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BACKGROUND Evidence-based decision-making is essential to improve public health benefits and resources, especially in low-middle-income countries (LMICs), but the mechanisms of its implementation remain less straightforward. The availability of high-quality, reliable, and sufficient data in LMICs can be challenging due to issues such as lack of human resource capacity and weak digital infrastructure, among others. Health information systems (HIS) have been critical for aggregating and integrating health-related data from different sources to support evidence-based decision-making. Nutrition Information Systems (NIS), which are nutrition-focused HIS, collect and report on nutrition-related indicators to improve issues related to malnutrition and food security – and can assist in improving populations’ nutritional statuses and the integration of nutrition programming into routine health services. Data visualization tools (DVT) such as dashboards have been recommended to support such evidence-based decision-making, leveraging data from HIS/NIS. The use of such DVTs to support decision-making has largely been unexplored within LMIC contexts. In Bangladesh, the Mukto dashboard was developed to display and visualize nutrition-related performance indicators at the national and sub-national levels. However, despite this effort, the current use of nutrition data to guide priorities and decisions remains relatively nascent and under-utilized. OBJECTIVE The goal of the study is to better understand how Bangladesh’s NIS has been utilized and areas for improvement to facilitate its use for evidence-based decision-making towards ameliorating nutrition-related service delivery and health status of communities in Bangladesh. METHODS Primary data collection was conducted through qualitative semi-structured interviews with key policy-level stakeholders (n=24). Key informants were identified through purposive sampling and were asked questions around how the experiences and challenges with the NIS and related nutrition dashboards. RESULTS Main themes such as trust, data usability, person power, and data use for decision-making emerged from the data. Trust in both data collection and quality was lacking among many stakeholders. Poor data usability stemmed from unstandardized indicators, irregular data collection, and differences between rural and urban data. Insufficient person power and staff training coupled with infrastructural challenges can negatively affect data at the input stage. While stakeholders understood and expressed the importance of evidence-based decision-making, ultimately, they noted that the data was not being utilized to its maximum potential. CONCLUSIONS Leveraging DVTs can improve the use of data for evidence-based decision-making, but decision-makers must trust that the data is believable, credible, timely, and responsive. Results support the significance of a tailored data ecosystem, which has not reached its full potential in Bangladesh. Recommendations to reach this potential include ensuring a clear intended user base, and accountable stakeholders are present. Systems should also have the capacity to ensure data credibility and support ongoing person power requirements.

Undetected and unmonitored hypertension carries substantial mortality and morbidity, especially during pregnancy. We assessed the accuracy of OptiBPTM, a smartphone application for estimating blood pressure (BP), across diverse settings. The study was conducted in community settings: Gaibandha, Bangladesh and Ifakara, Tanzania for general populations, and Kalafong Provincial Tertiary Hospital, South Africa for pregnant populations. Based on guidance from the International Organization for Standardization (ISO) 81,060–2:2018 for non-invasive BP devices and global consensus statement, we compared BP measurements taken by two independent trained nurses on a standard auscultatory cuff to the BP measurements taken by a research version of OptiBPTM called CamBP. For ISO criterion 1, the mean error was 0.5 ± 5.8 mm Hg for the systolic blood pressure (SBP) and 0.1 ± 3.9 mmHg for the diastolic blood pressure (DBP) in South Africa; 0.8 ± 7.0 mmHg for the SBP and −0.4 ± 4.0 mmHg for the DBP in Tanzania; 3.3 ± 7.4 mmHg for the SBP and −0.4 ± 4.3 mmHg for the DBP in Bangladesh. For ISO criterion 2, the average standard deviation of the mean error per subject was 4.9 mmHg for the SBP and 3.4 mmHg for the DBP in South Africa; 6.3 mmHg for the SBP and 3.6 mmHg for the DBP in Tanzania; 6.4 mmHg for the SBP and 3.8 mmHg for the DBP in Bangladesh. OptiBPTM demonstrated accuracy against ISO standards in study populations, including pregnant populations, except in Bangladesh for SBP (criterion 2). Further research is needed to improve performance across different populations and integration within health systems.

Many urban coastal communities are experiencing more profound flood impacts due to accelerated sea level rise that sometimes exceed their capacity to protect the built environment. In such cases, relocation may serve as a more effective hazard mitigation and adaptation strategy. However, it is unclear how urban residents living in flood-prone locations perceive the possibility of relocation and under what circumstances they would consider moving. Understanding the factors affecting an individual’s willingness to relocate because of coastal flooding is vital for developing accessible and equitable relocation policies. The main objective of this study is to identify the key considerations that would prompt urban coastal residents to consider permanent relocation because of coastal flooding. We leverage survey data collected from urban areas along the East Coast, assessing attitudes toward relocation, and design an artificial neural network (ANN) and a random forest (RF) model to find patterns in the survey data and indicate which considerations impact the decision to consider relocation. We trained the models to predict whether respondents would relocate because of socioeconomic factors, past exposure and experiences with flooding, and their flood-related concerns. Analyses performed on the models highlight the importance of flood-related concerns that accurately predict relocation behavior. Some common factors among the model analyses are concerns with increasing crime, the possibility of experiencing one more flood per year in the future, and more frequent business closures resulting from flooding.

This study investigates the effects of surface fluxes on ventilation pathways and the development of Hurricane Michael (2018), and is a real-case comparison to previous idealized modeling studies that investigate ventilation. Two modeling experiments are conducted by altering surface exchange coefficients to achieve a strong and weak experiment. Ventilation pathways are evaluated to understand how the vortex responds to dry-air infiltration. Pathways for dry-air infiltration are split into downdraft and radial ventilation. Results show that downdraft ventilation at low levels is maximized left of shear, exists between the surface and a height of 3 km, and is associated with rainband activity. Trajectories from downdraft ventilation demonstrate slower thermodynamic recovery for the weaker experiment. The slower recovery contributes to the initial intensity bifurcation between experiments. Radial ventilation has two pathways. At low levels, it is coupled with downdraft ventilation. Aloft, between heights of 5 and 10 km, it is maximized upshear and associated with storm-relative flow. This pathway is similar for each experiment initially, suggesting that the initial bifurcation of intensity is not a consequence of radial ventilation aloft. Trajectories from radial ventilation during a later time period show the destructive impact of lower-θe air in the near environment on convection upshear and right of shear for the weaker experiment. This study demonstrates how ventilation pathways at low levels and aloft are affected by surface fluxes, and how ventilation pathways operate, at different times, to affect tropical cyclone development.

Additional file 1: Figure S1. AFM11-101 study flow diagram. Figure S2. AFM11-102 study flow diagram. Table S1. Baseline characteristics per cohort in the AFM11-101 study. Table S2. Baseline characteristics per cohort in the AFM11-102 study. Table S3. PK parameters of AFM11 following two weekly intravenous infusions of AFM11 in study AFM11-102.

H37Rv is the most widely used Mycobacterium tuberculosis strain, and its genome is globally used as the M. tuberculosis reference sequence. Here, we present Bact-Builder, a pipeline that uses consensus building to generate complete and accurate bacterial genome sequences and apply it to three independently cultured and sequenced H37Rv aliquots of a single laboratory stock. Two of the 4,417,942 base-pair long H37Rv assemblies are 100% identical, with the third differing by a single nucleotide. Compared to the existing H37Rv reference, the new sequence contains ~6.4 kb additional base pairs, encoding ten new regions that include insertions in PE/PPE genes and new paralogs of esxN and esxJ, which are differentially expressed compared to the reference genes. New sequencing and de novo assemblies with Bact-Builder confirm that all 10 regions, plus small additional polymorphisms, are also present in the commonly used H37Rv strains NR123, TMC102, and H37Rv1998. Thus, Bact-Builder shows promise as an improved method to perform accurate and reproducible de novo assemblies of bacterial genomes, and our work provides important updates to the primary M. tuberculosis reference genome.

The authors have requested that this preprint be removed from Research Square.

Initial responses to tuberculosis treatment are poor predictors of final therapeutic outcomes in drug-susceptible disease suggesting that treatment success depends on features that are hidden within a small minority of the overall infecting Mycobacterium tuberculosis (Mtb) population. We developed a multi-transwell robotic system to perform numerous parallel cultures of genetically barcoded Mtb exposed to steady-state concentrations of rifampicin to uncover these difficult to eliminate minority populations. We found that tolerance repeatedly emerged from at least two subpopulations of barcoded cells, one that could not grow on solid agar media and a second that could form colonies, but whose kill curves diverged from the general bacterial population within 4 and 16 days of drug exposure, respectively. These tolerant subpopulations reproducibly passed through a phase characterized by multiple unfixed resistance mutations followed by emergent drug resistance in some cultures. Barcodes associated with drug resistance identified an especially privileged subpopulation that was rarely eliminated despite 20 days of drug treatment even in cultures that did not contain any drug resistant mutants. The association of this evolutionary scenario with a defined subset of barcodes across multiple independent cultures suggested a transiently heritable phenotype, and indeed glpK phase variation mutants were associated with up to 16 % of the resistant cultures. Drug tolerance and resistance were eliminated in ΔruvA mutant consistent with the importance of bacterial stress responses. This work provides a window into the origin and dynamics of bacterial drug tolerant subpopulations whose elimination may be critical to developing rapid and resistance free cures.ImportanceTuberculosis is unusual among bacterial diseases in that treatments which can rapidly resolve symptoms do not predictably lead to a durable cure unless treatment is continued for months after all clinical and microbiological signs of disease have been eradicated. Using a novel steady-state antibiotic exposure system combined with chromosomal barcoding, we identified small hidden Mycobacterium tuberculosis subpopulations that repeatedly enter into a state of drug tolerance with a predisposition to develop fixed drug resistance after first developing a cloud of unfixed resistance mutations. The existence of these difficult to eradicate subpopulations may explain the need for extended treatment regimen for tuberculosis. Their identification provides opportunities to test genetic and therapeutic approaches that may result in shorter and more effective TB treatments.

Many business colleges offer specialized marketing majors in addition to the general marketing major. Given the extra resources needed to maintain multiple majors, in a time when higher education budgets are being strained, a need exists to understand how students make choices among these majors and what students perceive to be the advantages of general marketing majors versus specialized marketing majors. Using social cognitive theory, we examine how students make selections among choices in marketing-related majors, focusing on influence and compatibility factors. We surveyed 608 marketing majors representing one general and five specialized marketing majors. The findings indicate that, compared with general marketing majors, students’ choice of a specialized major is significantly more likely to be influenced by faculty and other students in the major. Also, the results show that students rate specialized majors better than a general marketing major in terms of self-efficacy, culture, and professional fit. On the other hand, students rate the general marketing major better than specialized majors in flexibility. These results have implications for supporting the priorities of students in both general and specialized majors.

Scorpine is an antimicrobial and antimalarial peptide isolated from Pandinus imperator scorpion venom. As there are few functional and structural studies reported on scorpine-like peptides, we investigated the recombinant truncated N- and C-terminal domains as well as complete scorpine using biological assays and determined the N- and C-terminal structures using solution nuclear magnetic resonance. The study was conducted using recombinant N- and C-terminal peptides and complete scorpine expressed in Escherichia coli. The results showed that N-scorpine presented a random coil structure in water and adopted α-helical folding in the presence of 50% trifluoroethanol (TFE). C-scorpine contains three disulfide bonds with two structural domains: an unstructured N-terminal domain in water that can form a typical secondary alpha-helix structure in 50% TFE and a C-terminal domain with the CS-αβ motif. Our findings demonstrate cytolytic activity associated with C-scorpine, N-scorpine, and scorpine, as well as channel blocking activity associated with the C-scorpine domain.

Rapid emergence of drug resistance in Mycobacterium tuberculosis (Mtb) is one of the most significant healthcare challenges of our time. The cause of drug resistance is multifactorial, with the long course anti-tubercular therapy required to treat tuberculosis (TB) constituting a major contributing factor. Introduction of pyrazinamide (PZA) resulted in shortening of TB treatment from twelve to six months and consequently played a critical role in curbing drug resistance that developed over long course therapy. Nevertheless, because PZA is a prodrug activated by a nonessential amidase, PncA, resistance to PZA develops and frequently results in treatment failure. Here, we leveraged a whole cell drug screening approach to identify anti-tuberculars with unconventional mechanisms of action or activation that could be further developed into compounds effective at killing Mtb resistant to PZA. We discovered an amide containing prodrug, DG160, that was activated by the amidase, Rv2888c (AmiC). This amidase was capable of metabolizing a variety of amide containing compounds including a novel pyrazinoic acid-isoquinolin-1-amine prodrug, JSF-4302, which we developed as a potential PncA-independent replacement for PZA. As predicted, AmiC activation of JSF-4302 led to the generation of POA in Mtb including in a PZA resistant clinical isolate, thereby successfully delivering the active component of PZA while bypassing the need for activation by PncA. This work provides a framework for a new approach to drug development and prodrug activation in Mtb.SIGNIFICANCEPyrazinamide (PZA) is a vital component of Mycobacterium tuberculosis (Mtb) treatment since its inclusion shortened tuberculosis therapy by six months. However, PZA is a prodrug and resistance develops at a high frequency due to mutations in its activator PncA. Here, we present the discovery of amide-containing anti-tubercular prodrugs that are activated intracellularly by the Mtb amidase, AmiC. Taking advantage of this finding, we successfully designed and synthesized pyrazinoic acid (POA) prodrugs that were activated by AmiC and found that these compounds delivered intracellular POA to PZA- resistant Mtb isolates that contained a nonfunctional PncA. This new approach to prodrug development provides a method for delivering conjugated drugs into Mtb with the potential to overcome clinical drug resistance.

After examination and, in some cases, imaging, most of these injuries can be managed conservatively with splinting or injection. Some cases require prompt surgical referral.

The purpose of this study was to use quantitative structure-activity relationships (QSARs) to identify new triptan molecules that selectively bind to h 5-HT1B and h 5-HT1D to a greater extent than to the similar h 5-HT1A receptor in order to identify novel compounds that could lead to an alternative and potentially superior migraine relief drug. Due to its possibility in migraine abortive properties, binding affinities to h 5-HT1F were also modeled. Binding affinities for 12 different triptan drugs and structurally similar substances were compiled from the literature, and descriptors were generated for those and other potential drug candidates using a variety of programs. The most significant descriptors were identified using a stepwise model, and the final QSARs were built for each activity with those descriptors, and a neural network. QSARs for all four activities were validated using a holdback method and were all found to be highly accurate. With these QSARs, activities of novel compounds similar to triptan drugs were predicted and three potential drug candidates were suggested.

This study examines how midlevel dry air and vertical wind shear (VWS) can modulate tropical cyclone (TC) development via downdraft ventilation. A suite of experiments was conducted with different combinations of initial midlevel moisture and VWS. A strong, positive, linear relationship exists between the low-level vertical mass flux in the inner core and TC intensity. The linear increase in vertical mass flux with intensity is not due to an increased strength of upward motions but, instead, is due to an increased areal extent of strong upward motions (w > 0.5 m s−1). This relationship suggests physical processes that could influence the vertical mass flux, such as downdraft ventilation, influence the intensity of a TC. The azimuthal asymmetry and strength of downdraft ventilation is associated with the vertical tilt of the vortex: downdraft ventilation is located cyclonically downstream from the vertical tilt direction and its strength is associated with the magnitude of the vertical tilt. Importantly, equivalent potential temperature of parcels associated with downdraft ventilation trajectories quickly recovers via surface fluxes in the subcloud layer, but the areal extent of strong upward motions is reduced. Altogether, the modulating effects of downdraft ventilation on TC development are the downward transport of low–equivalent potential temperature, negative-buoyancy air left of shear and into the upshear semicircle, as well as low-level radial outflow upshear, which aid in reducing the areal extent of strong upward motions, thereby reducing the vertical mass flux in the inner core, and stunting TC development.

This study demonstrates how midlevel dry air and vertical wind shear (VWS) can modulate tropical cyclone (TC) development via radial ventilation. A suite of experiments was conducted with different combinations of initial midlevel moisture and VWS environments. Two radial ventilation structures are documented. The first structure is positioned in a similar region as rainband activity and downdraft ventilation (documented in Part I) between heights of 0 and 3 km. Parcels associated with this first structure transport low–equivalent potential temperature air inward and downward left of shear and upshear to suppress convection. The second structure is associated with the vertical tilt of the vortex and storm-relative flow between heights of 5 and 9 km. Parcels associated with this second structure transport low–relative humidity air inward upshear and right of shear to suppress convection. Altogether, the modulating effects of radial ventilation on TC development are the inward transport of low–equivalent potential temperature air, as well as low-level radial outflow upshear, which aid in reducing the areal extent of strong upward motions, thereby reducing the vertical mass flux in the inner core, and stunting TC development.

Summary Background Coronavirus disease 2019 has stretched the ability of many institutions to supply needed personal protective equipment, especially N95 respirators. N95 decontamination and re-use programmes provide one potential solution to this problem. Unfortunately, a comprehensive evaluation of the effects of decontamination on the fit of various N95 models using a quantitative fit test (QNFT) approach is lacking. Aims To investigate the effects of up to eight rounds of vaporized hydrogen peroxide (VHP) decontamination on the fit of N95 respirators currently in use in a hospital setting, and to examine if N95 respirators worn by one user can adapt to the face shape of a second user with no compromise to fit following VHP decontamination. Methods The PortaCount Pro+ Respirator Fit Tester Model 8038 was used to quantitatively define functional integrity, measured by fit, of N95 respirators following decontamination with VHP. Findings There was an observable downward trend in the functional integrity of Halyard Fluidshield 46727 N95 respirators throughout eight cycles of decontamination with VHP. Functional integrity of 3M 1870 N95 respirators was reduced significantly after the respirator was worn, decontaminated with VHP, and then quantitatively fit tested on a second user. Furthermore, inconsistencies between qualitative fit test and QNFT results were uncovered that may have strong implications on the fit testing method used by institutions. Conclusions The data revealed variability in the functional integrity of different N95 models after VHP decontamination, and exposed potential limitations of N95 decontamination and re-use programmes.

Study question Does lactate presence in the culture medium have an effect on embryo development, specifically during blastocyst formation? Is it an age related effect? Summary answer There is a statistical significative reduction of early blastocyst formation and a trend towards higher proportion of expanded and hatching blastocysts in lower lactate concentration. What is known already Embryos after embryonic genome activation start an active consumption of glucose to convert it into pyruvate and lactate for ATP production through the TCA cycle. Conversion from pyruvate to lactate to produce NADH through LDH (lactate dehydrogenase) can be counterbalanced by increased amounts of lactate, which then can alter the NAD+/NADH ratio resulting in a higher oxidative stress and reduced metabolic activity. Recently, a new commercial media formulation with a substantial reduction of lactate has come in to the market reporting increased efficiency of blastocyst formation and amount of euploid embryos compare to its version with a traditional lactate concentration. Study design, size, duration From September to November 2021 embryos were cultured in two different continuous media (SAGE 1-STEP and FUJIFILM IRVINE SCIENTIFIC CSCM-NXC). A total of 260 correctly fertilized embryos were allocated in both types of media (119 in 1-STEP and 141 in CSCM-NXC). Patients containing more than one zygote had their embryos allocated as equally as possible in both types of media. Participants/materials, setting, methods Age of participants ranged from 24-45 years. The embryos were cultured in embryoscope+ and their destination was assigned as Transfer, Vitrification or Discard (if by day 6 they did not reach a good quality blastocyst). Morphokinetic parameters were measured and Gardner's grading system for blastocyst quality annotated. For blastocyst quality comparison, only day 5 was considered. Variables studied were utilisation and blastocyst formation rates, expansion grade, ICM and TE quality, patient age, and pregnancy rates. Main results and the role of chance Incubation of embryos in reduced lactate concentration reduced significantly (p-value=0.013) the proportion of embryos with expansion grade 1 (14.3% 1STEP vs 3.4% CSCM-NXC), in contrast, a trend towards higher expansion grades, more importantly grade 5 (7.8% 1STEP vs 14.9% CSCM-NXC) was observed. A slight reduction in proportion of discarded embryos (47.52% CSCM-NXC vs 54.62% 1STEP) and increased proportion of vitrified embryos (34.75% CSCM-NXC vs 27.73% 1STEP) was also observed. Regarding ICM and TE qualities, in general there was also a trend in benefit of use of CSCM-NXC medium (55.3% CSCM-NXC vs 50.7% 1STEP for grade A in ICM; 36.8% CSCM-NXC vs 30.1% 1STEP for grade A in TE). Morphokinetic parameters were not different between groups, except T3 which showed to be significative (p-value=0.026) earlier in 1STEP than CSCM-NXC (37.13 h vs 38.71 h respectively). Age subgroups of patient showed no difference in utilisation rates for ages < 37 years old, however, for ages ≥37 there was a higher proportion of utilised embryos (56.3 CSCM-NXC vs 41.9% 1STEP for 37-40 years old; 60% CSCM-NXC vs 42.3% 1STEP for >40 years old). Finally, pregnancy rates were equal for those fresh transfers between both groups. Limitations, reasons for caution The study has a reduced sample size, so statistical power is reduced. Furthermore, it cannot be discarded that the effect is not a contribution to other differences in formulation of both media. Time to birth or cumulated pregnancy parameter would be more indicative of benefits. Wider implications of the findings Two main hypotheses that require further validation: First, excess of certain metabolites in culture can impair development of preimplantation embryos. Second, embryos may be more sensitive to certain medium composition depending on age, so medium designed according to this may be a near future direction to improve IVF outcomes. Trial registration number NA

Background An animal model that can mimic the SARS-CoV-2 infection in humans is critical to understanding the rapidly evolving SARS-CoV-2 virus and for development of prophylactic and therapeutic strategies to combat emerging mutants. Studies show that the spike proteins of SARS-CoV and SARS-CoV-2 bind to human angiotensin-converting enzyme 2 (hACE2, a well-recognized, functional receptor for SARS-CoV and SARS-CoV-2) to mediate viral entry. Several hACE2 transgenic (hACE2Tg) mouse models are being widely used, which are clearly invaluable. However, the hACE2Tg mouse model cannot fully explain: (1) low expression of ACE2 observed in human lung and heart, but lung or heart failure occurs frequently in severe COVID-19 patients; (2) low expression of ACE2 on immune cells, but lymphocytopenia occurs frequently in COVID-19 patients; and (3) hACE2Tg mice do not mimic the natural course of SARS-CoV-2 infection in humans. Moreover, one of most outstanding features of coronavirus infection is the diversity of receptor usage, which includes the newly proposed human CD147 (hCD147) as a possible co-receptor for SARS-CoV-2 entry. It is still debatable whether CD147 can serve as a functional receptor for SARS-CoV-2 infection or entry. Results Here we successfully generated a hCD147 knock-in mouse model (hCD147KI) in the NOD-scid IL2Rgammanull (NSG) background. In this hCD147KI-NSG mouse model, the hCD147 genetic sequence was placed downstream of the endogenous mouse promoter for mouse CD147 (mCD147), which creates an in vivo model that may better recapitulate physiological expression of hCD147 proteins at the molecular level compared to the existing and well-studied K18-hACE2-B6 (JAX) model. In addition, the hCD147KI-NSG mouse model allows further study of SARS-CoV-2 in the immunodeficiency condition which may assist our understanding of this virus in the context of high-risk populations in immunosuppressed states. Our data show (1) the human CD147 protein is expressed in various organs (including bronchiolar epithelial cells) in hCD147KI-NSG mice by immunohistochemical staining and flow cytometry; (2) hCD147KI-NSG mice are marginally sensitive to SARS-CoV-2 infection compared to WT-NSG littermates characterized by increased viral copies by qRT-PCR and moderate body weight decline compared to baseline; (3) a significant increase in leukocytes in the lungs of hCD147KI-NSG mice, compared to infected WT-NSG mice. Conclusions hCD147KI-NSG mice are more sensitive to COVID-19 infection compared to WT-NSG mice. The hCD147KI-NSG mouse model can serve as an additional animal model for further interrogation whether CD147 serve as an independent functional receptor or accessory receptor for SARS-CoV-2 entry and immune responses.

IntroductionHip fractures treated with total hip arthroplasty (THA) are at high risk of prosthesis instability, and dislocation is the most common indication for revision surgery. This study aims to determine whether dual mobility THA implants reduce the risk of dislocation compared with conventional THA in patients with hip fracture suitable to be treated with THA.Methods and analysisThis is a cluster-randomised, crossover, open-label trial nested within the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). The clusters will comprise hospitals that perform at least 12 THAs for hip fracture per annum. All adults age ≥50 years who meet the Australian and New Zealand Hip Fracture Registry guidelines for THA will be included. The intervention will be dual mobility THA and the comparator will be conventional THA. Each hospital will be allocated to two consecutive periods, one of dual mobility THA and the other of conventional THA in random order, aiming for an average of 16 patients eligible for the primary analysis per group (32 total per site), allowing different recruitment totals between sites. Data will be collected through the AOANJRR and linked with patient-level discharge data acquired through government agencies. The primary outcome is dislocation within 1 year. Secondary outcomes include revision surgery for dislocation and all-cause, complications and mortality at 1, 2 and 5 years. If dual mobility THA is found to be superior, a cost-effectiveness analysis will be conducted. The study will aim to recruit 1536 patients from at least 48 hospitals over 3 years.Ethics and disseminationEthics approval has been granted (Sydney Local Health District - Royal Prince Alfred Hospital Zone (approval X20-0162 and 2020/ETH00680) and site-specific approvals). Participant recruitment is via an opt-out consent process as both treatments are considered accepted, standard practice. The trial is endorsed by the Australia and New Zealand Musculoskeletal Clinical Trials Network.Trial registration numberACTRN12621000069853.

Background The Cholera Hospital-Based Intervention for 7 Days (CHoBI7) mobile health (mHealth) program was a cluster-randomized controlled trial of diarrhea patient households conducted in Dhaka, Bangladesh. Methods Patients were block-randomized to 3 arms: standard message on oral rehydration solution use; health facility delivery of CHoBI7 plus mHealth (no home visits); and health facility delivery of CHoBI7 plus 2 home visits and mHealth. The primary outcome was reported diarrhea in the past 2 weeks collected monthly for 12 months. The secondary outcomes were stunting, underweight, and wasting at a 12-month follow-up. Analysis was intention-to-treat. Results Between 4 December 2016 and 26 April 2018, 2626 participants in 769 households were randomly allocated to 3 arms: 849 participants to the standard message arm, 886 to mHealth with no home visits arm, and 891 to the mHealth with 2 home visits. Children Conclusions The CHoBI7 mHealth program lowered pediatric diarrhea and stunting among diarrhea patient households. Clinical Trials Registration NCT04008134.

The Cholera-Hospital-Based Intervention for 7-days (CHoBI7) mobile health (mHealth) program delivers mobile messages to diarrhoea patient households promoting water treatment and handwashing with soap. The randomised controlled trial (RCT) of the CHoBI7 mHealth program demonstrated this intervention was effective in significantly reducing diarrhoea and stunting amoung young children. The objective of this study was to assess the implementation of the CHoBI7 mHealth program in delivering mHealth messages during this RCT.517 diarrhoea patient households with 1777 participants received weekly text, voice and interactive voice response (IVR) messages from the CHoBI7 mHealth program over the 12-month program period. The program process evaluation indicators were the following: the percentage of CHoBI7 mHealth messages received and fully listened to by program households (program fidelity and dose), and household members reporting receiving and sharing an mHealth message from the program in the past two weeks (program reach).Ninety two percent of text messages were received by program households. Eighty three percent of voice and 86% of IVR messages sent were fully listened to by at least one household member. Eighty one percent of IVR quiz responses from households were answered correctly. Program households reported receiving a CHoBI7 mHealth message in the past two weeks at 79% of monthly household visits during the 12-month program. Seventy seven percent of participants reported sharing a program message with a spouse, 55% with a neighbour and 49% with a child during the program period.There was high fidelity, dose and reach of mobile messages delivered for the CHoBI7 mHealth program. This study presents an approach for process evaluation that can be implemented to evaluate future mHealth programs.Le programme CHoBI7 (Cholera-Hospital-Based-Intervention-for-7-days) de santé mobile (mHealth) délivre des messages mobiles aux ménages avec patients atteints de diarrhée pour promouvoir le traitement de l'eau et le lavage des mains au savon. L'essai contrôlé randomisé (ECR) du programme mHealth CHoBI7 a démontré que cette intervention était efficace pour réduire de manière significative la diarrhée et le retard de croissance chez les jeunes enfants. L'objectif de cette étude était d'évaluer la mise en œuvre du programme CHoBI7 mHealth dans la diffusion des messages mHealth au cours de cet ECR. MÉTHODES: 517 ménages avec des patients atteints de diarrhée ont reçu chaque semaine des messages SMS, vocaux et de réponse vocale interactive (RVI) du programme mHealth de CHoBI7 pendant les 12 mois du programme. Les indicateurs d'évaluation du processus du programme étaient les suivants: le pourcentage de messages mHealth du programme CHoBI7 reçus (fidélité au programme et dose) et entièrement écoutés par les ménages participant au programme (fidélité au programme et dose) et les bénéficiaires déclarant avoir reçu et partagé un message mHealth du programme (portée du programme) au cours des deux dernières semaines. RÉSULTATS: 92% des SMS ont été reçus par les ménages participant au programme. 83% des messages vocaux et 86% des messages RVI envoyés ont été entièrement écoutés par au moins un membre du ménage. 81% des réponses aux quiz RVI des ménages ont été correctement répondues. Les ménages du programme ont déclaré avoir reçu un message CHoBI7 mHealth au cours des deux dernières semaines dans 79% des visites mensuelles des ménages pendant les 12 mois du programme. 77% des participants ont déclaré avoir partagé un message du programme avec un conjoint, 55% avec un voisin et 49% avec un enfant pendant la durée du programme.La dose et les messages délivrés dans le cadre du programme mHealth de CHoBI7 l’ont été avec une fidélité élevée. Cette étude présente une approche d'évaluation des processus qui peut être mise en œuvre pour évaluer les futurs programmes mHealth.

Background The prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin’s lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. Methods Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. Results In AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. Conclusions AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated. Trial registration NCT02106091. Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911. Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.

BackgroundThe rapid emergence of new vaccine-resistant SARS-CoV-2 variants of concern (VOC) requires an equally rapid deployment of diagnostic tests to specifically identify each VOC as soon as it arises. Here, we report an expanded version of our previously described sloppy molecular beacon (SMB) Alpha/Beta/Gamma RT-PCR melting temperature (Tm) signature-based assay, which now includes modifications that allow specific detection of Delta (B.1.617.2) and Omicron (B.1.529) VOCs.MethodsWe developed a dual SMB assay (SMB-452), which targeted the T22917G (L452R) mutation in the SARS-CoV-2 spike protein to specifically detect the Delta VOC. We also identified a Tm profile in our existing SMB-501 and SMB-484 assays (which detect mutations in codons 501 and 484 of the SARS-CoV-2 spike protein, respectively) that differentiate the Omicron-specific N501Y (A23063T) and E484A (A23013C) mutations from both wild type (WT) and other VOCs. The entire six SMB three-codon assay was tested using reference SARS-CoV-2 RNAs. The assay was then validated using clinical samples from COVID-19 patients tested with a LightCycler 480 (LC480) (74 samples), Bio-Rad CFX96 (34 samples), Rotor-Gene Q (Qiagen) (34 samples) and an ABI-7500 (34 samples) RT-PCR instruments. Six SMB Tm results were then inputted into an Excel Analysis tool to generate specific VOC identifications.ResultsThe limit of detection (LOD) for the new SMB-452 assay, which specifically identified the Delta variant was 1 genomic equivalent (GE) per reaction. The LODs of the SMB-501 and SMB-484 assays, which detect Omicron were 100 and 103 GE respectively. Clinical validation of the 3-codon assay in the LC480 instrument showed the assay detected 94% of the samples as WT or VOCs in clinical samples and 6% of the tests producing indeterminate results. None of the samples were incorrectly identified as WT or as a different VOC. Thus, excluding samples with indeterminant results, the assay was 100% sensitive and 100% specific compared to sequencing. There was also 100% concordance between the LC480, BioRad, ABI and Qiagen results, excluding negative or indeterminate results; however, the Qiagen assay had significantly more indeterminates than the other assays.ConclusionThis new assay can serve as a robust diagnostic tool for selecting appropriate monoclonal antibody therapy and rapid VOC surveillance.

To describe a systematic process of transforming paper registers into a digital system optimized to enhance service provision and fulfil reporting requirements.We designed a formative study around primary health workers providing reproductive, maternal, newborn and child health services in three countries in Bangladesh, Indonesia and Pakistan. The study ran from November 2014 to June 2018. We developed a prototype digital application after conducting a needs assessment of health workers' responsibilities, workflows, routine data requirements and service delivery needs. Methods included desk reviews, focus group discussions, in-depth interviews; data mapping of paper registers; observations of health workers; co-design workshops with health workers; and usability testing. Finally, we conducted an observational feasibility assessment to monitor uptake of the application.Researchers reviewed a total of 17 paper registers across the sites, which we transformed into seven modules within a digital application running on mobile devices. Modules corresponded to the services provided, including household enumeration, antenatal care, family planning, immunization, nutrition and child health. A total of 65 health workers used the modules during the feasibility assessment, and average weekly form submissions ranged from 8 to 234, depending on the health worker and their responsibilities. We also observed variability in the use of modules, requiring consistent monitoring support for health workers.Lessons learnt from this study shaped key global initiatives and resulted in a software global good. The deployment of digital systems requires well-designed applications, change management and strengthening human resources to realize and sustain health system gains.Décrire un processus méthodique de transformation des registres papier en système numérique optimisé, en vue d'améliorer la fourniture de services et de remplir les exigences relatives à l'établissement de rapports.Nous avons conçu une étude formative consacrée aux professionnels des soins primaires proposant des services de santé reproductive et maternelle, de santé des nouveau-nés et de santé infantile dans trois pays: le Bangladesh, l'Indonésie et le Pakistan. Cette étude a été menée entre novembre 2014 et juin 2018. Nous avons mis au point un prototype d'application numérique après avoir évalué les besoins des soignants, leurs responsabilités, leur charge de travail, les données nécessaires à leurs activités quotidiennes et les impératifs liés à leurs prestations de service. Parmi les méthodes employées figuraient des examens documentaires, des discussions de groupes, des entretiens approfondis; une cartographie des données fondée sur les registres papier; une observation des professionnels de la santé; des ateliers de cocréation avec les soignants; et enfin, des tests d'utilisabilité. Pour terminer, nous avons effectué une analyse de faisabilité observationnelle afin de mesurer le taux d'adhésion à l'application.Les chercheurs ont passé au crible un total de 17 registres papier sur l'ensemble des sites, que nous avons transformés en sept modules repris dans une application numérique compatible avec les appareils mobiles. Ces modules correspondaient aux services proposés, dont le recensement des ménages, les soins prénatals, la planification familiale, la vaccination, la nutrition et la santé infantile. Au total, 65 soignants ont utilisé les modules au cours de l'analyse de faisabilité et le nombre moyen de formulaires soumis chaque semaine était compris entre 8 et 234, en fonction du soignant et de ses responsabilités. Nous avons également observé des variations dans l'utilisation des modules, ce qui montre la nécessité d'assurer un suivi permanent auprès des professionnels de la santé.Les leçons tirées de cette étude ont permis de façonner des initiatives internationales majeures et d'élaborer un logiciel d'intérêt mondial. Le déploiement de dispositifs numériques requiert des applications bien pensées, une bonne gestion du changement et un renforcement des ressources humaines afin d'obtenir et de préserver les avantages pour le système de santé.Describir un proceso sistemático que permita transformar los registros en papel en un sistema digital optimizado para mejorar la prestación de servicios y cumplir con los requisitos de información.Se diseñó un estudio formativo en torno a los profesionales de la salud primaria que prestan servicios de salud reproductiva, materna, neonatal e infantil en tres países: de Bangladesh, Indonesia y Pakistán. El estudio se realizódesarrolló entre noviembre de 2014 y junio de 2018. Se desarrolló un prototipo de aplicación digital después de realizar una evaluación sobre las necesidades de las responsabilidades de los profesionales sanitarios, los flujos de trabajo, los requisitos de datos rutinarios y las necesidades de prestación de servicios. Los métodos incluyeron revisiones de documentos, grupos de discusión, entrevistas en profundidad; mapeo de datos de los registros en papel; observaciones de los profesionales sanitarios; talleres de codiseño con los profesionales sanitarios; y pruebas de usabilidad. Por último, se llevó a cabo una evaluación de viabilidad observacional para supervisar la aceptación de la aplicación.Los investigadores revisaron un total de 17 registros en papel en todos los sitios, que se adaptaron a siete módulos dentro de una aplicación digital que funcionaba en dispositivos móviles. Los módulos correspondían a los servicios prestados, como la enumeración de los hogares, la atención prenatal, la planificación familiar, la inmunización, la nutrición y la salud infantil. Un total de 65 profesionales sanitarios utilizaron los módulos durante la evaluación de viabilidad, y la media de envíos de formularios semanales osciló entre 8 y 234, dependiendo del profesional sanitario y de sus responsabilidades. También se observó una variabilidad en el uso de los módulos, lo que requirió un apoyo de seguimiento constante por parte de los profesionales sanitarios.Las lecciones aprendidas de este estudio dieron forma a iniciativas globales clave y permitieron crear un programa informático de interés mundial. El despliegue de los sistemas digitales requiere aplicaciones bien diseñadas, la gestión del cambio y el fortalecimiento de los recursos humanos para realizar y mantener los beneficios del sistema sanitario.الغرض وصف عملية منهجية لتحويل السجلات الورقية إلى نظام رقمي مُحسّن لتحسين تقديم الخدمة وتلبية متطلبات إعداد التقارير. الطريقة قمنا بتصميم دراسة تكوينية عن العاملين في المجال الصحي الأولي، والذين يقدمون خدمات الصحة الإنجابية، وصحة الأم، والمواليد، والأطفال في ثلاث دول هي بنغلاديش وإندونيسيا وباكستان. استمرت الدراسة من نوفمبر/تشرين ثاني 2014 إلى يونيو/حزيران 2018. لقد طورنا تطبيقًا رقميًا أوليًا بعد إجراء تقييم لاحتياجات مسؤوليات العاملين في المجال الصحي، وعمليات سير العمل، ومتطلبات البيانات الروتينية، واحتياجات تقديم الخدمة. وشملت الطريقة المراجعات المكتبية، ومناقشات مجموعات التركيز، والمقابلات المتعمقة؛ وتخطيط بيانات السجلات الورقية؛ وملاحظات العاملين في المجال الصحي؛ والمشاركة في تصميم ورش العمل مع هؤلاء العاملين؛ واختبار قابلية الاستخدام. وأخيرًا، أجرينا تقييمًا للجدوى القائمة على الملاحظة لمراقبة استيعاب التطبيق. النتائج استعرض الباحثون ما يصل إلى 17 سجلاً ورقيًا عبر المواقع، والتي حولناها إلى سبع وحدات داخل تطبيق رقمي يعمل على الأجهزة المحمولة. تتوافق الوحدات مع الخدمات المقدمة، بما في ذلك التعداد الأسري، والرعاية قبل الولادة، وتنظيم الأسرة، والتحصين، والتغذية، وصحة الطفل. استخدم ما يصل إلى 65 من العاملين في المجال الصحي الوحدات أثناء تقييم الجدوى، وتراوحت عمليات الإدخال الأسبوعية من 8 إلى 234، اعتمادًا على العامل الصحي ومسؤولياته. كما لاحظنا تباينًا في استخدام الوحدات، مما يتطلب دعمًا متسقًا للرصد بواسطة العاملين في المجال الصحي. الاستنتاج أدى الدرس المستفاد من هذه الدراسة إلى تشكيل المبادرات العالمية الرئيسية، ونتج عنه منفعة عالمية للبرامج. يتطلب نشر الأنظمة الرقمية تطبيقات جيدة التصميم، وإدارة التغيير، وتقوية الموارد البشرية لتحقيق مكاسب النظام الصحي والحفاظ عليها.旨在描述将纸质登记转变为优化数字系统的系统化过程,以便提高服务水平并满足报告要求。.我们针对在巴基斯坦、孟加拉国和印度尼西亚三个国家提供生殖、孕产妇、新生儿和儿童健康服务的初级卫生保健人员设计了一项形成性研究。该研究在 2014 年 11 月至 2018 年 6 月期间进行。通过对卫生保健人员的职责、工作流程、常规数据要求和服务需求进行需求评估后,我们开发了一个原型数字应用程序。研究方法包括书面材料审查、专题小组讨论、深度采访;数据映射纸质登记内容;观察卫生保健人员;与卫生保健人员共同筹划研讨会;以及可用性测试。最后,我们根据观察结果进行了一项可行性评估,监测应用程序的使用情况。.研究人员审查了所有站点共 17 份纸质登记资料,我们将其转化为在移动设备上运行的数字应用程序中的七个模块。模块与提供的服务相对应,包括家庭统计、产前保健、家庭计划、免疫接种、营养和儿童健康。在可行性评估期间,共有 65 名卫生保健人员使用了这些模块,平均每周提交的表格从 8 个到 234 个不等,具体取决于卫生保健人员及其职责。我们还观察了模块使用的可变性,需要对卫生保健人员进行持续监测。.采用本调研中获得的经验制定关键的全球方案,开发全球性软件产品。部署数字系统时,需要采用精心设计的应用程序、变更管理和加强人力资源建设,才能实现和维持卫生系统的优化管理。.Описать систематический процесс преобразования бумажных реестров в цифровую систему, оптимизированную с целью улучшения предоставления услуг и выполнения требований к отчетности.Авторы разработали развивающее исследование, в котором приняли участие работники первичной медико-санитарной помощи, предоставляющие услуги в сфере репродуктивного здоровья, здоровья матерей, новорожденных и детей в трех странах: Бангладеш, Индонезии и Пакистане. Исследование проводилось с ноября 2014 года по июнь 2018 года. После проведения оценки потребностей медицинских работников, рабочих процессов, рутинных требований к данным и потребностей в предоставлении услуг авторы разработали прототип цифрового приложения. Методы включали анализ документации, дискуссии в фокус-группах, углубленные собеседования, привязку данных бумажных реестров, наблюдения за медицинскими работниками, разработку семинаров совместно с работниками здравоохранения и тестирование практичности. Наконец, авторы провели наблюдательную оценку осуществимости, чтобы отслеживать уровень применения приложения.Исследователи просмотрели в общей сложности 17 бумажных реестров во всех центрах, которые были преобразованы в семь модулей в цифровом приложении, работающем на мобильных устройствах. Модули соответствовали предоставляемым услугам, включая регистрацию домохозяйств, дородовую помощь, планирование семьи, иммунизацию, питание и здоровье детей. В общей сложности 65 медицинских работников использовали модули во время оценки осуществимости, и в среднем еженедельно заполнялось от 8 до 234 форм в зависимости от медицинского работника и его обязанностей. Авторы также пронаблюдали разницу в использовании модулей, что означает необходимость постоянной мониторинговой поддержки медицинских работников.Опыт, полученный из этого исследования, сформировал основные глобальные инициативы и привел к глобальному благу программного обеспечения. Внедрение цифровых систем требует хорошо разработанных приложений, управления изменениями и укрепления кадровых ресурсов для реализации и сохранения преимуществ системы здравоохранения.

Additional file 1: Figure S1. Similar distribution of transgenic hCD147 protein by immunohistochemistry in various tissues in hCD147KIhet-NSG mice relative to WT-NSG mice. Tissues from wild-type NSG mice (left) were stained for mouse CD147 protein using rabbit anti-mouse primary antibody (R&D Systems, BAF772; 1:100) and tissues from hCD147KIhet-NSG mice (right) were stained for human CD147 protein using mouse anti-human primary antibody (HIM6; 1:500). Images were taken using an Olympus Inverted Light Microscope. Scale bar represents 100 µm. Figure S2. Specificity of anti-human CD147 and anti-mouse CD147 antibodies tested against human and mouse cell lines. Representative contour plots of CD147 expression on BNL 1ME A.7R.1 (top) and HepG2 (bottom) cells using antibodies targeting either mouse CD147 protein, human CD147 protein, or a combination of both antibodies (far right). Relative percentages are listed, and significant shifts highlighted in red. Gating was determined based on donkey anti-goat and mouse isotype IgG antibody background staining. Figure S3. Reduction of body weight 2 days post-infection in SARS-CoV-2 infected hACE2KI-NSG and K18-hACE2-B6 mice, and slight body weight reduction in infected hCD147KI-NSG mice. Average body weight loss as a percent of original body weight in WT-NSG (n=3), hCD147KI-NSG (n=3), hACE2KI-NSG (n=4), and K18-hACE2-B6 (n=3) mice following intranasal infection with the TCID50 dose of SARS-CoV-2 virus (1×105 PFU in 25ul per nostril). Error bars represent standard error measure (SEM). Statistical significance was determined using an unpaired one-tailed Student t test. *indicates significance of p

11 páginas, 2 figuras, 1 tabla, Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance., I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)

The increased transmission of SARS-CoV-2 variants of concern (VOC), which originated in the United Kingdom (B.1.1.7/alpha), South Africa (B1.351/beta), Brazil (P.1/gamma), the United States (B.1.427/429 or epsilon), and India (B.1.617.2/delta), requires a vigorous public health response, including real-time strain surveillance on a global scale. Although genome sequencing is the gold standard for identifying these VOCs, it is time-consuming and expensive. Here, we describe a simple, rapid, and high-throughput reverse transcriptase PCR (RT-PCR) melting-temperature (Tm) screening assay that identifies the first three major VOCs. RT-PCR primers and four sloppy molecular beacon (SMB) probes were designed to amplify and detect the SARS-CoV-2 N501Y (A23063T) and E484K (G23012A) mutations and their corresponding wild-type sequences. After RT-PCR, the VOCs were identified by a characteristic Tm of each SMB. Assay optimization and testing was performed with RNA from SARS-CoV-2 USA WA1/2020 (wild type [WT]), B.1.1.7, and B.1.351 variant strains. The assay was then validated using clinical samples. The limit of detection for both the WT and variants was 4 and 10 genomic copies/reaction for the 501- and 484-codon assays, respectively. The assay was 100% sensitive and 100% specific for identifying the N501Y and E484K mutations in cultured virus and in clinical samples, as confirmed by Sanger sequencing. We have developed an RT-PCR melt screening test for the major VOCs that can be used to rapidly screen large numbers of patient samples, providing an early warning for the emergence of these variants and a simple way to track their spread.

BACKGROUND AND AIM: Arsenic methylation—the conversion of inorganic arsenic (iAs) to less toxic monomethyl (MMA) and dimethyl (DMA) species—could modify the developmental and reproductive toxicity ...

Tests that can replace sputum smear microscopy have been identified as a top priority diagnostic need for tuberculosis by the World Health Organization. High-quality evidence on diagnostic accuracy for tests that may meet this need is an essential requirement to inform decisions about policy and scale-up. However, test accuracy studies are often of low and inconsistent quality and poorly reported, leading to uncertainty about true test performance. Here we provide guidance for the design of diagnostic test accuracy studies of sputum smear-replacement tests. Such studies should have a cross-sectional or cohort design, enrolling either a consecutive series or a random sample of patients who require evaluation for tuberculosis. Adults with respiratory symptoms are the target population. The reference standard should at a minimum be a single, automated, liquid culture, but additional cultures, follow-up, clinical case definition, and specific measures to understand discordant results should also be included. Inclusion of smear microscopy and Xpert MTB/RIF (or MTB/RIF Ultra) as comparators is critical to allow broader comparability and generalizability of results, because disease spectrum can vary between studies and affects relative test performance. Given the complex nature of sputum (the primary specimen type used for pulmonary TB), careful design and reporting of the specimen flow is essential. Test characteristics other than accuracy (such as feasibility, implementation considerations, and data on impact on patient, population and health systems outcomes) are also important aspects.

This article examines the problem of interference in automotive radar. Different types of automotive radar as well as mechanisms and characteristics of interference and the effects of interference on radar system performance are described. The interference-to-noise ratio (INR) at the output of a detector is a measure of the susceptibility of a radar to interference. The INR is derived from different types of interfering and victim radars and depends on the location of both as well as parameters such as transmit power, antenna gain, and bandwidth. In addition, for victim radar with beamscanning, INR depends on the location of the target the victim radar is attempting to detect. Analysis is presented to show the effects of various interference scenarios on the INR. A review of the current state of the art in interference mitigation techniques previously deployed as well as areas of research currently being addressed is then provided. Finally, important future research directions are suggested.

Pesisir pantai, penyeberangan laut, dan alur pelayaran memainkan peran penting dalam transportasi laut. Sebagian besar kargo yang diangkut adalah angkutan domestik dan internasional. Transportasi laut telah mendapatkan perhatian selama bertahun-tahun karena dinilai hemat energi dan bahan bakar, terdapat peningkatan minat dalam memperluas rute perdagangan melalui laut untuk pengiriman barang domestik. Karena draf berlayar kapal terkait langsung dengan tonase yang dimuat, kedalaman saluran yang diperlukan untuk memastikan kapasitas angkut yang memadai. Tantangan bagi para pengambil keputusan adalah untuk secara optimal mengalokasikan pengeluaran berupa biaya pengerukan alur pelayaran di seluruh jaringan alur pelayaran yang luas untuk memaksimalkan manfaat secara nasional. Penelitian ini bertujuan untuk mengidentifikasi konsep manfaat jika proyek pengerukan alur pelayaran dilakukan dengan menggunakan analisis deskriptif. Berdasarkan hasil analisis, manfaat pengerukan adalah meningkatkan keamanan dan keselamatan alur pelayaran, meningkatkan kelayakan transportasi laut, meningkatkan stabilitas pergerakan barang, meningkatkan konektivitas antar pelabuhan, meningkatkan pembangunan infrastruktur pelabuhan, meningkatkan dimensi kapal yang dapat memasuki pelabuhan, meningkatkan stabilitas kinerja pelabuhan, meningkatkan jumlah kapal yang dapat memasuki pelabuhan, menurunkan laju sedimentasi di saluran akses, mengurangi pergantian waktu kapal, meningkatkan efisiensi kinerja pelabuhan, menurunkan biaya pelabuhan, dan meningkatkan pendapatan operator pelabuhan.

Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P

3003 Background: The p53 tumor suppressor protein is a transcription factor that acts to maintain genome stability in response to cellular stress. Spontaneous mutation of the TP53 gene leading to inactivation of the p53 protein is the most common mutational event across all human cancers. PC14586 is a novel, small molecule structural corrector that binds selectively to p53 Y220C mutant protein and restores the p53 wildtype conformation and transcriptional activity, resulting in potent preclinical antitumor activity. This Phase 1 multicenter dose escalation study assesses PC14586 safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy in patients (pts) with advanced solid tumors that harbor the TP53 Y220C mutation. Methods: Eligible adult pts with locally advanced or metastastic TP53 Y220C mutant solid tumors received increasing doses of oral PC14586 using the modified Toxicity Probability Interval design to estimate toxicity and to determine maximum tolerated dose and recommended phase 2 dose. Plasma PK was characterized using standard methods. Preliminary efficacy was assessed by RECIST v1.1. Reporting of interim results was approved by the study’s Safety Review Committee. Results: As of 08 Feb 2022, 29 pts (62% female, median age 62 years) with a variety of TP53 Y220C mutant solid tumor types (median number of prior lines of therapy 3; range 1 to 8) were treated in 7 dose cohorts of PC14586: 150 mg QD (3 pts), 300 mg QD (3 pts), 600 mg QD (4 pts), 1150 mg QD (5 pts), 2000 mg QD (7 pts), 2500 mg QD (4 pts) and 1500 mg BID (3 pts). PC14586 was generally well-tolerated; treatment-related AEs were observed in 79% of pts that were all Grade 1/2 in severity except 2 Grade 3 AEs (alanine aminotransferase increased and neutrophil count decreased). The most common AEs (≥15% of pts) were nausea (34%), vomiting (24%), fatigue (21%), and aspartate aminotransferase increased (17%). There were no dose limiting toxicities and enrollment continues. PK analysis showed dose proportional increases in Cmax and AUC. Amongst 21 efficacy evaluable pts, PRs were observed in 5 pts: 1 small cell lung and 1 breast with confirmed PR (cPR), both ongoing; 1 colorectal with unconfirmed PR (uPR), and 2 prostate with uPR and ongoing. In the 3 highest dose cohorts (total daily dose 2000 to 3000 mg), there were 3 PRs (2 uPR, 1cPR) and 7 SD out of 10 efficacy evaluable pts (all ongoing). Observations of decreasing p53 Y220C circulating tumor DNA and decreasing numbers of circulating tumor cells in pts further support on-target anti-tumor activity of PC14586. Conclusions: Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts. Additional safety, PK, PD and efficacy data will be reported at the annual meeting. Clinical trial information: NCT04585750.

We describe the design, development, analytical performance and a limited clinical evaluation of the 10-color Xpert MTB/XDR assay (CE-IVD only, not for sale in the US). This assay is intended as a reflex test to detect resistance to Isoniazid (INH), Fluoroquinolones (FLQ), Ethionamide (ETH) and Second Line Injectable Drugs Drugs (SLID) on unprocessed sputum samples and concentrated sputum sediments which are positive for Mycobacterium tuberculosis. The Xpert MTB/XDR assay simultaneously amplifies eight genes and promoter regions in M. tuberculosis and analyzes melting temperatures (Tms) using sloppy molecular beacon probes (SMB) to identify mutations associated with INH, FLQ, ETH and SLID resistance. Results can be obtained under 90 minutes and requires 10-color GeneXpert modules. The assay can differentiate low versus high-level resistance to INH and FLQ as well as cross-resistance versus individual resistance to SLIDs by identifying mutation-specific Tms or Tm patterns generated by the SMB probes. The assay has a Limit of Detection comparable to the Xpert MTB/RIF assay and succesfully detected 16 clinically significant mutations in a challenge set of clinical isolate DNA. In a clinical study performed at two sites with 100 sputum and 214 clinical isolates, the assay showed a sensitivity of 94-100% and a specificity of 100% for all drugs except for ETH when compared to sequencing. The sensitivity and specificity when compared to phenotypic drug susceptibility testing were in the same range. Used in combination with a primary tuberculosis diagnostic test, this assay is expected to expand the capacity for detection of drug-resistant tuberculosis.

SummaryBackgroundThe COVID-19 pandemic has caused a severe shortage of personal protective equipment (PPE), especially N95 respirators. Efficient, effective and economically feasible methods for large-scale PPE decontamination are urgently needed.Aims(1) to develop protocols for effectively decontaminating PPE using vaporized hydrogen peroxide (VHP); (2) to develop novel approaches that decrease set up and take down time while also increasing decontamination capacity (3) to test decontamination efficiency for N95 respirators heavily contaminated by makeup or moisturizers.MethodsWe converted a decommissioned Biosafety Level 3 laboratory into a facility that could be used to decontaminate N95 respirators. N95 respirators were hung on metal racks, stacked in piles, placed in paper bags or covered with makeup or moisturizer. A VHP®VICTORYTM unit from STERIS was used to inject VHP into the facility. Biological and chemical indicators were used to validate the decontamination process.FindingsN95 respirators individually hung on metal racks were successfully decontaminated using VHP. N95 respirators were also successfully decontaminated when placed in closed paper bags or if stacked in piles of up to six. Stacking reduced the time needed to arrange N95 respirators for decontamination by approximately two-thirds while almost tripling facility capacity. Makeup and moisturizer creams did not interfere with the decontamination process.ConclusionsRespirator stacking can reduce the hands-on time and increase decontamination capacity. When personalization is needed, respirators can be decontaminated in labeled paper bags. Make up or moisturizers do not appear to interfere with VHP decontamination.

We have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (SCV) phenotype, but this mutation does not change the MICs of any drug for wild-type M. tuberculosis However, the same orn mutation in a low-level EMB-resistant double embB-aftA mutant (MIC = 8 μg/ml) produces an SCV with an EMB MIC of 32 μg/ml. Reversible resistance is indistinguishable from a drug-persistent phenotype, because further culture of these orn-embB-aftA SCV mutants results in rapid reversion of the orn frameshifts, reestablishing the correct orn open reading frame, returning the culture to normal colony size, and reversing the EMB MIC back to that (8 μg/ml) of the parental strain. Transcriptomic analysis of orn-embB-aftA mutants compared to wild-type M. tuberculosis identified a 27-fold relative increase in the expression of embC, which is a cellular target for EMB. Expression of embC in orn-embB-aftA mutants was also increased 5-fold compared to that in the parental embB-aftA mutant, whereas large-colony orn frameshift revertants of the orn-embB-aftA mutant had levels of embC expression similar to that of the parental embB-aftA strain. Reversible frameshift mutants may contribute to a reversible form of microbiological drug resistance in human tuberculosis.

Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [18F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [18F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [18F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [18F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/R HL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation. This phase 1b study was registered at www.clinicaltrials.gov as NCT02665650.

Nucleic acid amplification tests (NAATs) are the primary means of identifying acute infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accurate and fast test results may permit more efficient use of protective and isolation resources and allow rapid therapeutic interventions. We evaluated the analytical and clinical performance characteristics of the Xpert Xpress SARS-CoV-2 (Xpert) test, a rapid, automated molecular test for SARS-CoV-2. Analytical sensitivity and specificity/interference were assessed with infectious SARS-CoV-2; other infectious coronavirus species, including SARS-CoV; and 85 nasopharyngeal swab specimens positive for other respiratory viruses, including endemic human coronaviruses (hCoVs)., Nucleic acid amplification tests (NAATs) are the primary means of identifying acute infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accurate and fast test results may permit more efficient use of protective and isolation resources and allow rapid therapeutic interventions. We evaluated the analytical and clinical performance characteristics of the Xpert Xpress SARS-CoV-2 (Xpert) test, a rapid, automated molecular test for SARS-CoV-2. Analytical sensitivity and specificity/interference were assessed with infectious SARS-CoV-2; other infectious coronavirus species, including SARS-CoV; and 85 nasopharyngeal swab specimens positive for other respiratory viruses, including endemic human coronaviruses (hCoVs). Clinical performance was assessed using 483 remnant upper- and lower-respiratory-tract specimens previously analyzed by standard-of-care (SOC) NAATs. The limit of detection of the Xpert test was 0.01 PFU/ml. Other hCoVs, including Middle East respiratory syndrome coronavirus, were not detected by the Xpert test. SARS-CoV, a closely related species in the subgenus Sarbecovirus, was detected by a broad-range target (E) but was distinguished from SARS-CoV-2 (SARS-CoV-2-specific N2 target). Compared to SOC NAATs, the positive agreement of the Xpert test was 219/220 (99.5%), and the negative agreement was 250/261 (95.8%). A third tie-breaker NAAT resolved all but three of the discordant results in favor the Xpert test. The Xpert test provided sensitive and accurate detection of SARS-CoV-2 in a variety of upper- and lower-respiratory-tract specimens. The high sensitivity and short time to results of approximately 45 min may impact patient management.

The identity of metal ions surrounding DNA is key to its biological function and materials applications. In this work, we compare atomistic molecular dynamics simulations of double strand DNA (dsDNA) with four alkaline earth metal ions (Mg2+, Ca2+, Sr2+, and Ba2+) to elucidate the physical interactions that govern DNA-ion binding. Simulations accurately model the ion-phosphate distance of Mg2+ and reproduce ion counting experiments for Ca2+, Sr2+, and Ba2+. Our analysis shows that alkaline earth metal ions prefer to bind at the phosphate backbone compared to the major groove and negligible binding occurs in the minor groove. Larger alkaline earth metal ions with variable first solvation shells (Ca2+, Sr2+, and Ba2+) show both direct and indirect binding, where indirect binding increases with ion size. Mg2+ does not fit this trend because the strength of its first solvation shell predicts indirect binding only. Ions bound to the phosphate backbone form fewer contacts per ion compared to the major groove. Within the major groove, metal ions preferentially bind to guanine-cystosine base pairs and form simultaneous contacts with the N7 and O6 atoms of guanine. Overall, we find that the interplay among ion size, DNA-ion interaction, and the size and flexibility of the first solvation shell are key to predicting how alkaline earth metal ions interact with DNA.

We have identified a previously unknown mechanism of reversible high-level ethambutol (EMB) resistance in Mycobacterium tuberculosis that is caused by a reversible frameshift mutation in the M. tuberculosis orn gene. A frameshift mutation in orn produces the small-colony-variant (SCV) phenotype, but this mutation does not change the MICs of any drug for wild-type M. tuberculosis. However, the same orn mutation in a low-level EMB-resistant double embB-aftA mutant (MIC = 8 μg/ml) produces an SCV with an EMB MIC of 32 μg/ml. Reversible resistance is indistinguishable from a drug-persistent phenotype, because further culture of these orn-embB-aftA SCV mutants results in rapid reversion of the orn frameshifts, reestablishing the correct orn open reading frame, returning the culture to normal colony size, and reversing the EMB MIC back to that (8 μg/ml) of the parental strain. Transcriptomic analysis of orn-embB-aftA mutants compared to wild-type M. tuberculosis identified a 27-fold relative increase in the expression of embC, which is a cellular target for EMB. Expression of embC in orn-embB-aftA mutants was also increased 5-fold compared to that in the parental embB-aftA mutant, whereas large-colony orn frameshift revertants of the orn-embB-aftA mutant had levels of embC expression similar to that of the parental embB-aftA strain. Reversible frameshift mutants may contribute to a reversible form of microbiological drug resistance in human tuberculosis.

Bonded concrete overlays of asphalt pavements (BCOA) consist of a concrete overlay placed on an existing asphalt or composite pavement. This technique is intended as a cost-effective rehabilitation solution for marginally distressed in-service asphalt or composite pavements. BCOA with panel sizes between 4.5 ft and 8.5 ft have become popular as they reduce curling stresses while keeping the longitudinal joints out of the wheelpath. The BCOA-ME (mechanistic empirical) design procedure and Pavement ME short jointed plain concrete pavement (SJPCP) module can both be used to design BCOA with mid-size panels. However, these design procedures differ in the assumptions used to develop the mechanistic computational model, fatigue models used to predict failure, treatment of environmental conditions, estimate of asphalt stiffness, consideration of structural fibers, the application of traffic loading, and the calibration process. This results in the procedures producing different overlay thicknesses and predicted distresses. The strengths and limitations of each procedure are evaluated and comparisons are made between the design thicknesses obtained from them.

Transverse joint faulting is a common distress in bonded concrete overlays of asphalt pavements (BCOAs), also known as whitetopping. However, to date, there is no predictive faulting model available for these structures. To account for conditions unique to BCOA, a computational model was developed using a three-dimensional finite element program, ABAQUS, to predict the response of these structures. The model was validated with falling weight deflectometer (FWD) data from existing field sections at the Minnesota Road Research Facility (MnROAD) as well as at the University of California Pavement Research Center (UCPRC). A large database of analyses was then developed using a fractional factorial design. The database is used to develop predictive models, based on artificial neural networks (ANNs), to rapidly estimate the structural response at the joint in BCOA to environmental and traffic loads. The structural response will be related to damage using the differential energy concept. Future work includes the implementation of the developed ANNs in this study into a faulting prediction model for designing BCOA.