Long-term tolerance to skin commensals is established neonatally through a specialized dendritic cell subgroup.

Early-life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here, we showed that tolerance in skin was controlled by microbial interaction with a specialized subset of antigen-presenting cells. More particularly, CD301b+ type 2 conventional dendritic cells (DCs) in neonatal skin were specifically capable of uptake and presentation of commensal antigens for the generation of regulatory T (Treg) cells. CD301b+ DC2 were enriched for phagocytosis and maturation programs, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early-life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic-acid-producing enzyme, RALDH2, the deletion of which limited commensal-specific Treg cell generation. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early-life tolerance at the cutaneous interface.

Integration of estimated regional gene expression with neuroimaging and clinical phenotypes at biobank scale.

An understanding of human brain individuality requires the integration of data on brain organization across people and brain regions, molecular and systems scales, as well as healthy and clinical states. Here, we help advance this understanding by leveraging methods from computational genomics to integrate large-scale genomic, transcriptomic, neuroimaging, and electronic-health record data sets. We estimated genetically regulated gene expression (gr-expression) of 18,647 genes, across 10 cortical and subcortical regions of 45,549 people from the UK Biobank. First, we showed that patterns of estimated gr-expression reflect known genetic-ancestry relationships, regional identities, as well as inter-regional correlation structure of directly assayed gene expression. Second, we performed transcriptome-wide association studies (TWAS) to discover 1,065 associations between individual variation in gr-expression and gray-matter volumes across people and brain regions. We benchmarked these associations against results from genome-wide association studies (GWAS) of the same sample and found hundreds of novel associations relative to these GWAS. Third, we integrated our results with clinical associations of gr-expression from the Vanderbilt Biobank. This integration allowed us to link genes, via gr-expression, to neuroimaging and clinical phenotypes. Fourth, we identified associations of polygenic gr-expression with structural and functional MRI phenotypes in the Human Connectome Project (HCP), a small neuroimaging-genomic data set with high-quality functional imaging data. Finally, we showed that estimates of gr-expression and magnitudes of TWAS were generally replicable and that the p-values of TWAS were replicable in large samples. Collectively, our results provide a powerful new resource for integrating gr-expression with population genetics of brain organization and disease.

Evolving standards of care and new challenges in the management of HER2-positive breast cancer.

The management of human epidermal growth factor receptor (HER2)-positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2-targeted therapies for the treatment of early-stage and/or advanced-stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2-positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2-positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de-escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2-positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2-positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2-positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2-positive BC going forward.

Integrin mechanosensing relies on a pivot-clip mechanism to reinforce cell adhesion.

Cells intricately sense mechanical forces from their surroundings, driving biophysical and biochemical activities. This mechanosensing phenomenon occurs at the cell-matrix interface, where mechanical forces resulting from cellular motion, such as migration or matrix stretching, are exchanged through surface receptors, primarily integrins, and their corresponding matrix ligands. A pivotal player in this interaction is the α5ß1 integrin and fibronectin (FN) bond, known for its role in establishing cell adhesion sites for migration. However, upregulation of the α5ß1-FN bond is associated with uncontrolled cell metastasis. This bond operates through catch bond dynamics, wherein the bond lifetime paradoxically increases with greater force. The mechanism sustaining the characteristic catch bond dynamics of α5ß1-FN remains unclear. Leveraging molecular dynamics simulations, our approach unveils a pivot-clip mechanism. Two key binding sites on FN, namely the synergy site and the RGD (Arg-Gly-Asp) motif, act as active points for structural changes in α5ß1 integrin. Conformational adaptations at these sites are induced by a series of hydrogen bond formations and breaks at the synergy site. We disrupt these adaptations through a double mutation on FN, known to reduce cell adhesion. A whole-cell finite-element model is employed to elucidate how the synergy site may promote dynamic α5ß1-FN binding, resisting cell contraction. In summary, our study integrates molecular- and cellular-level modeling to propose that FN's synergy site reinforces cell adhesion through enhanced binding dynamics and a mechanosensitive pivot-clip mechanism. This work sheds light on the interplay between mechanical forces and cell-matrix interactions, contributing to our understanding of cellular behaviors in physiological and pathological contexts.

Cell-Free Nonequilibrium Assembly for Hierarchical Protein/Peptide Nanopillars.

Cells contain intricate protein nanostructures, but replicating them outside of cells presents challenges. One such example is the vertical fibronectin pillars observed in embryos. Here, we demonstrate the creation of cell-free vertical fibronectin pillar mimics using nonequilibrium self-assembly. Our approach utilizes enzyme-responsive phosphopeptides that assemble into nanotubes. Enzyme action triggers shape changes in peptide assemblies, driving the vertical growth of protein nanopillars into bundles. These bundles, with peptide nanotubes serving as a template to remodel fibronectin, can then recruit collagen, which forms aggregates or bundles depending on their types. Nanopillar formation relies on enzyme-catalyzed nonequilibrium self-assembly and is governed by the concentrations of enzyme, protein, peptide, the structure of the peptide, and peptide assembly morphologies. Cryo-EM reveals unexpected nanotube thinning and packing after dephosphorylation, indicating a complex sculpting process during assembly. Our study demonstrates a cell-free method for constructing intricate, multiprotein nanostructures with directionality and composition.

Metagenomic Detection of Bacterial Zoonotic Pathogens among Febrile Patients, Tanzania, 2007-20091.

Bacterial zoonoses are established causes of severe febrile illness in East Africa. Within a fever etiology study, we applied a high-throughput 16S rRNA metagenomic assay validated for detecting bacterial zoonotic pathogens. We enrolled febrile patients admitted to 2 referral hospitals in Moshi, Tanzania, during September 2007-April 2009. Among 788 participants, median age was 20 (interquartile range 2-38) years. We performed PCR amplification of V1-V2 variable region 16S rRNA on cell pellet DNA, then metagenomic deep-sequencing and pathogenic taxonomic identification. We detected bacterial zoonotic pathogens in 10 (1.3%) samples: 3 with Rickettsia typhi, 1 R. conorii, 2 Bartonella quintana, 2 pathogenic Leptospira spp., and 1 Coxiella burnetii. One other sample had reads matching a Neoerhlichia spp. previously identified in a patient from South Africa. Our findings indicate that targeted 16S metagenomics can identify bacterial zoonotic pathogens causing severe febrile illness in humans, including potential novel agents.

Priming chondrocytes during expansion alters cell behavior and improves matrix production in 3D culture.

OBJECTIVE: Cartilage tissue engineering strategies that use autologous chondrocytes require in vitro expansion of cells to obtain enough cells to produce functional engineered tissue. However, chondrocytes dedifferentiate during expansion culture, limiting their ability to produce chondrogenic tissue and their utility for cell-based cartilage repair strategies. The current study identified conditions that favor cartilage production and the mechanobiological mechanisms responsible for these benefits. DESIGN: Chondrocytes were isolated from juvenile bovine knee joints and cultured with (primed) or without (unprimed) a growth factor cocktail. Gene expression, cell morphology, cell adhesion, cytoskeletal protein distribution, and cell mechanics were assessed. Following passage 5, cells were embedded into agarose hydrogels to evaluate functional properties of engineered cartilage. RESULTS: Priming cells during expansion culture altered cell phenotype and chondrogenic tissue production. Unbiased ribonucleic acid-sequencing analysis suggested, and experimental studies confirmed, that growth factor priming delays dedifferentiation associated changes in cell adhesion and cytoskeletal organization. Priming also overrode mechanobiological pathways to prevent chondrocytes from remodeling their cytoskeleton to accommodate the stiff, monolayer microenvironment. Passage 1 primed cells deformed less and had lower yes associated protein 1 activity than unprimed cells. Differences in cell adhesion, morphology, and cell mechanics between primed and unprimed cells were mitigated by passage 5. CONCLUSIONS: Priming suppresses mechanobiologic cytoskeletal remodeling to prevent chondrocyte dedifferentiation, resulting in more cartilage-like tissue-engineered constructs.

Machine learning-enabled computer vision for plant phenotyping: a primer on AI/ML and case study on stomatal patterning.

Artificial intelligence and machine learning (AI/ML) can be used to automatically analyze large image datasets. One valuable application of this approach is estimation of plant trait data contained within images. Here we review 39 papers that describe the development and/or application of such models for estimation of stomatal traits from epidermal micrographs. In doing so, we hope to provide plant biologists with a foundational understanding of AI/ML and summarize the current capabilities and limitations of published tools. While most models show human-level performance for stomatal density (SD) quantification at superhuman speed, they are often likely to be limited in how broadly they can be applied across phenotypic diversity associated with genetic, environmental or developmental variation. Other models can make predictions across greater phenotypic diversity and/or additional stomatal/epidermal traits, but require significantly greater time investment to generate ground-truth data. We discuss the challenges and opportunities presented by AI/ML-enabled computer vision analysis, and make recommendations for future work to advance accelerated stomatal phenotyping.

2023 Undetectable = Untransmittable global policy roundtable report: a multistakeholder perspective on Undetectable = Untransmittable research and policy priorities.

Background Launched in 2016 by Prevention Access Campaign, the 'Undetectable=Untransmittable' (U=U) campaign empowers people living with HIV to live full social, sexual and reproductive lives, dismantle stigma, promote increased treatment access, and advocate for updated HIV guidelines. Methods Key priorities for promoting improvements to community-centred, evidence-informed U=U policy and research were the focus of a half-day global roundtable held in 2023 alongside the 12th International AIDS Society Conference in Brisbane, Australia. After a series of presentations, experts in U=U research, policymaking, advocacy and HIV clinical care participated in facilitated discussions, and detailed notes were taken on issues related to advancing U=U policy and research. Results Expert participants shared that knowledge and trust in U=U remains uneven, and is largely concentrated among people living with HIV, particularly those connected to gay and bisexual networks. It was agreed that there is a need to ensure all members of priority populations are explicitly included in U=U policies that promote U=U. Participants also identified a need for policymakers, healthcare professionals, advocates and researchers to work closely with community-based organisations to ensure the U=U message is relevant, useful, and utilised in the HIV response. Adopting language, such as 'zero risk', was identified as crucial when describing undetectable viral load as an effective HIV prevention strategy. Conclusion U=U can have significant benefits for the mental and physical wellbeing of people living with HIV. There is an urgent need to address the structural barriers to HIV care and treatment access to ensure the full benefits of U=U are realised.

Understanding decision-makers and their needs: framing Global Burden of Animal Diseases offerings to enhance relevance and increase impact.

In a world characterised by data deserts and data swamps, translating evidence into actionable policies and practices is not easy. This article addresses this challenge through the lens of evidence emerging from the Global Burden of Animal Diseases (GBADs) initiative. It emphasises the need for an intentional approach that connects research information with the specific needs of decision-makers and identifies specific impact pathways associated with different groups of decision-makers. The GBADs programme aims to support animal health decisions, and the authors outline the diverse landscape of decision-makers in this field, encompassing the public and private sectors, livestock keepers, civil society and international development agencies. Key issues such as disease prioritisation and lobbying are also discussed. The authors propose an â€Ëœevidence ecosystem'approach, one that understands data users and their interactions, for analysing the needs of decision-makers, and framing GBADs offerings according to these needs. Two case studies, a recently concluded global case study of disease prioritisation decision-making and an ongoing policy analysis and needs assessment for GBADs in Indonesia, are presented to demonstrate how evidence ecosystem analysis and audience segmentation could be used to tailor GBADs information offerings for different decision-making groups. The article concludes by recommending that GBADs'future applications prioritise information offerings, adapt them to decision-makers'needs and consider how different segments of decision-makers will utilise the information to achieve real-world impacts.

Dans un monde où l'on rencontre aussi bien des déserts de données que des marécages de données, il n'est guère facile d'utiliser avec succès des données probantes pour les traduire en politiques et en pratiques exploitables. Les auteurs abordent cette difficulté dans l'optique des données actuellement générées dans le cadre de l'initiative " Impact mondial des maladies animales " (GBADs). Ils soulignent l'importance de disposer d'une méthode volontariste capable de relier l'information issue de la recherche avec les besoins spécifiques des décideurs, en tenant compte des chemins d'impact spécifiques associés à chaque catégorie de décideurs. Le programme GBADs vise à soutenir les décisions relatives à la santé animale ; les auteurs donnent une vue d'ensemble de la diversité des décideurs intervenant dans ce domaine, qui recouvre les secteurs public et privé, les éleveurs, la société civile et les organismes internationaux de développement. Certaines questions majeures comme le classement des maladies par ordre de priorité et les activités des groupes de pression sont également abordées. Afin de pouvoir analyser les besoins de ces décideurs et d'encadrer les propositions du GBADs en conséquence, les auteurs proposent une approche qualifiée d'" écosystème d'éléments probants ", qui permet de comprendre les utilisateurs de données et leurs interactions. À travers deux études de cas, l'une récemment achevée sur l'établissement des priorités sanitaires dans les prises de décision à l'échelle mondiale et l'autre actuellement en cours sur l'analyse des politiques et l'évaluation des besoins dans le cadre du GBADs en Indonésie, les auteurs démontrent comment l'analyse de l'écosystème d'éléments probants et la segmentation des destinataires permettent de moduler les informations proposées par le GBADs en fonction des différents groupes de décideurs auxquels elle sont destinées. Les auteurs concluent en recommandant que les applications futures du GBADs établissent des priorités parmi les informations proposées, en les adaptant aux besoins des décideurs et en considérant le nombre de segments différents de décideurs qui vont utiliser l'information en vue de résultats tangibles.

En un mundo caracterizado por los desiertos y los pantanos de datos, no es una misión fácil traducir los datos en políticas y prácticas viables. Este artículo aborda este reto desde la óptica de los datos procedentes de la iniciativa sobre el impacto global de las enfermedades animales (GBADs). Asimismo, subraya la necesidad de un planteamiento intencionado que conecte la información de las investigaciones con las necesidades específicas de los responsables de la toma de decisiones e identifique vías de impacto concretas asociadas a los distintos grupos de decisores. El programa del GBADs busca respaldar las decisiones en materia de sanidad animal y, a este respecto, los autores del artículo describen la diversidad de responsables de la toma de decisiones en dicho ámbito, entre los que figuran los sectores público y privado, los ganaderos, la sociedad civil y los organismos internacionales de desarrollo. También se abordan cuestiones clave como la priorización de enfermedades y los grupos de presión. Los autores proponen un enfoque basado en un "ecosistema de datos" que tenga en cuenta a los usuarios de los datos y sus interacciones a fin de analizar las necesidades de los responsables de la toma de decisiones y enmarcar los servicios del GBADs en función de dichas necesidades. Se presentan dos estudios de casos, uno mundial sobre la toma de decisiones en materia de priorización de enfermedades, que concluyó recientemente, y otro en curso sobre análisis de políticas y evaluación de necesidades del GBADs en Indonesia, con miras a demostrar cómo el análisis del ecosistema de datos y la segmentación de la audiencia podrían utilizarse para adaptar los servicios de información del GBADs a los distintos grupos de responsables de la toma de decisiones. El artículo concluye recomendando que las futuras aplicaciones del GBADs prioricen los servicios de información, los adapten a las necesidades de los responsables de la toma de decisiones y tengan en cuenta cómo utilizarán la información los distintos grupos de responsables para lograr repercusiones en el mundo real.

Pharmacokinetics of intraarticular liposomal amphotericin B in goats (Capra aegagrus hircus).

Lameness is a significant welfare concern in goats. Amphotericin B is used via intraarticular (IA) administration in models to study experimentally induced lameness in large animals. The main objective of this study was to estimate plasma pharmacokinetic (PK) parameters for amphotericin B in goats after a single IA administration. Liposomal amphotericin B was administered to ten Kiko-cross goats at a dose of 10 mg total (range: 0.34-0.51 mg/kg) via IA administration into the right hind lateral distal interphalangeal joint. Plasma samples were collected over 96 h. Amphotericin B concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive PK parameters. Following single IA administration, maximum plasma concentration was estimated at 54.6 ± 16.5 ng/mL, and time to maximum concentration ranged from 6 to 12 h. Elimination half-life was estimated at 30.9 ± 16.5 h, and mean residence time was 45.1 ± 10.4 h. The volume of distribution after IA administration was 13.3 ± 9.4 L/kg. The area under the curve was 1481 ± 761 h*ng/mL. The achieved maximum concentration was less than the observed concentrations for other species and routes of administration. Further research is needed into the pharmacodynamics of IA liposomal amphotericin B in goats to determine specific research strategies.

Early Detection of Severe Acute Respiratory Syndrome Coronavirus 2 Variants Using Traveler-based Genomic Surveillance at 4 US Airports, September 2021-January 2022.

We enrolled arriving international air travelers in a severe acute respiratory syndrome coronavirus 2 genomic surveillance program. We used molecular testing of pooled nasal swabs and sequenced positive samples for sublineage. Traveler-based surveillance provided early-warning variant detection, reporting the first US Omicron BA.2 and BA.3 in North America.

Prevalence of HIV drug resistance among adolescents receiving ART in Cameroon with low- or high-level viraemia.

OBJECTIVES: To characterize HIV drug resistance (HIVDR) below and above the WHO threshold of 1000 copies/mL, considered for the definition of HIV ART failure in resource-limited settings. METHODS: From a cohort of 280 adolescents (aged 10-19 years) receiving ART for at least 6 months, genotypic resistance testing (GRT) was attempted for two groups of participants: participants with low-level viraemia [LLV; viral load (VL) 200-999 copies/mL] and those in virological failure (VF; confirmed VL ≥1000 copies/mL) using an in-house method. The Stanford HIValg Program was used to identify relevant HIVDR mutations and predict the efficacy of the newly introduced tenofovir-lamivudine-dolutegravir combination. RESULTS: GRT was successfully performed in 54/58 (93.1%) eligible participants, of which 28/31 (90.3%) were in VF and 26/27 (96.3%) had LLV. A high level of resistance was found both in adolescents with LLV and those in VF, with respectively 84.6% (22/26) and 75.0% (21/28) of participants harbouring at least one HIVDR mutation. NRTIs and NNRTIs were the most affected drug classes in both population groups. In contrast, PIs were not significantly affected and dolutegravir was expected to be active for all participants tested. However, for the newly introduced dolutegravir-based combination, functional monotherapy (dolutegravir only) was potentially possible for 22.7% (5/22) of the participants with LLV. CONCLUSIONS: Our findings show that the 1000 copies/mL threshold is not an indicator of virological success and we call for a revision of the current WHO definition of VF in resource-limited countries.

Cholera Vaccine: Recommendations of the Advisory Committee on Immunization Practices, 2022.

THIS REPORT SUMMARIZES ALL RECOMMENDATIONS FROM CDC'S ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) FOR THE USE OF LYOPHILIZED CVD 103-HGR VACCINE (CVD 103-HGR) (VAXCHORA, EMERGENT BIOSOLUTIONS, GAITHERSBURG, MD) IN THE UNITED STATES. THE LIVE ATTENUATED ORAL CHOLERA VACCINE IS DERIVED FROM: Vibrio cholerae O1 and is administered in a single dose. Cholera is a toxin-mediated bacterial gastrointestinal illness caused by toxigenic V. cholerae serogroup O1 or, uncommonly, O139. Up to 10% of infections manifest as severe cholera (i.e., cholera gravis), profuse watery diarrhea that can cause severe dehydration and death within hours. Fluid replacement therapy can reduce the fatality rate to <1%. Risk factors for cholera gravis include high dose exposure, blood group O, increased gastric pH (e.g., from antacid therapy), and partial gastrectomy. Cholera is rare in the United States, but cases occur among travelers to countries where cholera is endemic or epidemic and associated with unsafe water and inadequate sanitation. Travelers might be at increased risk for poor outcomes from cholera if they cannot readily access medical services or if they have a medical condition that would be worsened by dehydration, such as cardiovascular or kidney disease. This report describes previously published ACIP recommendations about use of CVD 103-HgR for adults aged 18-64 years and introduces a new recommendation for use in children and adolescents aged 2-17 years. ACIP recommends CVD 103-HgR, the only cholera vaccine licensed for use in the United States, for prevention of cholera among travelers aged 2-64 years to an area with active cholera transmission. Health care providers can use these guidelines to develop the pretravel consultation for persons traveling to areas with active cholera transmission.

Disseminated cryptococcosis with gastrointestinal involvement and false-negative cryptococcal antigen testing due to postzone phenomenon: a case report and review of the literature.

BACKGROUND: Cryptococcosis is an increasingly common infection given the growing immunocompromised population worldwide. Cryptococcal antigen (CrAg) testing demonstrates excellent sensitivity and specificity and is the mainstay of diagnosis. However, there may be rare instances in which false-negative CrAg results can delay diagnosis and early treatment, which are critical to ensure positive outcomes. CASE PRESENTATION: A 31-year-old man living with HIV/AIDS who was not taking antiretroviral therapy was hospitalized with fever, diarrhea, and headaches. CD4 count on presentation was 71 cells/uL, and HIV viral load was 3,194,949 copies/mL. Serum CrAg testing was initially negative, however CSF CrAg performed several days later was positive at 1:40 and blood and CSF cultures grew Cryptococcus neoformans. Colonoscopy revealed mucosal papules throughout the sigmoid colon, and tissue biopsy showed yeast within the lamina propria consistent with GI cryptococcosis. Given the high burden of disease, the original serum CrAg specimen was serially diluted and subsequently found to be positive at 1:2,560, confirming the postzone phenomenon. CONCLUSION: Cryptococcosis has a wide array of presentations including intraluminal GI disease, as seen in this patient. While serum CrAg testing displays excellent test characteristics, it is important for clinicians to be aware of the rare instances in which false-negative results may occur in the presence of excess antigen, as in this case.

Torque- and Muscle-Driven Flexion Induce Disparate Risks of In Vitro Herniation: A Multiscale and Multiphasic Structure-Based Finite Element Study.

The intervertebral disc is a complex structure that experiences multiaxial stresses regularly. Disc failure through herniation is a common cause of lower back pain, which causes reduced mobility and debilitating pain, resulting in heavy socioeconomic burdens. Unfortunately, herniation etiology is not well understood, partially due to challenges in replicating herniation in vitro. Previous studies suggest that flexion elevated risks of herniation. Thus, the objective of this study was to use a multiscale and multiphasic finite element model to evaluate the risk of failure under torque- or muscle-driven flexion. Models were developed to represent torque-driven flexion with the instantaneous center of rotation (ICR) located on the disc, and the more physiologically representative muscle-driven flexion with the ICR located anterior of the disc. Model predictions highlighted disparate disc mechanics regarding bulk deformation, stress-bearing mechanisms, and intradiscal stress-strain distributions. Specifically, failure was predicted to initiate at the bone-disc boundary under torque-driven flexion, which may explain why endplate junction failure, instead of herniation, has been the more common failure mode observed in vitro. By contrast, failure was predicted to initiate in the posterolateral annulus fibrosus under muscle-driven flexion, resulting in consistent herniation. Our findings also suggested that muscle-driven flexion combined with axial compression could be sufficient for provoking herniation in vitro and in silico. In conclusion, this study provided a computational framework for designing in vitro testing protocols that can advance the assessment of disc failure behavior and the performance of engineered disc implants.

Results from the Philippines' 2022 report card on physical activity for children and adolescents.

Background/Objective: The 2022 Philippine Report Card on Physical Activity for Children and Adolescents provides a comprehensive assessment of physical activity and other related behaviors, including the various factors and settings that influence these behaviors. It serves as an advocacy tool to increase awareness of the physical activity situation among children and young people in the country. This article describes the development and results of the first Philippine Report Card on Physical Activity for Children and Adolescents. Methods: Following a systematic process provided by the Active Healthy Kids Global Alliance, a team consisting of 25 sports and physical activity specialists identified and reviewed the best available nationally representative data related to physical activity indicators. These data were then used to inform the grades of the ten (10) physical activity indicators. Results: Sufficient data were identified to assign grades to five (5) indicators: Overall Physical Activity (F), Active Transportation (D), Sedentary Behavior (B), School (C-), and Government (B). Insufficient data existed to assign grades to the remaining five (5) indicators: Organized Sport and Physical Activity, Active Play, Physical Fitness, Family and Peers, and Community and Environment. Conclusion: Despite government policies related to physical activity in the country, the majority of children and adolescents in the Philippines do not meet the recommended amount of physical activity for health. More work is needed to improve the translation of these policies into measurable programs, highlighting the need to create better physical activity opportunities and develop national surveillance mechanisms.

Typhoid Fever in the US Pediatric Population, 1999-2015: Opportunities for Improvement.

BACKGROUND: Typhoid fever in the United States is acquired primarily through international travel by unvaccinated travelers. There is currently no typhoid vaccine licensed in the United States for use in children <2 years. METHODS: We reviewed Salmonella enterica serotype Typhi infections reported to the Centers for Disease Control and Prevention (CDC) and antimicrobial-resistance data on Typhi isolates in CDC's National Antimicrobial Resistance Monitoring System from 1999 through 2015. RESULTS: 5131 cases of typhoid fever were diagnosed and 5004 Typhi isolates tested for antimicrobial susceptibility. Among 1992 pediatric typhoid fever patients, 1616 (81%) had traveled internationally within 30 days of illness onset, 1544 (81%) of 1906 were hospitalized (median duration, 6 days; range, 0-50), and none died. Forty percent (799) were <6 years old; 12% were <2 years old. Based on age and travel destination, 1435 (83%) of 1722 pediatric patients were vaccine-eligible; only 68 (5%) of 1361 were known to be vaccinated. Of 2003 isolates tested for antimicrobial susceptibility, 1216 (61%) were fluoroquinolone-nonsusceptible, of which 272 (22%) were also resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (multidrug-resistant [MDR]). All were susceptible to ceftriaxone and azithromycin. MDR and fluoroquinolone-nonsusceptible isolates were more common in children than adults (16% vs 9%, P < .001, and 61% vs 54%, P < .001, respectively). Fluoroquinolone nonsusceptibility was more common among travel-associated than domestically acquired cases (70% vs 17%, P < .001). CONCLUSIONS: Approximately 95% of currently vaccine-eligible pediatric travelers were unvaccinated, and antimicrobial-resistant infections were common. New public health strategies are needed to improve coverage with currently licensed vaccines. Introduction of an effective pretravel typhoid vaccine for children <2 years could reduce disease burden and prevent drug-resistant infections.

Intervertebral Disc Mechanics With Nucleotomy: Differences Between Simple and Dual Loading.

Painful herniated discs are treated surgically by removing extruded nucleus pulposus (NP) material (nucleotomy). NP removal through enzymatic digestion is also commonly performed to initiate degenerative changes to study potential biological repair strategies. Experimental and computational studies have shown a decrease in disc stiffness with nucleotomy under single loading modalities, such as compression-only or bending-only loading. However, studies that apply more physiologically relevant loading conditions, such as compression in combination with bending or torsion, have shown contradicting results. We used a previously validated bone-disc-bone finite element model (Control) to create a Nucleotomy model to evaluate the effect of dual loading conditions (compression with torsion or bending) on intradiscal deformations. While disc joint stiffness decreased with nucleotomy under single loading conditions, as commonly reported in the literature, dual loading resulted in an increase in bending stiffness. More specifically, dual loading resulted in a 40% increase in bending stiffness under flexion and extension and a 25% increase in stiffness under lateral bending. The increase in bending stiffness was due to an increase and shift in compressive stress, where peak stresses migrated from the NP-annulus interface to the outer annulus. In contrast, the decrease in torsional stiffness was due to greater fiber reorientation during compression. In general, large radial strains were observed with nucleotomy, suggesting an increased risk for delamination or degenerative remodeling. In conclusion, the effect of nucleotomy on disc mechanics depends on the type and complexity of applied loads.

An evaluation of an influenza vaccination campaign targeting pregnant women in 27 clinics in two provinces of South Africa, 2015 - 2018.

INTRODUCTION: Despite prioritization, routine antenatal influenza vaccine coverage is < 16% in South Africa. We aimed to describe maternal influenza vaccine coverage in 27 antenatal clinics (ANCs) in Gauteng and Western Cape (WC) Provinces, where in collaboration with the Department of Health (DoH), we augmented the annual influenza vaccination programme among pregnant women. METHODS: From 2015 through 2018, 40,230 additional doses of influenza vaccine were added to the available stock and administered as part of routine antenatal care. Educational talks were given daily and data were collected on women attending ANCs. We compared characteristics of vaccinated and unvaccinated women using multivariable logistic regression. RESULTS: We screened 62,979 pregnant women during the period when Southern Hemisphere influenza vaccines were available (27,068 in Gauteng and 35,911 in WC). Vaccine coverage at the targeted clinics was 78.7% (49,355/62682), although pregnant women in WC were more likely to be vaccinated compared to those in the Gauteng (Odds ratio (OR) =3.7 p < 0.001). Women aged 25-29 and > 35 years were less likely to be vaccinated than women aged 18-24 years (OR = 0.9 p = 0.053; OR = 0.9 p < 0.001). HIV positive status was not associated with vaccination (OR = 1.0 p = 0.266). Reasons for not vaccinating included: vaccine stock-outs where ANCs depleted available stock of vaccines and/or were awaiting delivery of vaccines (54.6%, 6949/12723), refusal/indecision (25.8%, 3285), and current illness that contraindicated vaccination (19.6%, 2489). CONCLUSION: Antenatal vaccination uptake was likely improved by the increased vaccine supply and vaccine education offered during our campaign.