Prediction of measles cases in US counties: A machine learning approach.

BACKGROUND: Although measles was declared eliminated from the United States in 2000, the frequency of measles outbreaks has increased in recent years. The ability to predict the locations of future cases could aid efforts to prevent and contain measles in the United States. METHODS: We estimated county-level measles risk using a machine learning model with 17 predictor variables, which was trained on 2014 and 2018 United States county-level measles case data and tested on data from 2019. We compared the predicted and actual locations of 2019 measles cases. RESULTS: The model accurately predicted 95 % (specificity) of United States counties without measles cases and 72 % (sensitivity) of the United States counties that experienced ≥1 measles case in 2019, accounting for 94 % of all measles cases in 2019. Among the top 30 counties with the highest risk scores, the model accurately predicted 22 (73 %) counties with a measles case in 2019, corresponding to 72 % of all measles cases. CONCLUSIONS: This machine learning model accurately predicted a majority of the United States counties at high risk for measles and could be used as a framework by state and national health agencies in their measles prevention and containment efforts.

Past, present, and future policy considerations regarding meningococcal vaccination in the United States.

INTRODUCTION: In 2005, the United States Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination against invasive meningococcal disease (IMD) caused by serogroups A, C, W, and Y (MenACWY) for all 11-12-year-olds, as well as 2-10-year-olds at high risk. In 2010, a booster dose was recommended for all 16-year-olds, as well as for high-risk patients every 3-5 years. In 2015, optional (as opposed to routine) vaccination against meningococcal serogroup B (MenB) at the preferred age of 16-18 years was recommended (Category B, later changed to shared clinical decision-making). In 2023, a vaccine (MenABCWY) against the five serogroups primarily responsible for IMD in the U.S. became available. AREAS COVERED: This review summarizes the evolution of public policy that led to each milestone vaccine recommendation, reviews epidemiologic data published following the recommendations, and discusses the current state of meningococcal immunization policy. EXPERT OPINION: The use of MenABCWY has the potential to consolidate policy, improve coverage rates for the five serogroups, address disparities in vaccination coverage, and simplify vaccine delivery.

SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3-KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3-KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling.

Structure of biofilm-forming functional amyloid PSMα1 from Staphylococcus aureus.

Biofilm-protected pathogenic Staphylococcus aureus causes chronic infections that are difficult to treat. An essential building block of these biofilms are functional amyloid fibrils that assemble from phenol-soluble modulins (PSMs). PSMα1 cross-seeds other PSMs into cross-ß amyloid folds and is therefore a key element in initiating biofilm formation. However, the paucity of high-resolution structures hinders efforts to prevent amyloid assembly and biofilm formation. Here, we present a 3.5 Å resolution density map of the major PSMα1 fibril form revealing a left-handed cross-ß fibril composed of two C2-symmetric U-shaped protofilaments whose subunits are unusually tilted out-of-plane. Monomeric α-helical PSMα1 is extremely cytotoxic to cells, despite the moderate toxicity of the cross-ß fibril. We suggest mechanistic insights into the PSM functional amyloid formation and conformation transformation on the path from monomer-to-fibril formation. Details of PSMα1 assembly and fibril polymorphism suggest how S. aureus utilizes functional amyloids to form biofilms and establish a framework for developing therapeutics against infection and antimicrobial resistance.

Scintigraphic Imaging of Extra-Esophageal Manifestation of Gastresophageal Reflux Disease.

OBJECTIVES: There is currently no reference standard test for the detection of the extra-esophageal manifestations of gastroesophageal reflux disease (GERD). The current suite of diagnostic tests principally assesses reflux events in the esophagus. A new scintigraphic technique has been developed and validated against reference standards. It allows direct visualization of refluxate in the laryngopharynx and lungs. METHODS: Fifty patients were assessed by scintigraphy before and after fundoplication at a single nuclear medicine facility. Standardized reflux symptom indices (RSIs) were obtained from each patient before and after surgery. Patients were scanned after oral 99 m technetium Fyton administration with early dynamic images and delayed SPECT/CT images of the head, neck, and lungs. ANOVA, Spearman correlation, and the Student's t-test were utilized for analysis. RESULTS: The study population (35F, 15 M) had a mean age of 63.9 years. Mean BMI was 26.8 with 67% being overweight or obese. All patients had significant reflux. SPECT/CT showed LPR events in 45/50 and pulmonary micro-aspiration (PMA) in 45/50 preoperatively and in 36/50 and 20/50 postoperatively, respectively. The RSI, cough, and throat clearing indices showed a significant fall postoperatively (p < 0.001). Frequency of scintigraphic reflux events was reduced from a mean of 4.5 in 30 min to 2.9 (t = 9.1, p = 0.004). CONCLUSION: The novel scintigraphic test detects esophageal and extra-esophageal reflux events and permits direct visualization of refluxate in the head and neck structures and lungs. It correlates well with symptoms of reflux in the esophagus and extra-esophageal structures and the response to therapy. LEVEL OF EVIDENCE: Although prospective, the study did not randomize patients and in effect each patient became their own control following an intervention (fundoplication). Thus, the study is Level 3 evidence Laryngoscope, 2024.

Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease.

Introduction: Inflammation is a significant contributor to cardiorenal morbidity and mortality in diabetic kidney disease (DKD). The pathophysiological mechanisms linking systemic, subacute inflammation and local, kidney injury-initiated immune maladaptation is partially understood. Methods: Here, we explored the expression of proinflammatory cytokines in patients with DKD; investigated mouse models of type 1 and type 2 diabetes (T2D); evaluated glomerular signaling in vitro; performed post hoc analyses of systemic and urinary markers of inflammation; and initiated a phase 2b clinical study (FRONTIER-1; NCT04170543). Results: Transcriptomic profiling of kidney biopsies from patients with DKD revealed significant glomerular upregulation of interleukin-33 (IL-33). Inhibition of IL-33 signaling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model (T2D/DKD). On a cellular level, inhibiting IL-33 improved glomerular endothelial health by decreasing cellular inflammation and reducing release of proinflammatory cytokines. Therefore, FRONTIER-1 was designed to test the safety and efficacy of the IL-33-targeted monoclonal antibody tozorakimab in patients with DKD. So far, 578 patients are enrolled in FRONTIER-1. The baseline inflammation status of participants (N > 146) was assessed in blood and urine. Comparison to independent reference cohorts (N > 200) validated the distribution of urinary tumor necrosis factor receptor 1 (TNFR1) and C-C motif chemokine ligand 2 (CCL2). Treatment with dapagliflozin for 6 weeks did not alter these biomarkers significantly. Conclusion: We show that blocking the IL-33 pathway may mitigate glomerular endothelial inflammation in DKD. The findings from the FRONTIER-1 study will provide valuable insights into the therapeutic potential of IL-33 inhibition in DKD.

Myxococcus xanthus encapsulin cargo protein EncD is a flavin-binding protein with ferric reductase activity.

Encapsulins are protein nanocompartments that regulate cellular metabolism in several bacteria and archaea. Myxococcus xanthus encapsulins protect the bacterial cells against oxidative stress by sequestering cytosolic iron. These encapsulins are formed by the shell protein EncA and three cargo proteins: EncB, EncC, and EncD. EncB and EncC form rotationally symmetric decamers with ferroxidase centers (FOCs) that oxidize Fe+2 to Fe+3 for iron storage in mineral form. However, the structure and function of the third cargo protein, EncD, have yet to be determined. Here, we report the x-ray crystal structure of EncD in complex with flavin mononucleotide. EncD forms an α-helical hairpin arranged as an antiparallel dimer, but unlike other flavin-binding proteins, it has no ß-sheet, showing that EncD and its homologs represent a unique class of bacterial flavin-binding proteins. The cryo-EM structure of EncA-EncD encapsulins confirms that EncD binds to the interior of the EncA shell via its C-terminal targeting peptide. With only 100 amino acids, the EncD α-helical dimer forms the smallest flavin-binding domain observed to date. Unlike EncB and EncC, EncD lacks a FOC, and our biochemical results show that EncD instead is a NAD(P)H-dependent ferric reductase, indicating that the M. xanthus encapsulins act as an integrated system for iron homeostasis. Overall, this work contributes to our understanding of bacterial metabolism and could lead to the development of technologies for iron biomineralization and the production of iron-containing materials for the treatment of various diseases associated with oxidative stress.

Ionic liquid-coated lipid nanoparticles increase siRNA uptake into CNS targets.

Lipidoid nanoparticles (LNPs) have transformed the field of drug delivery and are clinically used for the delivery of nucleic acids to liver and muscle targets. Post-intravenous administration, LNPs are naturally directed to the liver due to the adsorption of plasma proteins like apolipoprotein E. In the present work, we have re-engineered LNPs with ionic liquids (ILs) to reduce plasma protein adsorption and potentially increase the accumulation of LNPs in hard-to-deliver central nervous system (CNS) targets such as brain endothelial cells (BECs) and neurons. We have developed two approaches to re-engineer LNPs using a choline trans-2-hexenoate IL: first, we have optimized an IL-coating process using the standard LNP formulation and in the second approach, we have incorporated ILs into the LNPs by replacing the PEG-lipid component in the standard formulation using ILs. IL-coated as well as IL-incorporated LNPs were colloidally stable with morphologies similar to the standard LNPs. IL-coated LNPs showed superior uptake into mouse BECs and neurons and demonstrated reduced mouse plasma protein adsorption compared to the standard LNPs. Overall, our results (1) demonstrate the feasibility of re-engineering the clinically approved LNP platform with highly tunable biomaterials like ILs for the delivery of therapeutics to CNS targets like BECs and neurons and (2) suggest that the surface properties of LNPs play a critical role in altering their affinity to and uptake into hard-to-deliver cell types.

Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy.

The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment.

Continuing Professional Development at Two Rural Hospitals in Ecuador.

Background: E-learning Continuing Professional Development (CPD) is an activity demonstrated to improve the quality of healthcare delivery. The CPD of medical and nursing staff in high income countries (HICs) is commonplace. CPD of administrative staff is less common, but increasingly frequent. In low- and middle-income countries (LMICs), CPD of any kind is infrequent, particularly in rural and remote areas. Objective: The aim of this study was to describe a hospital-based e-learning CPD program for clinical and non-clinical personnel as a unique example of a successful, ongoing educational pilot, quality improvement program involving a broad cohort of employees, in a country that does not require such activities. Methods: Using the online educational platform Chamilo, e-learning modules were created for eight groups including clinical and non-clinical employees. Upon completion of each module, one to two paragraph discussions were provided for each incorrect answer submitted. Two additional chances were offered for the employee to achieve a passing score of 70%. This study reports on the first 10-month period of the program. Findings: All participants achieved the 70% passing threshold after the first or second attempt. There was 100% participation by the employees required to complete the e-learning modules. Employee feedback suggested the modules were good for continuing education, but some felt the CPD was imposed on them. Conclusion: E-learning CPD is an important and emerging element for CPD and may provide opportunities for healthcare service quality improvement as part of broader pedagogical modalities, such as conferences and directed readings, in rural and remote areas of LMICs. These pilot programs could provide important information to develop Spanish-language e-learning CPD programs across a broader region, promote collaboration with regional professional societies, and possibly contribute to the establishment of national health program CPD standards.

Cultivation, chemistry, and genome of Psilocybe zapotecorum.

Psilocybe zapotecorum is a strongly blue-bruising psilocybin mushroom used by indigenous groups in southeastern Mexico and beyond. While this species has a rich history of ceremonial use, research into its chemistry and genetics have been limited. Herein, we detail mushroom morphology and report on cultivation parameters, chemical profile, and the full genome sequence of P. zapotecorum . First, growth and cloning methods are detailed that are simple, and reproducible. In combination with high resolution microscopic analysis, the strain was barcoded, confirming species-level identification. Full genome sequencing reveals the architecture of the psilocybin gene cluster in P. zapotecorum, and can serve as a reference genome for Psilocybe Clade I. Characterization of the tryptamine profile revealed a psilocybin concentration of 17.9±1.7 mg/g, with a range of 10.6-25.7 mg/g (n=7), and similar tryptamines (psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, 4-HO-tryptamine, and tryptamine) in lesser concentrations for a combined tryptamine concentration of 22.5±3.2 mg/g. These results show P. zapotecorum to be a potent - and variable - Psilocybe mushroom. Chemical profiling, genetic analysis, and cultivation assist in demystifying these mushrooms. As clinical studies with psilocybin gain traction, understanding the diversity of psilocybin mushrooms will assure that psilocybin therapy does not become synonymous with psilocybin mushrooms.

Defined extracellular matrix compositions support stiffness-insensitive cell spreading and adhesion signaling.

Integrin-dependent adhesion to the extracellular matrix (ECM) mediates mechanosensing and signaling in response to altered microenvironmental conditions. In order to provide tissue- and organ-specific cues, the ECM is composed of many different proteins that temper the mechanical properties and provide the necessary structural diversity. Despite most human tissues being soft, the prevailing view from predominantly in vitro studies is that increased stiffness triggers effective cell spreading and activation of mechanosensitive signaling pathways. To address the functional coupling of ECM composition and matrix rigidity on compliant substrates, we developed a matrix spot array system to screen cell phenotypes against different ECM mixtures on defined substrate stiffnesses at high resolution. We applied this system to both cancer and normal cells and surprisingly identified ECM mixtures that support stiffness-insensitive cell spreading on soft substrates. Employing the motor-clutch model to simulate cell adhesion on biochemically distinct soft substrates, with varying numbers of available ECM-integrin-cytoskeleton (clutch) connections, we identified conditions in which spreading would be supported on soft matrices. Combining simulations and experiments, we show that cell spreading on soft is supported by increased clutch engagement on specific ECM mixtures and even augmented by the partial inhibition of actomyosin contractility. Thus, "stiff-like" spreading on soft is determined by a balance of a cell's contractile and adhesive machinery. This provides a fundamental perspective for in vitro mechanobiology studies, identifying a mechanism through which cells spread, function, and signal effectively on soft substrates.

Health Care Providers Working Cross-Culturally: Pitfalls, Pearls, and Preparation Resources for Culture Shock.

Health care providers engaging in cross-cultural work will likely experience culture shock, a psychological, behavioral, and physiologic response to new cultural environments that can significantly affect travelers. Culture shock has the potential for both negative and positive outcomes. Well-being, health, and professionalism can be negatively influenced during the peak of culture shock, but the experience may also positively promote transformative learning and professional identity formation. Culture shock has been carefully researched for different types of sojourners, such as undergraduate students and business personnel, but minimally for health care providers. This article defines culture shock, describes different health care-related cross-cultural opportunities, identifies factors contributing to culture shock, describes complexities related to measuring culture shock, depicts common cross-cultural challenges encountered by traveling health care providers, and offers tangible guidance to help prepare for culture shock. We conclude with a call for further research and resource development to support the well-being of an increasingly global health care workforce. [Pediatr Ann. 2023;52(9):e335-e343.].

IGFBP2 secretion by mammary adipocytes limits breast cancer invasion.

The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is the precursor to metastatic disease. In this work, we have identified insulin-like growth factor-binding protein 2 (IGFBP2) as a potent adipocrine factor secreted by healthy breast adipocytes that acts as a barrier against invasive progression. In line with this role, adipocytes differentiated from patient-derived stromal cells were found to secrete IGFBP2, which significantly inhibited breast cancer invasion. This occurred through binding and sequestration of cancer-derived IGF-II. Moreover, depletion of IGF-II in invading cancer cells using small interfering RNAs or an IGF-II-neutralizing antibody ablated breast cancer invasion, highlighting the importance of IGF-II autocrine signaling for breast cancer invasive progression. Given the abundance of adipocytes in the healthy breast, this work exposes the important role they play in suppressing cancer progression and may help expound upon the link between increased mammary density and poorer prognosis.

A symmetry mismatch unraveled: How phage HK97 scaffold flexibly accommodates a 12-fold pore at a 5-fold viral capsid vertex.

Tailed bacteriophages and herpesviruses use a transient scaffold to assemble icosahedral capsids with hexameric capsomers on the faces and pentameric capsomers at all but one vertex where a 12-fold portal is thought to nucleate the assembly. How does the scaffold orchestrate this step? We have determined the portal vertex structure of the bacteriophage HK97 procapsid, where the scaffold is a domain of the major capsid protein. The scaffold forms rigid helix-turn-strand structures on the interior surfaces of all capsomers and is further stabilized around the portal, forming trimeric coiled-coil towers, two per surrounding capsomer. These 10 towers bind identically to 10 of 12 portal subunits, adopting a pseudo-12-fold organization that explains how the symmetry mismatch is managed at this early step.

Insights into a viral motor: the structure of the HK97 packaging termination assembly.

Double-stranded DNA viruses utilise machinery, made of terminase proteins, to package viral DNA into the capsid. For cos bacteriophage, a defined signal, recognised by small terminase, flanks each genome unit. Here we present the first structural data for a cos virus DNA packaging motor, assembled from the bacteriophage HK97 terminase proteins, procapsids encompassing the portal protein, and DNA containing a cos site. The cryo-EM structure is consistent with the packaging termination state adopted after DNA cleavage, with DNA density within the large terminase assembly ending abruptly at the portal protein entrance. Retention of the large terminase complex after cleavage of the short DNA substrate suggests that motor dissociation from the capsid requires headful pressure, in common with pac viruses. Interestingly, the clip domain of the 12-subunit portal protein does not adhere to C12 symmetry, indicating asymmetry induced by binding of the large terminase/DNA. The motor assembly is also highly asymmetric, showing a ring of 5 large terminase monomers, tilted against the portal. Variable degrees of extension between N- and C-terminal domains of individual subunits suggest a mechanism of DNA translocation driven by inter-domain contraction and relaxation.

A comprehensive review of clinical and real-world safety data for the four-component serogroup B meningococcal vaccine (4CMenB).

INTRODUCTION: Neisseria meningitidis causes invasive meningococcal disease and, globally, significant morbidity, with serogroup B (MenB) being the most common cause of endemic disease and outbreaks in several regions. Extensive use of the four-component serogroup B meningococcal vaccine (4CMenB; Bexsero, GSK) and its inclusion in immunization programs in several countries have generated substantial safety data during the 9 years since its first authorization in 2013. AREAS COVERED: 4CMenB safety data from clinical trials and post-marketing surveillance studies (2011 to 2022), and spontaneously reported adverse events of medical interest from the GSK global safety database. We discuss these safety findings in relation to the benefit of 4CMenB vaccination and implications for further enhancing vaccine confidence. EXPERT OPINION: 4CMenB has been consistently well tolerated across clinical trials and post-licensure surveillance studies, despite a higher incidence of fever reported in infants than with other pediatric vaccines. Surveillance data have not identified any significant safety issues, consistent with an acceptable safety profile of 4CMenB. These findings highlight the need to balance the risk of relatively common, transient, post-immunization fever with the benefit of affording protection that reduces the risk of uncommon but potentially fatal meningococcal infection.

The four-component serogroup B meningococcal vaccine 4CMenB (Bexsero®, GSK) was licensed in 2013 and has acquired substantial safety evidence through clinical trial and real-world data. Availability of real-world and clinical 4CMenB safety evidence is important to help address vaccination hesitancy. This comprehensive review of safety data, from 9 years of 4CMenB use including recent data from the real world, shows no significant safety issues in a variety of age groups. Data show that transient fever may occur after vaccination. Invasive meningococcal disease, although rare, can be life-threatening. Abundant safety data from this review can help reassure individuals and healthcare providers on the use of 4CMenB.

Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse.

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models. We also show that the dynamics of AKT activation can be monitored in real time in diverse tissues, including in individual islets of the pancreas, in the brown and white adipose tissue, and in the skeletal muscle. Thus, the Akt-FRET biosensor mouse provides an important tool to study AKT dynamics in live tissue contexts and has broad preclinical applications.

Health facility assessments of cervical cancer prevention, early diagnosis, and treatment services in Gulu, Uganda.

BACKGROUND: Cervical cancer is ranked globally in the top three cancers for women younger than 45 years, with the average age of death at 59 years of age. The highest burden of disease is in low-to-middle income countries (LMICs), responsible for 90% of the 311,000 cervical cancer deaths in 2018. This growing health disparity is due to the lack of quality screening and treatment programs, low human papillomavirus (HPV) vaccination rates, and high human immunodeficiency virus (HIV) co-infection rates. To address these gaps in care, we need to develop a clear understanding of the resources and capabilities of LMICs' health care facilities to provide prevention, early diagnosis through screening, and treatment for cervical cancer. OBJECTIVES: This project aimed to assess baseline available cervical cancer prevention, early diagnosis, and treatment resources, at facilities designated as Health Center III or above, in Gulu, Uganda. METHODS: We adapted the World Health Organization's Harmonized Health Facility Assessment for our own HFA and grading scale, deploying it in October 2021 for a cross-sectional analysis of 21 health facilities in Gulu. RESULTS: Grading of Health Center IIIs (n = 16) concluded that 37% had "excellent" or "good" resources available, and 63% of facilities had "poor" or "fair" resources available. Grading of Health Center IVs and above (n = 5) concluded that 60% of facilities had "excellent" or "good" resources, and 40% had "fair" resources available. DISCUSSION: The analysis of health facilities in Gulu demonstrated subpar resources available for cervical cancer prevention, early diagnosis, and treatment. Focused efforts are needed to expand health centers' resources and capability to address rising cervical cancer rates and related health disparities in LMICs. The development process for this project's HFA can be applied to global cervical cancer programming to determine gaps in resources and indicate areas to target improved health equity.