nav 1.1, Nav 1.2, and Nav 1.6 in solubilized membrane proteins from stable HEK293 cell lines, rodents, and human brain tissues.

RATIONALE: Nav 1.1, 1.2, and 1.6 are transmembrane proteins acting as voltage-gated sodium channels implicated in various forms of epilepsy. There is a need for knowing their actual concentration in target tissues during drug development. METHODS: Unique peptides for Nav 1.1, Nav 1.2, and Nav 1.6 were selected as quantotropic peptides for each protein and used for their quantification in membranes from stably transfected HEK293 cells and rodent and human brain samples using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. RESULTS: Nav 1.1, 1.2, and 1.6 protein expressions in three stably individually transfected HEK293 cell lines were found to be 2.1 ± 0.2, 6.4 ± 1.2, and 4.0 ± 0.6 fmol/µg membrane protein, respectively. In brains, Nav 1.2 showed the highest expression, with approximately three times higher (P < 0.003) in rodents than in humans at 3.05 ± 0.57, with 3.35 ± 0.56 in mouse and rat brains and 1.09 ± 0.27 fmol/µg in human brain. Both Nav 1.1 and 1.6 expressions were much lower in the brains, with approximately 40% less expression in human Nav 1.1 than rodent Nav 1.1 at 0.49 ± 0.1 (mouse), 0.43 ± 0.3 (rat), and 0.28 ± 0.04 (humans); whereas Nav 1.6 had approximately 60% less expression in humans than rodents at 0.27 ± 0.09 (mouse), 0.26 ± 0.06 (rat), and 0.11 ± 0.02 (humans) fmol/µg membrane proteins. CONCLUSIONS: Multiple reaction monitoring was used to quantify sodium channels Nav 1.1, 1.2, and 1.6 expressed in stably transfected HEK293 cells and brain tissues from mice, rats, and humans. We found significant differences in the expression of these channels in mouse, rat, and human brains. Nav expression ranking among the three species was Nav 1.2 ≫ Nav 1.1 > Nav 1.6, with the human brain expressing much lower concentrations overall compared to rodent brain.

Review of pediatric emergency care and the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic posed new challenges in health care delivery for patients of all ages. These included inadequate personal protective equipment, workforce shortages, and unknowns related to a novel virus. Children have been uniquely impacted by COVID-19, both from the system of care and socially. In the initial surges of COVID-19, a decrease in pediatric emergency department (ED) volume and a concomitant increase in critically ill adult patients resulted in re-deployment of pediatric workforce to care for adult patients. Later in the pandemic, a surge in the number of critically ill children was attributed to multisystem inflammatory syndrome in children. This was an unexpected complication of COVID-19 and further challenged the health care system. This article reviews the impact of COVID-19 on the entire pediatric emergency care continuum, factors affecting ED care of children with COVID-19 infection, including availability of vaccines and therapeutics approved for children, and pediatric emergency medicine workforce innovations and/or strategies. Furthermore, it provides guidance to emergency preparedness for optimal delivery of care in future health-related crises.

The Utility of a Virtual Emergency Medicine Elective for Visiting Medical Students.

Background Away rotations allow emergency medicine (EM)-bound fourth-year medical students to experience a residency program's educational culture and influence the ranking of residency programs. The financial cost and geographic distance have limited student participation in away electives. In recent years, COVID-19 pandemic-related restrictions on away rotations resulted in the creation of multiple virtual courses. Despite the lifting of restrictions, these courses may still have utility in helping students circumvent barriers to away rotations. Limitations of previously described courses include insufficient student-faculty interaction, which influences students' understanding of the educational environment. We sought to develop and evaluate a virtual EM elective for fourth-year medical students, focused on student-faculty interaction including precepted patient contact. Methodology We developed a two-week virtual EM elective for fourth-year medical students incorporating teaching sessions designed to optimize student-faculty interactions and attending-supervised telemedicine visits. After completion of the course, students completed an anonymous course evaluation. Results Course evaluations showed that the course improved students' understanding of our residency's educational environment by providing students with access to our residency program. The most frequently cited factors preventing participation in a traditional away elective were financial cost, limit in the allowed number of away rotations, and challenges in finding housing. Conclusions We believe this course may be an effective way of improving visiting students' understanding of the educational culture of our EM residency program. Thus, although pandemic-related restrictions have been lifted, this course may serve as a valuable adjunct to the traditional away EM rotation.

Novel RXFP3 negative allosteric modulator RLX-33 reduces alcohol self-administration in rats.

There is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising target for therapeutic intervention is the relaxin family peptide 3 (RXFP3) receptor, a cognate receptor for neuropeptide relaxin-3, which has previously been implicated in regulating alcohol drinking behavior. Recently, we developed the first small-molecule RXFP3-selective negative allosteric modulator (NAM) RLX-33. Therefore, the goal of the present work was to characterize the impact of this novel NAM on affective-related behaviors and alcohol self-administration in rats. First, the effects of RLX-33 were tested on alcohol and sucrose self-administration in Wistar and alcohol-preferring P rats to determine the dose-response profile and specificity for alcohol. Then, we assessed the effects of systemic RLX-33 injection in Wistar rats in a battery of behavioral assays (open-field test, elevated zero maze, acoustic startle response test, and prepulse inhibition) and tested for alcohol clearance. We found that the lowest effective dose (5 mg/kg) reduced alcohol self-administration in both male and female Wistar rats, while in alcohol-preferring P rats, this effect was restricted to males, and there were no effects on sucrose self-administration or general locomotor activity. The characterization of affective and metabolic effects in Wistar rats generally found few locomotor, affective, or alcohol clearance changes, particularly at the 5 mg/kg dose. Overall, these findings are promising and suggest that RXFP3 NAM has potential as a pharmacological target for treating AUD.

Structure-function relationship of new peptides activating human Nav1.1.

Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.

Curated collections for educators: Nine key articles and article series for teaching qualitative research methods.

Background: Qualitative research explains observations, focusing on how and why phenomena and experiences occur. Qualitative methods go beyond quantitative data and provide critical information inaccessible through quantitative methods. However, at all levels of medical education, there is insufficient exposure to qualitative research. As a result, residents and fellows complete training ill-equipped to appraise and conduct qualitative studies. As a first step to increasing education in qualitative methods, we sought to create a curated collection of papers for faculty to use in teaching qualitative research at the graduate medical education (GME) level. Methods: We conducted literature searches on the topic of teaching qualitative research to residents and fellows and queried virtual medical education and qualitative research communities for relevant articles. We searched the reference lists of all articles found through the literature searches and online queries for additional articles. We then conducted a three-round modified Delphi process to select papers most relevant to faculty teaching qualitative research. Results: We found no articles describing qualitative research curricula at the GME level. We identified 74 articles on the topic of qualitative research methods. The modified Delphi process identified the top nine articles or article series most relevant for faculty teaching qualitative research. Several articles explain qualitative methods in the context of medical education, clinical care, or emergency care research. Two articles describe standards of high-quality qualitative studies, and one article discusses how to conduct the individual qualitative interview to collect data for a qualitative study. Conclusions: While we identified no articles reporting already existing qualitative research curricula for residents and fellows, we were able to create a collection of papers on qualitative research relevant to faculty seeking to teach qualitative methods. These papers describe key qualitative research concepts important in instructing trainees as they appraise and begin to develop their own qualitative studies.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or ß-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.

Long-Term Consumption of 10 Food Groups and Cardiovascular Mortality: A Systematic Review and Dose Response Meta-Analysis of Prospective Cohort Studies.

A large body of evidence exists on diet and cardiovascular mortality, but limited studies have investigated the long-term intake of food groups, which may have cumulative effects on cardiovascular health in the long term. This review therefore evaluated the relationship between the long-term consumption of 10 food groups and cardiovascular mortality. We conducted a systematic search in Medline, Embase, Scopus, CINAHL, and Web of Science till January 2022. Of the 5318 studies initially identified, 22 studies with a total of 70,273 participants with cardiovascular mortality were included. Summary HRs and 95% CIs were estimated using a random effects model. We found that a long-term high intake of whole grains (HR: 0.87; 95% CI: 0.80, 0.95; P = 0.001), fruits and vegetables (HR: 0.72; 95% CI: 0.61, 0.85; P < 0.0001), and nuts (HR: 0.73; 95% CI: 0.66, 0.81; P < 0.00001) significantly reduced cardiovascular mortality. Each 10-gram increase in whole grain consumption per day was associated with a 4% reduction in the risk of cardiovascular mortality, whereas each 10-gram increase in red/processed meat consumption per day was associated with a 1.8% increase in the risk of cardiovascular mortality. Compared with the lowest intake category, red/processed meat consumption in the highest category was associated with an increased risk of cardiovascular mortality (HR: 1.23; 95% CI: 1.09, 1.39; P = 0.006). High intake of dairy products (HR: 1.11; 95% CI: 0.92, 1.34; P = 0.28), and legumes (HR: 0.86; 95% CI: 0.53, 1.38; P = 0.53) were not associated with cardiovascular mortality. However, in the dose-response analysis, each 10-gram increase in legume intake per week was associated with a 0.5% reduction in cardiovascular mortality. We conclude that the long-term high intake of whole grains, vegetables, fruits, nuts, and a low intake of red/processed meat are associated with reduced cardiovascular mortality. More data on the long-term effects of legumes on cardiovascular mortality are encouraged. This study was registered at PROSPERO as CRD42020214679.

Comparing Factors Associated With Intimate Partner Violence Among Rural and Urban Women in Northern Uganda.

Intimate partner violence (IPV) is an important public health issue with negative effects at individual and societal levels. In northern Uganda, IPV prevalence is high but literature on it is limited. Northern Uganda has a long history of socio-economic and political upheavals, which are recognized risk factors for IPV. We compare IPV prevalence among rural and urban women in northern Uganda. This was a cross-sectional survey of 856 northern Ugandan women, 409 women living in rural areas, and 447 women working in an urban marketplace. Data were analyzed using logistic regression. High rates of emotional, physical, and sexual IPV were found. Almost four of five participants had experienced at least one type of IPV during their lifetime, and approximately half of the participants had experienced IPV in the 12 months prior to the survey. Many women stated that IPV was justified in certain situations. Younger age was a significant determinant of IPV in both cohorts (adjusted odds ratio [aOR] 0.95, 95% confidence interval [CI] [0.93-0.97]). Determinants of IPV among the rural cohort included male partner's alcohol abuse (aOR 2.22, CI [1.34-3.73]); having been in a physical fight with another man (aOR 1.90, 95% CI [1.12-3.23]); and controlling behaviors (aOR 1.21, CI [1.08-1.36]). Possible protective factors in the urban cohort included markers of economic empowerment such as being the decision maker on large household items (59.2% vs. 44.6%, p = .002) and having a mobile phone (20.4% vs. 12.4%, p = .024). Our study shows that IPV is a significant issue in northern Uganda. Economic empowerment is associated with lower rates of IPV in urban women, and interventions to reduce gender wealth inequality may reduce IPV prevalence. Further studies on enablers of IPV and the effect of conflict on IPV prevalence are needed to inform future interventions.

Small molecule inhibitor binds to NLRP3 and prevents inflammasome activation.

Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation. The fold of NLRP3 pyrin domain contains amino acids and a protein fold similar to hOGG1. Amino acids that enable hOGG1 to bind and cleave oxidized DNA are conserved in NLRP3. We found NLRP3 could bind and cleave oxidized guanine within mitochondrial DNA. The binding of oxidized DNA to NLRP3 was prevented by small molecule drugs which also inhibit hOGG1. These same drugs also inhibited inflammasome activation. Elucidating this mechanism will enable design of drug memetics that treat inflammasome pathologies, illustrated herein by NLRP3 pyrin domain inhibitors which suppressed interleukin-1ß (IL-1ß) production in macrophages. One-Sentence Summary: NLRP3 cleaves oxidized DNA and small molecule drug binding inhibits inflammasome activation.

Nondestructive and multiplex differentiation of pathogenic microorganisms from spoilage microflora on seafood using paper chromogenic array and neural network.

Non-destructive detection of human foodborne pathogens is critical to ensuring food safety and public health. Here, we report a new method using a paper chromogenic array coupled with a machine learning neural network (PCA-NN) to detect viable pathogens in the presence of background microflora and spoilage microbe in seafood via volatile organic compounds sensing. Morganella morganii and Shewanella putrefaciens were used as the model pathogen and spoilage bacteria. The study evaluated microbial detection in monoculture and cocktail multiplex detection. The accuracy of PCA-NN detection was first assessed on standard media and later validated on cod and salmon as real seafood models with pathogenic and spoilage bacteria, as well as background microflora. In this study PCA-NN method successfully identified pathogenic microorganisms from microflora with or without the prevalent spoilage microbe, Shewanella putrefaciens in seafood, with accuracies ranging from 90% to 99%. This approach has the potential to advance smart packaging by achieving nondestructive pathogen surveillance on food without enrichment, incubation, or other sample preparation.

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures.

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the nine human channel subtypes, Nav1.1, Nav1.2 and Nav1.6 are prominently expressed in the adult central nervous system (CNS). All three of these sodium channel subtypes are sensitive to block by the neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all three subtypes. In the present study we have used TTX to determine the fractional block of Nav channels required to impair action potential firing in pyramidal neurons and reduce network seizure-like activity. Using automated patch-clamp electrophysiology, we first determined the IC50s of TTX on mouse Nav1.1, Nav1.2 and Nav1.6 channels expressed in HEK cells, demonstrating this to be consistent with previously published data on human orthologs. We then compared this data to the potency of block of Nav current measured in pyramidal neurons from neocortical brain slices. Interestingly, we found that it requires nearly 10-fold greater concentration of TTX over the IC50 to induce significant block of action potentials using a current-step protocol. In contrast, concentrations near the IC50 resulted in a significant reduction in AP firing and increase in rheobase using a ramp protocol. Surprisingly, a 20% reduction in action potential generation observed with 3 nM TTX resulted in significant block of seizure-like activity in the 0 Mg2+ model of epilepsy. Additionally, we found that approximately 50% block in pyramidal cell intrinsic excitability is sufficient to completely block all seizure-like events. Furthermore, we also show that the anticonvulsant drug phenytoin blocked seizure-like events in a manner similar to TTX. These data serve as a critical starting point in understanding how fractional block of Nav channels affect intrinsic neuronal excitability and seizure-like activity. It further suggests that seizures can be controlled without significantly compromising intrinsic neuronal activity and determines the required fold over IC50 for novel and clinically relevant Nav channel blockers to produce efficacy and limit side effects.

Prevalence and characteristics of advocacy curricula in Australian public health degrees.

BACKGROUND: Public health advocacy is a fundamental part of health promotion practice. Advocacy efforts can lead to healthier public policies and positive impacts on society. Public health educators are responsible for equipping graduates with cross-cutting advocacy competencies to address current and future public health challenges. PROBLEM: Knowledge of the extent to which students are taught public health advocacy is limited. To determine whether advocacy teaching within public health degrees matches industry needs, knowledge of pedagogical approaches to advocacy curricula is required. This study sought to understand the extent to which advocacy is taught and assessed within Australian public health degrees. METHODOLOGY: Australian public health Bachelor's and Master's degrees were identified using the CRICOS database. Open-source online unit guides were reviewed to determine where and how advocacy was included within core and elective units (in title, unit description or learning outcomes). Degree directors and convenors of identified units were surveyed to further garner information about advocacy in the curriculum. RESULTS: Of 65 identified degrees, 17 of 26 (65%) undergraduate degrees and 24 of 39 (62%) postgraduate degrees included advocacy within the core curriculum, while 6 of 26 (23%) undergraduate and 8 of 39 (21%) postgraduate offered no advocacy curriculum. IMPLICATIONS: Australian and international public health competency frameworks indicate advocacy curriculum should be included in all degrees. This research suggests advocacy competencies are not ubiquitous within Australian public health curricula. The findings support the need to advance public health advocacy teaching efforts further.

NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

Applications of Musculoskeletal Ultrasound in the Pediatric Emergency Department.

Musculoskeletal ultrasound is an emerging point-of-care ultrasound (POCUS) imaging modality that can be used to assess patients who present to the pediatric emergency department with musculoskeletal complaints. It is useful in detecting effusions resulting from infection or injury and can also help identify fractures and foreign bodies. Ultrasound is particularly useful in guiding joint aspiration and foreign body removal. This article reviews the role of POCUS in evaluating for hip, knee, ankle, and elbow effusions, long bone fractures, and foreign bodies. [Pediatr Ann. 2021;50(10):e411-e418.].

Provision of cervical cancer prevention services in Northern Uganda: a survey of health workers from rural health centres.

BACKGROUND: Cervical cancer is the leading cancer among Ugandan women, contributing to 40 % of all cancer cases recorded in the cancer registry. Having identified the substantial impact of cervical cancer among Ugandan women, the Ministry of Health in 2010 launched a Strategic Plan for Cervical Cancer prevention and control. This study was conducted to determine if health workers working in rural health centres (HCs) III and IV in Northern Uganda provide cervical cancer screening services as recommended in the Strategic Plan. METHODS: A cross-sectional survey using a structured questionnaire was conducted among nurses, midwives and clinical officers working in rural HC III and IV in Northern Uganda. Data were entered in Epidata 3.1 and analysed using Stata 16 statistical software. Univariate, bivariate, and multivariate analyses were performed. Any factor with p-value ≤ 0.05 was considered a significant predictor of outcome. RESULTS: We surveyed 286 health workers. Fifty-one (18 %) health workers were screening women for cervical cancer. Fifty-eight (21 %) health workers have guideline for cervical cancer screening in their HCs, 93 (33 %) participants were trained to screen women for cervical cancer. Two hundred sixty-two (92 %) participants provided HPV vaccination. Two hundred forty-six (87 %) participants were conducting health education about cervical cancer in their HCs. Factors associated with screening women for cervical cancer include: being a staff member from HCs III (AOR = 0.30, 95 % CI 0.13-0.68, p = 0.00), being staff of HCs that have organization to support cervical cancer screening services (AOR = 4.38, 95 % CI 1.99-9.63, p-=0.00), being a health worker who had been trained to screen for cervical cancer (AOR = 2.21, 95 % CI 1.00-4.90, p = 0.05) and staff from HCs that has guideline for cervical cancer screening (AOR = 2.89, 95 % CI 1.22-6.86, p = 0.02). CONCLUSIONS: This study shows an overall structural problem related to the delivery of cervical cancer screening services in HC III and IV in Northern Uganda which the Strategic Plan has not addressed. These structural problems need urgent attention if the Uganda government and other sub-Saharan African (SSA) countries are to achieve the World Health Organization (WHO) 90-70-90 targets by 2030 to be on track for cervical cancer elimination.

Identification of aryl sulfonamides as novel and potent inhibitors of NaV1.5.

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of NaV1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide NaV inhibitors that bind to the channel voltage sensors, these NaV1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.