Bioenergetic stress potentiates antimicrobial resistance and persistence.

Antimicrobial resistance (AMR) is a global health crisis and there is an urgent need to better understand AMR mechanisms. Antibiotic treatment alters several aspects of bacterial physiology, including increased ATP utilization, carbon metabolism, and reactive oxygen species (ROS) formation. However, how the "bioenergetic stress" induced by increased ATP utilization affects treatment outcomes is unknown. Here we utilized a synthetic biology approach to study the direct effects of bioenergetic stress on antibiotic efficacy. We engineered a genetic system that constitutively hydrolyzes ATP or NADH in Escherichia coli. We found that bioenergetic stress potentiates AMR evolution via enhanced ROS production, mutagenic break repair, and transcription-coupled repair. We also find that bioenergetic stress potentiates antimicrobial persistence via potentiated stringent response activation. We propose a unifying model that antibiotic-induced antimicrobial resistance and persistence is caused by antibiotic-induced. This has important implications for preventing or curbing the spread of AMR infections.

Plasma exchange and intravenous immunoglobulin for the peri-operative management of type 2 heparin-induced thrombocytopaenia in a patient requiring urgent surgery for critical limb ischaemia.

We report the case of a 61-year-old female who developed heparin-induced thrombocytopaenia following treatment of a submassive pulmonary embolism, and who then required an above knee amputation for critical limb ischaemia. Heparin-induced thrombocytopaenia is a rare, immune-mediated complication associated with an in-hospital mortality rate of 10%. It is more common in surgical patients, with patients undergoing orthopaedic surgery more likely to develop it than patients undergoing cardiac surgery, but heparin-dependent immunoglobulin G antibodies are more likely to be formed in the latter. Peri-operative management remains a challenge. Ideally, it is preferable to wait for the platelet count to improve; but in certain cases, surgery cannot be delayed. Heparin-induced thrombocytopaenia is usually managed with direct thrombin inhibitors, such as argatroban and bivalirudin. Newer therapeutic modalities, such as plasmapheresis and intravenous immunoglobulin, as used in this case, can rapidly remove antibodies, but the certainty of evidence is low. Our case adds to the literature regarding the use of these modalities and highlights the multidisciplinary team approach required to manage such complex cases.

Ulnar Buttress Arthroplasty without Ulnar Stump Stabilization for Giant Cell Tumor of Distal Ulna.

Purpose Reconstruction and stabilization of ulnar stump after distal ulna tumor resection is still a matter of debate. We present the outcomes of ulnar buttress arthroplasty without stabilization of the ulna stump in giant cell tumor of bone (GCTB) of the distal ulna. Methods Evaluation of functional outcome was performed using Musculoskeletal Tumor Society 93 (MSTS93) score, Modified Mayo Wrist score (MMWS), and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. We also assessed the hand grip strength, range of motion at the wrist, and ulnar carpal translation. Results The study included 8 patients with Campanacci grade 3 GCTB of the distal ulna with a mean follow-up of 35.5 ± 9.1 months. The mean resection length was 7.7 ± 1.3 cm. The mean hand grip strength on the operated side was noted to be 90 ± 0.04% of the contralateral side. Mean MSTS93 score was 27.9 ± 1.25, mean MMWS was 86.9 ± 4.58%, and the mean DASH score was 4.9 ± 1.67, depicting a good to excellent functional outcome with low degree of disability. No radiocarpal instability, ulnar carpal translation, prominence, or instability of the proximal ulnar stump was noted in any patient. Conclusion Reconstruction of the distal radioulnar joint using iliac crest bone graft for ulnar buttress without stabilization of the ulnar stump after resection of the distal ulna is an effective reconstruction option with good functional outcome and preservation of good hand grip strength. Level of Evidence Level IV, Therapeutic study.

Elevated Electron Temperature Coincident with Observed Fusion Reactions in a Sheared-Flow-Stabilized Z Pinch.

The sheared-flow-stabilized Z pinch concept has been studied extensively and is able to produce fusion-relevant plasma parameters along with neutron production over several microseconds. We present here elevated electron temperature results spatially and temporally coincident with the plasma neutron source. An optical Thomson scattering apparatus designed for the FuZE device measures temperatures in the range of 1-3 keV on the axis of the device, 20 cm downstream of the nose cone. The 17-fiber system measures the radial profiles of the electron temperature. Scanning the laser time with respect to the neutron pulse time over a series of discharges allows the reconstruction of the T_{e} temporal response, confirming that the electron temperature peaks simultaneously with the neutron output, as well as the pinch current and inductive voltage generated within the plasma. Comparison to spectroscopic ion temperature measurements suggests a plasma in thermal equilibrium. The elevated T_{e} confirms the presence of a plasma assembled on axis, and indicates limited radiative losses, demonstrating a basis for scaling this device toward net gain fusion conditions.

Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial.

BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.

High-magnification Faraday rotation imaging and analysis of X-pinch implosion dynamics.

An X-pinch load driven by an intense current pulse (>100 kA in ∼100 ns) can result in the formation of a small radius, runaway compressional micro-pinch. A micro-pinch is characterized by a hot (>1 keV), current-driven (>100 kA), high-density plasma column (near solid density) with a small neck diameter (1-10 µm), a short axial extent (<1 mm), and a short duration (≲1 ns). With material pressures often well into the multi-Mbar regime, a micro-pinch plasma often radiates an intense, sub-ns burst of sub-keV to multi-keV x rays. A low-density coronal plasma immediately surrounding the dense plasma neck could potentially shunt current away from the neck and thus reduce the magnetic drive pressure applied to the neck. To study the current distribution in the coronal plasma, a Faraday rotation imaging diagnostic (1064 nm) capable of producing simultaneous high-magnification polarimetric and interferometric images has been developed for the MAIZE facility at the University of Michigan. Designed with a variable magnification (1-10×), this diagnostic achieves a spatial resolution of ∼35 µm, which is useful for resolving the ∼100-µm-scale coronal plasma immediately surrounding the dense core. This system has now been used on a reduced-output MAIZE (100-200 kA, 150 ns) to assess the radial distribution of drive current immediately surrounding the dense micro-pinch neck. The total current enclosed was found to increase as a function of radius, r, from a value of ≈50±25 kA at r ≈ 140 µm (at the edge of the dense neck) to a maximal value of ≈150±75 kA for r ≥ 225 µm. This corresponds to a peak magnetic drive pressure of ≈75±50 kbar at r ≈ 225 µm. The limitations of these measurements are discussed in the paper.

The bright Easter bunny sign: a useful aide-memoire on MRI for costotransverse joint inflammation in axial spondyloarthritis.

AIM: To assess the significance of the "bright Easter bunny" sign on magnetic resonance imaging (MRI) to indicate inflammatory costotransverse joint (CtJ) lesions to diagnose axial spondyloarthritis (ax-SpA). MATERIALS AND METHODS: Consecutive cases of patients with ax-SpA from a specialist rheumatology clinic were analysed retrospectively over two cohorts, between 2012-2014 and 2018-2020, to determine newly diagnosed patients under the Assessment of SpondyloArthritis international Society (ASAS) criteria. Biological naive adult patients who underwent spine MRI and sacroiliac imaging with full immunological work-up and a C-reactive protein reading within 3 months of the scan were included. Blinded images were reviewed by experienced musculoskeletal radiologists. RESULT: From the 1,284 cases that were identified, 40 cases met the inclusion criteria for this study. Seven out of the 40 cases (17.5%) identified inflammatory lesions at the CtJ with five (70%) showing concordance with the bright Easter bunny sign. CONCLUSION: The bright Easter bunny sign is concordant with inflammatory costotransverse enthesitis. This aide-memoire radiological sign is often on overlooked edge-of-field sections and this emphasises the need to ensure adequate coverage of the CtJ on spine MRI protocols as an important anatomical site of inflammatory change in ax-SpA assessment.

Local-scale phylodynamics reveal differential community impact of SARS-CoV-2 in a metropolitan US county.

SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.

Genomic Epidemiology of Treponema pallidum and Circulation of Strains With Diminished tprK Antigen Variation Capability in Seattle, 2021-2022.

BACKGROUND: The incidence of syphilis continues to increase in the United States, yet little is known about Treponema pallidum genomic epidemiology within American metropolitan areas. METHODS: We performed whole-genome sequencing and tprK deep sequencing of 28 T. pallidum-containing specimens, collected mostly from remnant Aptima swab specimens from 24 individuals from Seattle Sexual Health Clinic during 2021-2022. RESULTS: All 12 individuals infected with Nichols-lineage strains were men who have sex with men, while a specific SS14 cluster (mean, 0.33 single-nucleotide variant) included 1 man who has sex with women and 5 women. All T. pallidum strains sequenced were azithromycin resistant via 23S ribosomal RNA A2058G mutation. Identical T. pallidum genomic sequences were found in pharyngeal and rectal swab specimens taken concurrently from the same individuals. The tprK sequences were less variable between patient-matched specimens and between epidemiologically linked clusters. We detected a 528-base pair deletion in the tprK donor site locus, eliminating 9 donor sites, in T. pallidum genomes of 3 individuals with secondary syphilis, associated with diminution of TprK diversity. CONCLUSIONS: We developed an end-to-end workflow for public health genomic surveillance of T. pallidum from remnant Aptima swab specimens. tprK sequencing may assist in linking cases beyond routine T. pallidum genome sequencing. T. pallidum strains with deletions in tprK donor sites currently circulate and are associated with diminished TprK antigenic diversity.

Harnessing the potential of data-driven strategies to optimise transfusion practice.

No one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.

Ethnomedicinal uses of plants for various diseases in the remote areas of Changa Manga Forest, Pakistan / Usos etnomedicinais de plantas para várias doenças nas áreas remotas da Floresta Changa Manga, Paquistão

This study aims at reporting the indigenous knowledge of the medicinal flora from the inhabitants of surroundings of the World's largest artificial planted forest "Changa Manga", Pakistan. Data were collected by direct interviews and group meetings from 81 inhabitants including 32 local healers having information regarding the use of indigenous medicinal plants over a period of one year. Different statistical tools were applied to analyze the data including Frequency citation (FC), Relative frequency citation (RFC), Use Value, Factor of informants consensus and fidelity level. This study reported 73 plant species belonging to 37 plant families and 46 genera. The majority of plant species belong to compositae family. The most commonly used medicinal plants were P. hysterophorus L., P. dactylifera L., S. indicum L, P. harmala L., P. emblica L., and A. indica A.Juss. The greatest number of species was used to cure gastrointestinal disorders. The highest fidelity level (68.18%) was of E. helioscopia to cure gastrointestinal disorders. Maximum fresh uses (17) were reported by C. dactylon (L.) Pars. While the highest number of species reporting fresh uses in similar number was 13. In this study, five novel plants are being reported for the first time in Pakistan for their ethnomedicinal worth. Our data reflect unique usage of the medicinal plants in the study area. The statistical tools used in the study proved useful in pointing the most important and disease category specific plants. High use value plant and the new reported medicinal plants might prove an important source of the isolation of pharmacologically active compounds.

Este estudo tem como objetivo relatar o conhecimento indígena sobre a flora medicinal dos habitantes do entorno da maior floresta artificial plantada do mundo, a Changa Manga, no Paquistão. Os dados foram coletados por meio de entrevistas diretas e reuniões em grupo de 81 habitantes, incluindo 32 curandeiros locais, com informações sobre o uso de plantas medicinais indígenas durante o período de um ano. Diferentes ferramentas estatísticas foram aplicadas para analisar os dados, incluindo citação de frequência (FC), citação de frequência relativa (RFC), valor de uso, fator de consenso dos informantes e nível de fidelidade. Este estudo relatou 73 espécies de plantas pertencentes a 37 famílias de plantas e 46 gêneros. A maioria das espécies de plantas pertence à família Compositae. As plantas medicinais mais utilizadas foram P. hysterophorus L., P. dactylifera L., S. indicum L., P. harmala L., P. emblica L. e A. indica A. Juss. O maior número de espécies foi usado para curar distúrbios gastrointestinais. O maior nível de fidelidade (68,18%) foi de E. helioscopia para cura de distúrbios gastrointestinais. Os usos máximos em fresco (17) foram relatados por C. dactylon (L.) Pars. enquanto o maior número de espécies relatando usos frescos em número semelhante foi de 13. Neste estudo, cinco novas plantas estão sendo relatadas pela primeira vez no Paquistão por seu valor etnomedicinal. Nossos dados refletem o uso exclusivo das plantas medicinais na área de estudo. As ferramentas estatísticas utilizadas no estudo mostraram-se úteis para apontar as plantas mais importantes e específicas da categoria de doença. Plantas de alto valor de uso e as novas plantas medicinais relatadas podem ser uma importante fonte de isolamento de compostos farmacologicamente ativos.

Implementation of extreme ultraviolet spectroscopy on a sheared-flow-stabilized Z pinch.

A diagnostic for extreme ultraviolet spectroscopy was fielded on the sheared-flow-stabilized (SFS) fusion Z-pinch experiment (FuZE-Q) for the first time. The spectrometer collected time-gated plasma emission spectra in the 5-40 nm wavelength (30-250 eV) range for impurity identification, radiative power studies, and for plasma temperature and density measurements. The unique implementation of the diagnostic included fast (10 ns risetime) pulsed high voltage electronics and a multi-stage differential pumping system that allowed the vacuum-coupled spectrometer to collect three independently timed spectra per FuZE-Q shot while also protecting sensitive internal components. Analysis of line emission identifies oxygen (N-, C-, B-, Be-, Li-, and He-like O), peaking in intensity shortly after maximum current (>500 kA). This work provides a foundation for future high energy spectroscopy experiments on SFS Z-pinch devices.

Dopant engineering for ZnO electron transport layer towards efficient perovskite solar cells.

The conventional electron transport layer (ETL) TiO2 has been widely used in perovskite solar cells (PSCs), which have produced exceptional power conversion efficiencies (PCE), allowing the technology to be highly regarded and propitious. Nevertheless, the recent high demand for energy harvesters in wearable electronics, aerospace, and building integration has led to the need for flexible solar cells. However, the conventional TiO2 ETL layer is less preferred, where a crystallization process at a temperature as high as 450 °C is required, which degrades the plastic substrate. Zinc oxide nanorods (ZnO NRs) as a simple and low-cost fabrication material may fulfil the need as an ETL, but they still suffer from low PCE due to atomic defect vacancy. To delve into the issue, several dopants have been reviewed as an additive to passivate or substitute the Zn2+ vacancies, thus enhancing the charge transport mechanism. This work thereby unravels and provides a clear insight into dopant engineering in ZnO NRs ETL for PSC.

Extension of shelf life of Nile tilapia (Oreochromis niloticus) fillets using seaweed extracts during refrigerated storage.

The effects of seaweed (Padina tetrastromatica, Sargassum natans, and Sargassum fluitans) ethanolic extracts on the quality and shelf life extension of Nile tilapia (Oreochromis niloticus) fillets were investigated during refrigerated storage for 20 days. Each of the seaweed ethanolic extracts solution (2%, w/v) was used for dipping the fish fillets for 10 min at 4°C. The control and seaweed extract-treated fillets were stored at 4 ± 1°C in air-tight polyethylene bags, and chemical, bacteriological, and sensory evaluation were performed at every 4 days' intervals. During the storage period, P. tetrastromatica extract significantly (p < .05) reduced the increment of pH, peroxide value, thiobarbituric acid reactive substances, and total volatile basic nitrogen values in Nile tilapia fillets compared to other seaweed extracts-treated and untreated fillets. The maximal total viable count of control, P. tetrastromatica, S. natans, and S. fluitans extracts-treated fillets was 6.53, 7.11, 6.75, and 7.10 log CFU/g at the 8th, 20th, 12th, and 16th days of storage, respectively. The total psychrotrophic count of control and seaweed extracts-treated fillets was also significantly increased (p < .05) throughout the storage period. The P. tetrastromatica extracts-treated fillets showed better sensory characteristics than other seaweed extracts-treated and control fillets. Results of this study suggest that ethanolic extracts (2%, w/v) of P. tetrastromatica extend the shelf life for 12 days longer than the control fillets in refrigerated conditions.

KatG catalase deficiency confers bedaquiline hyper-susceptibility to isoniazid resistant Mycobacterium tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) is a growing source of global mortality and threatens global control of tuberculosis (TB) disease. The diarylquinoline bedaquiline (BDQ) recently emerged as a highly efficacious drug against MDR-TB, defined as resistance to the first-line drugs isoniazid (INH) and rifampin. INH resistance is primarily caused by loss-of-function mutations in the catalase KatG, but mechanisms underlying BDQ's efficacy against MDR-TB remain unknown. Here we employ a systems biology approach to investigate BDQ hyper-susceptibility in INH-resistant Mycobacterium tuberculosis . We found hyper-susceptibility to BDQ in INH-resistant cells is due to several physiological changes induced by KatG deficiency, including increased susceptibility to reactive oxygen species and DNA damage, remodeling of transcriptional programs, and metabolic repression of folate biosynthesis. We demonstrate BDQ hyper-susceptibility is common in INH-resistant clinical isolates. Collectively, these results highlight how altered bacterial physiology can impact drug efficacy in drug-resistant bacteria.

The Capture the Fracture® Partnership: an overview of a global initiative to increase the secondary fracture prevention care for patient benefit.

The Capture the Fracture® Partnership (CTF-P) is a unique collaboration between the International Osteoporosis Foundation, academic units and industry partners to enhance the implementation of effective, efficient fracture liaison services (FLSs) with a good patient experience. CTF-P has generated valuable resources for the specific countries as well as the broader FLS community to improve the initiation, effectiveness and sustainability of FLS in a wide range of healthcare settings.