Combinations of the azaquinazoline anti-Wolbachia agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis.

Lymphatic filariasis and onchocerciasis are two major neglected tropical diseases that are responsible for causing severe disability in 50 million people worldwide, whilst veterinary filariasis (heartworm) is a potentially lethal parasitic infection of companion animals. There is an urgent need for safe, short-course curative (macrofilaricidal) drugs to eliminate these debilitating parasite infections. We investigated combination treatments of the novel anti-Wolbachia azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: Brugia malayi-CB.17 SCID mice, B. malayi-Mongolian gerbils, B. pahangi-Mongolian gerbils, and Litomosoides sigmodontis-Mongolian gerbils. Combination treatments synergised to elicit threshold (>90%) Wolbachia depletion from female worms in 5 days of treatment, using 2-fold lower dose-exposures of AWZ1066S than monotherapy. Short-course lowered dose AWZ1066S-albendazole combination treatments also delivered partial adulticidal activities and/or long-lasting inhibition of embryogenesis, resulting in complete transmission blockade in B. pahangi and L. sigmodontis gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of Wolbachia populations within both germline and hypodermal tissues of B. malayi female worms and in hypodermal tissues in male worms, indicating that anti-Wolbachia synergy is not limited to targeting female embryonic tissues. Our data provides pre-clinical proof-of-concept that sub-seven-day combinations of rapid-acting novel anti-Wolbachia agents with benzimidazole anthelmintics are a promising curative and transmission-blocking drug treatment strategy for filarial diseases of medical and veterinary importance.

The 2022 Hunga-Tonga megatsunami: Near-field simulation of a once-in-a-century event.

The Hunga Tonga-Hunga Ha'apai (HTHH) volcanic eruption in January 2022 generated catastrophic tsunami and contends for the largest natural explosion in more than a century. The main island, Tongatapu, suffered waves up to 17 m, and Tofua Island suffered waves up to 45 m, comfortably placing HTHH in the "megatsunami" league. We present a tsunami simulation of the Tongan Archipelago calibrated by field observations, drone, and satellite data. Our simulation emphasizes how the complex shallow bathymetry of the area acted as a low-velocity wave trap, capturing tsunami for more than 1 hour. Despite its size and long duration, few lives were lost. Simulation suggests that HTHH's location relative to urban centers saved Tonga from a worse outcome. Whereas 2022 seems to have been a lucky escape, other oceanic volcanoes have the capacity to spawn future tsunami at HTHH scale. Our simulation amplifies the state of understanding of volcanic explosion tsunami and provides a framework for assessment of future hazards.

Correction: A Neolithic Mega-Tsunami Event in the Eastern Mediterranean: Prehistoric Settlement Vulnerability Along the Carmel Coast, Israel.

[This corrects the article DOI: 10.1371/journal.pone.0243619.].

A Neolithic mega-tsunami event in the eastern Mediterranean: Prehistoric settlement vulnerability along the Carmel coast, Israel.

Tsunami events in antiquity had a profound influence on coastal societies. Six thousand years of historical records and geological data show that tsunamis are a common phenomenon affecting the eastern Mediterranean coastline. However, the possible impact of older tsunamis on prehistoric societies has not been investigated. Here we report, based on optically stimulated luminescence chronology, the earliest documented Holocene tsunami event, between 9.91 to 9.29 ka (kilo-annum), from the eastern Mediterranean at Dor, Israel. Tsunami debris from the early Neolithic is composed of marine sand embedded within fresh-brackish wetland deposits. Global and local sea-level curves for the period, 9.91-9.29 ka, as well as surface elevation reconstructions, show that the tsunami had a run-up of at least ~16 m and traveled between 3.5 to 1.5 km inland from the palaeo-coastline. Submerged slump scars on the continental slope, 16 km west of Dor, point to the nearby "Dor-complex" as a likely cause. The near absence of Pre-Pottery Neolithic A-B archaeological sites (11.70-9.80 cal. ka) suggest these sites were removed by the tsunami, whereas younger, late Pre-Pottery Neolithic B-C (9.25-8.35 cal. ka) and later Pottery-Neolithic sites (8.25-7.80 cal. ka) indicate resettlement following the event. The large run-up of this event highlights the disruptive impact of tsunamis on past societies along the Levantine coast.

Mechanical Ventilation of Severe Traumatic Brain Injury Patients in the Prehospital Setting.

OBJECTIVE: Suboptimal ventilation may impact outcomes in patients with traumatic brain injury (TBI). This study compares the incidence of eucapnia between manually and mechanically ventilated patients with severe TBI during helicopter transport. METHODS: This retrospective chart review included consecutive intubated adults with severe TBI (Glasgow Coma Scale score < 9) transported by helicopter from the scene of injury to a level 1 trauma center between 2009 and 2015. The primary outcome was the first venous partial pressure of carbon dioxide obtained in the emergency department. Hypocapnia, eucapnia, and hypercapnia were defined based on the normal range for the testing instrument. The Fisher exact test was used to compare groups. RESULTS: Of 1,070 trauma patients intubated and transported, 93 met the inclusion criteria with full data. The mean age was 43 years, 81 of 93 were white, and 70 of 93 were men. The mean Injury Severity Score was 29, and 26 of 93 were mechanically ventilated. Hypocapnia occurred in 4 of 93 and hypercapnia in 56 of 93. There was no difference in the rate of eucapnia in manually ventilated compared with mechanically ventilated patients (36% vs. 35%, P = 1.00). CONCLUSION: Eucapnia at emergency department arrival occurred in 36% of patients and was unaffected by whether ventilation was manually or mechanically controlled. Few patients were hypocapnic, indicating a low incidence of hyperventilation during helicopter transport.

COPD Care Bundle in Emergency Department Observation Unit Reduces Emergency Department Revisits.

BACKGROUND: COPD exacerbations lead to accelerated decline in lung function, poor quality of life, and increased mortality and cost. Emergency department (ED) observation units provide short-term care to reduce hospitalizations and cost. Strategies to improve outcomes in ED observation units following COPD exacerbations are needed. We sought to reduce 30-d ED revisits for COPD exacerbations managed in ED observation units through implementation of a COPD care bundle. The study setting was an 800-bed, academic, safety-net hospital with 700 annual ED encounters for COPD exacerbations. Among those discharged from ED observation unit, the 30-d all-cause ED revisit rate (ie, the outcome measure) was 49% (baseline period: August 2014 through September 2016). METHODS: All patients admitted to the ED observation unit with COPD exacerbations were included. A multidisciplinary team implemented the COPD bundle using iterative plan-do-study-act cycles with a goal adherence of 90% (process measure). The bundle, adopted from our inpatient program, was developed using care-delivery failures and unmet subject needs. It included 5 components: appropriate inhaler regimen, 30-d inhaler supply, education on devices available after discharge, standardized discharge instructions, and a scheduled 15-d appointment. We used statistical process-control charts for process and outcome measures. To compare subject characteristics and process features, we sampled consecutive patients from the baseline (n = 50) and postbundle (n = 83) period over 5-month and 7-month intervals, respectively. Comparisons were made using t tests and chi-square tests with P < .05 significance. RESULTS: During baseline and postbundle periods, 410 and 165 subjects were admitted to the ED observation unit, respectively. After iterative plan-do-study-act cycles, bundle adherence reached 90% in 6 months, and the 30-d ED revisit rate declined from 49% to 30% (P = .003) with a system shift on statistical process-control charts. There was no difference in hospitalization rate from ED observation unit (45% vs 51%, P = .16). Subject characteristics were similar in the baseline and postbundle periods. CONCLUSIONS: Reliable adherence to a COPD care bundle reduced 30-d ED revisits among those treated in the ED observation unit.

Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/µl) and uncomplicated malaria (3,700/µl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/µl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria.

Examining the Initiation of the Polymerization Mechanism and Network Development in Aromatic Polybenzoxazines.

Three bis-benzoxazine monomers based on the aniline derivatives of bisphenol A (BA-a), bisphenol F (BF-a), and 3,3'-thiodiphenol (BT-a) are examined using a variety of spectroscopic, chromatographic, and thermomechanical techniques. The effect on the polymerization of the monomers is compared using two common compounds, 3,3'-thiodiphenol (TDP) and 3,3'-thiodipropionic acid (TDA), at a variety of loadings. It is found that the diacid has a greater effect on reducing the onset of polymerization and increasing cross-link density and Tg for a given benzoxazine. However, the addition of >5 wt % of the diacid had a detrimental effect on the cross-link density, Tg, and thermal stability of the polymer. The kinetics of the polymerization of BA-a were found to be well described using an autocatalytic model for which values of n = 1.64 and m = 2.31 were obtained for the early and later stages of reaction (activation energy = 81 kJ/mol). Following recrystallization the same monomer yielded values n = 1.89, m = 0.89, and Ea = 94 kJ/mol (confirming the influence of higher oligomers on reactivity). The choice of additive (in particular the magnitude of its pKa) appears to influence the nature of the network formation from a linear toward a more clusterlike growth mechanism.

Solving the problem of building models of crosslinked polymers: an example focussing on validation of the properties of crosslinked epoxy resins.

The construction of molecular models of crosslinked polymers is an area of some difficulty and considerable interest. We report here a new method of constructing these models and validate the method by modelling three epoxy systems based on the epoxy monomers bisphenol F diglycidyl ether (BFDGE) and triglycidyl-p-amino phenol (TGAP) with the curing agent diamino diphenyl sulphone (DDS). The main emphasis of the work concerns the improvement of the techniques for the molecular simulation of these epoxies and specific attention is paid towards model construction techniques, including automated model building and prediction of glass transition temperatures (T(g)). Typical models comprise some 4200-4600 atoms (ca. 120-130 monomers). In a parallel empirical study, these systems have been cast, cured and analysed by dynamic mechanical thermal analysis (DMTA) to measure T(g). Results for the three epoxy systems yield good agreement with experimental T(g) ranges of 200-220°C, 270-285°C and 285-290°C with corresponding simulated ranges of 210-230°C, 250-300°C, and 250-300°C respectively.

Synthesis and biological activities of 4-N-(anilinyl-n-[oxazolyl])-7-chloroquinolines (n=3' or 4') against Plasmodium falciparum in in vitro models.

The synthesis (Pd-mediated coupling strategy) and characterization (NMR, IR, elemental analysis, etc.) of a short series of quinoline-oxazole hybrid compounds has been carried out. These materials are found to be moderately active against Plasmodium falciparum in vitro, with activities in the sub-micromolar range, and to display acceptable cytotoxicity to mononuclear leukocytes. Chemical modification strategies, with the intention to increase the biological potency of this new class of anti-malarial agents, are discussed.

The association between ambulance hospital turnaround times and patient acuity, destination hospital, and time of day.

INTRODUCTION: The availability of ambulances to respond to emergency calls is related to their ability to return to service from the hospital. Extended hospital turnaround times decrease the number of available unit hours ambulances are deployed, which in turn can increase coverage costs or sacrifice coverage. OBJECTIVE: To determine whether ambulance turnaround times were associated with patient acuity, destination hospital, and time of day. METHODS: This retrospective analysis of ambulance hospital turnaround times utilized 12 months of data from a single, countywide, metropolitan emergency medical services (EMS) service. Turnaround time was defined as the interval between the time of ambulance arrival at the hospital and the time the ambulance became available to respond to another call. Independent variables included patient acuity (low [BLS nonemergency transport], medium [ALS care and nonemergency transport], and high [ALS care and emergency transport]), destination hospital (seven regional hospitals), and time of day (one-hour intervals). Data analysis consisted of descriptive statistics, t-tests, and linear regression. RESULTS: Of the 61,094 patient transports, the mean turnaround time was 35.6 minutes (standard deviation [SD] = 16.5). Turnaround time was significantly associated with patient acuity (p < 0.001). High-acuity calls had a mean turnaround time of 52.5 minutes (SD = 21.5), whereas moderate-acuity and low-acuity calls had mean turnaround times of 42.0 minutes (SD = 16.4) and 32.5 minutes (SD = 14.4), respectively. A statistically significant relationship between destination hospital and turnaround time was found, with the differences in means ranging from 30 seconds to 8 minutes. Similarly, time of day was associated with turnaround time, with the longest turnaround times occurring between 0600 and 1500 hours. CONCLUSION: This study demonstrated that patient acuity, destination hospital, and time of day were associated with variation in ambulance turnaround times. Research describing other system characteristics such as current emergency department census and patient handoff procedures may further demonstrate areas for improvement in HTAT. Results from this analysis may be used to inspire EMS administrators and EMS medical directors to start tracking these times to create a predictive model of EMS staffing needs.

Association between prehospital time intervals and ST-elevation myocardial infarction system performance.

BACKGROUND: Among individuals experiencing an ST segment-elevation myocardial infarction, current guidelines recommend that the interval from first medical contact to percutaneous coronary intervention be ≤90 minutes. The objective of this study was to determine whether prehospital time intervals were associated with ST-elevation myocardial infarction system performance, defined as first medical contact to percutaneous coronary intervention. METHODS AND RESULTS: Study patients presented with an acute ST-elevation myocardial infarction diagnosed by prehospital ECG between May 2007 and March 2009. Prehospital time intervals were as follows: 9-1-1 call receipt to ambulance on scene ≤10 minutes, ambulance on scene to 12-lead ECG acquisition ≤8 minutes, on-scene time ≤15 minutes, prehospital ECG acquisition to ST-elevation myocardial infarction team notification ≤10 minutes, and scene departure to patient on cardiac catheterization laboratory table ≤30 minutes. Time intervals were derived and analyzed with descriptive statistics and logistic regression. There were 181 prehospital patients who received percutaneous coronary intervention, with 165 (91.1) having complete data. Logistic regression indicated that table time, response time, and on-scene time were the benchmark time intervals with the greatest influence on the probability of achieving percutaneous coronary intervention in ≤90 minutes. Individuals with a time from scene departure to arrival on cardiac catheterization laboratory table of ≤30 minutes were 11.1 times (3.4 to 36.0) more likely to achieve percutaneous coronary intervention in ≤90 minutes than those with extended table times. CONCLUSIONS: In this patient population, prehospital timing benchmarks were associated with system performance. Although meeting all 5 benchmarks may be an ideal goal, this model may be more useful for identifying areas for system improvement that will have the greatest clinical impact.

The association between prehospital endotracheal intubation attempts and survival to hospital discharge among out-of-hospital cardiac arrest patients.

OBJECTIVES: The benefit of prehospital endotracheal intubation (ETI) among individuals experiencing out-of-hospital cardiac arrest (OOHCA) has not been fully examined. The objective of this study was to determine if prehospital ETI attempts were associated with return of spontaneous circulation (ROSC) and survival to discharge among individuals experiencing OOHCA. METHODS: This retrospective study included individuals who experienced a medical cardiac arrest between July 2006 and December 2008 and had resuscitation efforts initiated by paramedics from Mecklenburg County, North Carolina. Outcome variables were prehospital ROSC and survival to hospital discharge, while the primary independent variable was the number of prehospital ETI attempts. RESULTS: There were 1,142 cardiac arrests included in the analytic data set. Prehospital ROSC occurred in 299 individuals (26.2%). When controlling for initial arrest rhythm and other confounding variables, individuals with no ETI attempted were 2.33 (95% confidence interval [CI] = 1.63 to 3.33) times more likely to have ROSC compared to those with one successful ETI attempt. Of the 299 individuals with prehospital ROSC, 118 (39.5%) were subsequently discharged alive from the hospital. Individuals having no ETI were 5.46 (95% CI = 3.36 to 8.90) times more likely to be discharged from the hospital alive compared to individuals with one successful ETI attempt. CONCLUSIONS: Results from these analyses suggest a negative association between prehospital ETI attempts and survival from OOHCA. In this study, the individuals most likely to have prehospital ROSC and survival to hospital discharge were those who did not have a reported ETI attempt. Further comparative research should assess the potential causes of the demonstrated associations.

Juvenile idiopathic arthritis (JIA): a screening study to measure class II skeletal pattern, TMJ PDS and use of systemic corticosteroids.

OBJECTIVE: To screen patients with oligoarticular and polyarticular forms of Juvenile Idiopathic Arthritis (JIA) to determine (i) the severity of their class II skeletal pattern; (ii) temporomandibular joint signs and symptoms and (iii) use of systemic corticosteroids. DESIGN: Cross-sectional screening. SUBJECTS AND SETTING: Sixty-eight children with JIA aged between 9 and 16 years old who were screened at four regional treatment centres in the UK. METHOD: Patients were screened clinically and radiographically for the presence of class II skeletal pattern and temporomandibular (TMJ) pain dysfunction syndrome. In addition, the JIA sub-type and history of disease activity and medication were recorded. MAIN OUTCOME MEASURES: Class II skeletal pattern, TMJ signs and symptoms, use of systemic corticosteroids. RESULTS: The mean ANB values were 4.2 degrees (SD = 2.9 degrees) in the oligoarticular group and 5.1 degrees (SD = 3.8 degrees) in the polyarticular group. Just under one-third of children had a moderate or severe class II skeletal pattern and a further quarter of children had a mild class II skeletal pattern. Clinical signs and symptoms of temporomandibular joint pain dysfunction syndrome were low (<20%), except for crepitus and click which affected between 24 and 40% of JIA children. Radiographically, 57% of oligoarticular and 77% of polyarticular cases exhibited condylar erosion. Use of systemic corticosteroids varied between centres, but overall, was prescribed more in polyarticular cases (P = 0.001). CONCLUSIONS: Just under one-third of oligoarticular and polyarticular JIA patients exhibited a moderate or severe class II skeletal pattern. It is, therefore, likely that any future clinical trial to investigate the effect of functional appliance treatment in JIA patients, will need multicentre co-operation to fulfil potential sample size requirements. Clinical signs and symptoms of temporomandibular joint pain dysfunction syndrome were low except for crepitus and click. However, radiographic evidence of condylar erosion was high particularly in the polyarticular group. Use of systemic corticosteroids was prescribed more in polyarticular cases and this is likely to reflect the severity of the disease.

Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics.

The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.

Sperm DNA: organization, protection and vulnerability: from basic science to clinical applications--a position report.

This article reports the results of the most recent in a series of EHSRE workshops designed to synthesize the current state of the field in Andrology and provide recommendations for future work (for details see Appendix). Its focus is on methods for detecting sperm DNA damage and potential application of new knowledge about sperm chromatin organization, vulnerability and repair to improve the diagnosis and treatment of clinical infertility associated with that damage. Equally important is the use and reliability of these tests to identify the extent to which environmental contaminants or pharmaceutical agents may contribute to the incidence of sperm DNA damage and male fertility problems. A working group (for workshop details, see Appendix) under the auspices of ESHRE met in May 2009 to assess the current knowledgebase and suggest future basic and clinical research directions. This document presents a synthesis of the working group's understanding of the recent literature and collective discussions on the current state of knowledge of sperm chromatin structure and function during fertilization. It highlights the biological, assay and clinical uncertainties that require further research and ends with a series of 5 key recommendations.