Exploring measurement tools to optimise hospital physician distribution.

INTRODUCTION: Equitable healthcare delivery is essential and requires resources to be distributed, which include assets and healthcare workers. To date, there is no gold standard for measuring the correct number of physicians to meet healthcare needs. This rapid review aims to explore measurement tools employed to optimise the distribution of hospital physicians, with a focus on ensuring fair resource allocation for equitable healthcare delivery. MATERIALS AND METHODS: A literature search was performed across PubMed, EMBASE, Emerald Insight and grey literature sources. The key terms used in the search include 'distribution', 'method', and 'physician', focusing on research articles published in English from 2002 to 2022 that described methods or tools to measure hospital-based physicians' distribution. Relevant articles were selected through a two-level screening process and critically appraised. The primary outcome is the measurement tools used to assess the distribution of hospital-based physicians. Study characteristics, tool advantages and limitations were also extracted. The extracted data were synthesised narratively. RESULTS: Out of 7,199 identified articles, 13 met the inclusion criteria. Among the selected articles, 12 were from Asia and one from Africa. The review identified eight measurement tools: Gini coefficients and Lorenz curve, Robin Hood index, Theil index, concentration index, Workload Indicator of Staffing Need method, spatial autocorrelation analysis, mixed integer linear programming model and cohortcomponent model. These tools rely on fundamental data concerning population and physician numbers to generate outputs. Additionally, five studies employed a combination of these tools to gain a comprehensive understanding of physician distribution dynamics. CONCLUSION: Measurement tools can be used to assess physician distribution according to population needs. Nevertheless, each tool has its own merits and limitations, underscoring the importance of employing a combination of tools. The choice of measuring tool should be tailored to the specific context and research objectives.

Low Rates of Colorectal Cancer Screening in First-Degree Relatives of Our Patients: Are We Failing Them?

BACKGROUND: Guidelines recommend screening those with a family history of early-onset colorectal cancer at age 40 years or 10 years before the age of their relative's diagnosis. Currently, there is no literature reporting the screening rate in these individuals, and no protocols are in place to identify and target this population for screening awareness. OBJECTIVE: This study aimed to assess adherence to current screening guidelines among first-degree relatives of patients with early-onset colorectal cancer. DESIGN: Retrospective and qualitative study involving a telephone survey where patients were asked about relative's screening status and barriers to screening. SETTINGS: Two community-based institutions between January 2018 and December 2021. PATIENTS: Individuals diagnosed with early-onset colorectal cancer who had undergone surgery at our institutions. MAIN OUTCOME MEASURES: Rate of screening in first-degree relatives of our patients with early-onset colorectal cancer. Other factors measured included demographics, clinicopathologic characteristics, and screening barriers. RESULTS: Thirty-six patients were identified. The survey response rate was 66.6% (n = 24). A total of 88 first-degree relatives who met the screening criteria resulted in 67.1% of patients (n = 59) having a known screening status. Of the 59 patients with known screening status, only 44% (n = 26) had undergone screening. Patients of Black race, having stage III/IV disease, having Medicare/Medicaid insurance, and living within Baltimore City County were more likely to have family members with unknown or no screening. Lack of insurance coverage was the most common barrier, which was noted in 12.5% of patients (n = 3), whereas 54.1% of patients (n = 13) reported no barriers to screening. LIMITATIONS: Retrospective design. CONCLUSIONS: Most first-degree relatives of patients diagnosed with early-onset colorectal cancer do not undergo colorectal cancer screening. This could be attributed to the lack of protocols that could guarantee these individuals are informed of their elevated risk and the different options available for screening. Furthermore, our study suggests that racial and socioeconomic disparities exist among high-risk patients who should pursue screening. See Video Abstract . BAJAS TASAS DE DETECCIN DEL CNCER COLORRECTAL EN LOS FAMILIARES DE PRIMER GRADO DE NUESTROS PACIENTES LES ESTAMOS FALLANDO: ANTECEDENTES:Las directrices recomiendan realizar pruebas de detección a las personas con antecedentes familiares de cáncer colorrectal de aparición temprana a los 40 años o 10 años antes de la edad del diagnóstico de su familiar. Actualmente, no hay literatura que informe la tasa de detección en estos individuos y no existen protocolos para identificar y dirigirse a esta población para concientizar sobre la detección.OBJETIVO:Evaluar el cumplimiento de las pautas de detección actuales entre los FDR de pacientes con cáncer colorrectal de aparición temprana.DISEÑO:Estudio retrospectivo y cualitativo que incluyó una encuesta telefónica en la que se preguntó a los pacientes sobre el estado de detección de sus familiares y las barreras para la detección.AJUSTES:Dos instituciones comunitarias entre enero de 2018 y diciembre de 2021.PACIENTES:Personas diagnosticadas con cáncer colorrectal de inicio temprano que habían sido intervenidas quirúrgicamente en nuestras instituciones.PRINCIPALES MEDIDAS DE RESULTADO:Tasa de detección en familiares de primer grado de nuestros pacientes con cáncer colorrectal de aparición temprana. Otros factores medidos incluyeron datos demográficos, características clínico-patológicas y barreras de detección.RESULTADOS:Se identificaron treinta y seis pacientes. La tasa de respuesta a la encuesta fue del 66,6% (n = 24). Resultaron un total de 88 familiares de primer grado que cumplieron con los criterios para la detección, y el 67,1% (n = 59) tenía un estado de detección conocido. De los 59 con estado de detección conocido, se informó que solo el 44% (n = 26) se había sometido a pruebas de detección. Los pacientes de raza afroamericana, enfermedad en etapa III/IV, Medicare/Medicaid y que vivían dentro del condado de la ciudad de Baltimore tenían más probabilidades de tener familiares con pruebas de detección desconocidas o sin ellas. La falta de cobertura de seguro fue la barrera más común observada por el 12,5% (n = 3); mientras que el 54,1% (n = 13) no informó ninguna barrera para el cribado.LIMITACIONES:Diseño retrospectivo.CONCLUSIONES:La mayoría de los familiares de primer grado de pacientes diagnosticados con cáncer colorrectal de aparición temprana no se someten a pruebas de detección de cáncer colorrectal. Esto podría atribuirse a la falta de protocolos que garanticen que estas personas estén informadas sobre su elevado riesgo y las diferentes opciones disponibles para el cribado. Además, nuestro estudio sugiere que existen disparidades raciales y socioeconómicas entre los pacientes de alto riesgo que deberían someterse a pruebas de detección. (Traducción-Dr. Francisco M. Abarca-Rendon).

Paraproteinemic Neuropathies.

OBJECTIVE: Coexistence of polyneuropathy and gammopathy is a common but potentially challenging situation in clinical practice. This article reviews the clinical, electrophysiologic, and hematologic phenotypes of the paraproteinemic neuropathies and the diagnostic and treatment strategies for each. LATEST DEVELOPMENTS: Advances in our understanding of the underlying pathophysiology of various paraproteinemic neuropathies and their corresponding phenotypes have identified potential new therapeutic targets. Therapeutic strategies to diminish anti-myelin-associated glycoprotein (MAG) IgM antibodies have shown partial and inconsistent efficacy; however, antigen-specific immune therapy is being investigated as a novel treatment to remove the presumably pathogenic anti-MAG antibody. Advances in genetic and cell signaling studies have resulted in the approval of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Monoclonal antibodies are being investigated for the treatment of light chain amyloidosis. ESSENTIAL POINTS: Early recognition and treatment of underlying plasma cell disorders improves clinical outcomes in patients with paraproteinemic neuropathy. Despite significant progress, our knowledge regarding underlying mechanisms for paraproteinemic neuropathy is still limited. Clinicians' awareness of clinical phenotypes, electrophysiologic hallmarks, and hematologic findings of the different paraproteinemic neuropathies is crucial to promptly identify and treat patients and to avert misdiagnosis. Multidisciplinary collaboration among specialists, including neurologists and hematologists, is paramount for the optimal treatment of these patients with overlapping conditions.

Quantitative whole-tissue 3D imaging reveals bacteria in close association with mouse jejunum mucosa.

Because the small intestine (SI) epithelium lacks a thick protective mucus layer, microbes that colonize the thin SI mucosa may exert a substantial effect on the host. For example, bacterial colonization of the human SI may contribute to environmental enteropathy dysfunction (EED) in malnourished children. Thus far, potential bacterial colonization of the mucosal surface of the SI has only been documented in disease states, suggesting mucosal colonization is rare, likely requiring multiple perturbations. Furthermore, conclusive proof of bacterial colonization of the SI mucosal surface is challenging, and the three-dimensional (3D) spatial structure of mucosal colonies remains unknown. Here, we tested whether we could induce dense bacterial association with jejunum mucosa by subjecting mice to a combination of malnutrition and oral co-gavage with a bacterial cocktail (E. coli and Bacteroides spp.) known to induce EED. To visualize these events, we optimized our previously developed whole-tissue 3D imaging tools with third-generation hybridization chain reaction (HCR v3.0) probes. Only in mice that were malnourished and gavaged with the bacterial cocktail did we detect dense bacterial clusters surrounding intestinal villi suggestive of colonization. Furthermore, in these mice we detected villus loss, which may represent one possible consequence that bacterial colonization of the SI mucosa has on the host. Our results suggest that dense bacterial colonization of jejunum mucosa is possible in the presence of multiple perturbations and that whole-tissue 3D imaging tools can enable the study of these rare events.

Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis.

Objective: ADAPT+ assessed the long-term safety, tolerability, and efficacy of efgartigimod in adult participants with generalized myasthenia gravis (gMG). Methods: ADAPT+ was an open-label, single-arm, multicenter, up to 3-year extension of the pivotal phase 3 ADAPT study. Efgartigimod was administered in treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week). Initiation of subsequent treatment cycles was individualized based on clinical evaluation. Safety endpoints included incidence and severity of adverse events. Efficacy endpoints assessed disease severity using Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Results: As of January 2022, 151 participants had rolled over to ADAPT+ and 145 had received ≥1 dose of efgartigimod, of whom, 111 (76.6%) were AChR-Ab+ and 34 (23.4%) were AChR-Ab-. Mean study duration (treatment plus follow-up) was 548 days, and participants received up to 17 treatment cycles, corresponding to 217.6 participant-years of exposure. In the overall population, 123 (84.8%) participants reported ≥1 treatment-emergent adverse event; most frequent were headache (36 [24.8%]), COVID-19 (22 [15.2%]), and nasopharyngitis (20 [13.8%]). Clinically meaningful improvement (CMI) in mean MG-ADL and QMG scores was seen as early as 1 week following the first infusion across multiple cycles in AChR-Ab+ and AChR-Ab- participants. Maximal MG-ADL and QMG improvements aligned with onset and magnitude of total IgG and AChR-Ab reductions. For AChR-Ab+ participants at any time point in each of the first 10 treatment cycles, more than 90% had a maximum reduction of ≥2 points (CMI) in MG-ADL total score; across the 7 cycles in which QMG was measured, 69.4% to 91.3% of participants demonstrated a maximum reduction of ≥3 points (CMI) in QMG total score. Many participants demonstrated improvements well beyond CMI thresholds. In AChR-Ab+ participants with ≥1 year of combined follow-up between ADAPT and ADAPT+, mean number of annualized cycles was 4.7 per year (median [range] 5.0 [0.5-7.6]). Conclusion: Results of ADAPT+ corroborate the substantial clinical improvements seen with efgartigimod in ADAPT and support its long-term safety, tolerability, and efficacy, as well as an individualized dosing regimen for treatment of gMG. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT03770403, NCT03770403.

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial.

INTRODUCTION: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. METHODS: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100-300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. RESULTS: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. CONCLUSIONS: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. CLINICALTRIALS: gov: NCT02528253.

Theoretical treatment of IO-X (X = N2, CO, CO2, H2O) complexes.

Iodine monoxide (IO) is an important component of the biogeochemical cycle of iodine. For instance, it is present in the troposphere, where it plays a crucial role in the physical chemical processes involving iodine containing compounds. Here, we present a theoretical study on a series of atmospherically relevant complexes of IO with N2, CO, CO2 and H2O, where their structural and spectroscopic properties and their interaction energies are computed. Calculations are carried out by means of ab initio post Hartree-Fock (RCCSD(T) and RMP2) methods and density functional theory DFT (PBE0 and M05-2X) based approaches with and without the inclusion of dispersion correction. After comparison to RCCSD(T), we highlight the good performance of M05-2X(+D3) DFT in describing the bonding between IO and X (X = N2, CO, CO2, H2O). Moreover, we found that the IO-X (X = N2, CO, CO2, H2O) complexes are formed by non-covalent interactions between the two monomers. In sum, we characterized two types of complexes: I-bonded and O-bonded, where the former is more stable. The atmospheric implications of the present findings are also discussed such as in the formation of the iodine oxide particles (IOPs).

Reducing body myopathy associated with the LIM2 p.(His123Arg) FHL1 variant.

Reducing body myopathy (RBM) is a rare muscle disorder, with marked presence of characteristic intracytoplasmic aggregates in affected muscle fibers. RBM is associated with FHL1 gene mutations. Clinical presentations of RBM have ranged from early fatal to adult onset progressive muscle weakness. We present herein the clinical, electrodiagnostic, and muscle biopsy findings of a 17-year-old female with progressive muscle weakness and contracture. Muscle biopsy showed atrophic fibers that contained menadione nitroblue tetrazolium (NBT) positive reducing bodies. Genetic testing revealed a variant of uncertain significance in the FHL1 gene at a position known to be pathogenic when substituted by other amino acids (p.His123Arg). This variant was later reclassified as pathogenic.

Fano Lineshapes and Rabi Splittings: Can They Be Artificially Generated or Obscured by the Numerical Aperture?

Fano resonances and Rabi splittings are routinely reported in the scientific literature. Asymmetric resonance lineshapes are usually associated with Fano resonances, and two split peaks in the spectrum are often attributed to a Rabi splitting. True Fano resonances and Rabi splittings are unequivocal signatures of coherent coupling between subsystems. However, can the same spectral lineshapes characterizing Fano resonances and Rabi splittings arise from a purely incoherent sum of intensities? Here we answer this question through experiments with a tunable Fabry-Pérot cavity containing a CsPbBr3 perovskite crystal. By measuring the transmission and photoluminescence of this system using microscope objectives with different numerical aperture (NA), we find that even a modest NA = 0.4 can artificially generate Fano resonances and Rabi splittings. We furthermore show that this modest NA can obscure the anticrossing of a bona fide strongly coupled light-matter system. Through transfer matrix calculations we confirm that these spectral artifacts are due to the incoherent sum of transmitted intensities at different angles captured by the NA. Our results are relevant to the wide nanophotonics community, characterizing dispersive optical systems with high numerical aperture microscope objectives. We conclude with general guidelines to avoid pitfalls in the characterization of such optical systems.

Individualizing Therapy in CIDP: A Mini-Review Comparing the Pharmacokinetics of Ig With SCIg and IVIg.

Immunoglobulin (Ig) therapy is a first-line treatment for CIDP, which can be administered intravenously (IVIg) or subcutaneously (SCIg) and is often required long term. The differences between these modes of administration and how they can affect dosing strategies and treatment optimization need to be understood. In general, the efficacy of IVIg and SCIg appear comparable in CIDP, but SCIg may offer some safety and quality of life advantages to some patients. The differences in pharmacokinetic (PK) profile and infusion regimens account for many of the differences between IVIg and SCIg. IVIg is administered as a large bolus every 3-4 weeks resulting in cyclic fluctuations in Ig concentration that have been linked to systemic adverse events (AEs) (potentially caused by high Ig levels) and end of dose "wear-off" effects (potentially caused by low Ig concentration). SCIg is administered as a smaller weekly, or twice weekly, volume resulting in near steady-state Ig levels that have been linked to continuously maintained function and reduced systemic AEs, but an increase in local reactions at the infusion site. The reduced frequency of systemic AEs observed with SCIg is likely related to the avoidance of high Ig concentrations. Some small studies in immune-mediated neuropathies have focused on serum Ig data to evaluate its potential use as a biomarker to aid clinical decision-making. Analyzing dose data may help understand how establishing and monitoring patients' Ig concentration could aid dose optimization and the transition from IVIg to SCIg therapy.

New Criteria on Oscillatory and Asymptotic Behavior of Third-Order Nonlinear Dynamic Equations with Nonlinear Neutral Terms.

In the paper, we provide sufficient conditions for the oscillatory and asymptotic behavior of a new type of third-order nonlinear dynamic equations with mixed nonlinear neutral terms. Our theorems not only improve and extend existing theorems in the literature but also provide a new approach as far as the nonlinear neutral terms are concerned. The main results are illustrated by some particular examples.

Concomitant Immunosuppressive Therapy Use in Eculizumab-Treated Adults With Generalized Myasthenia Gravis During the REGAIN Open-Label Extension Study.

Introduction: Chronic, broad-spectrum immunosuppressive therapy (IST) can be associated with side effects in many people with generalized myasthenia gravis (gMG), and treatment guidelines recommend that the IST dose be tapered once patients achieve a stable treatment response. We therefore examined IST use in eculizumab-treated patients with refractory gMG. Methods: The REGAIN open-label extension (OLE) enrolled 117 adults with refractory anti-acetylcholine receptor antibody-positive gMG who had completed the 6-month, randomized, double-blind, placebo-controlled REGAIN study of eculizumab. Eligible patients had received ≥2 ISTs for ≥1 year or ≥1 IST with intravenous immunoglobulin or plasma exchange ≥4 times in 1 year, without symptom control. During REGAIN, changes in concomitant MG therapies were not permitted; during the OLE, they were permitted at the investigators' discretion. Participants received eculizumab 1,200 mg every 2 weeks for up to 4 years; concomitant prednisone and related corticosteroids (PRED), azathioprine (AZA), and mycophenolate mofetil (MMF) use was recorded. Changes in MG Activities of Daily Living and Quantitative MG total scores, MG exacerbations, and adverse events were also recorded. Results: At last OLE assessment, 88.0% (103/117) of participants were using ≥1 IST vs. 98.3% (115/117) at OLE baseline. During the OLE, 76.9% (90/117) of patients experienced a total of 719 IST changes. Almost half of participants [48.7% (57/117)] stopped or decreased ≥1 IST owing to MG symptom improvement, representing 38.9% (280/719) of all changes. In patients who decreased and/or stopped ≥1 IST, mean daily doses of PRED, AZA, and MMF decreased between OLE baseline and last assessment by 60.8% [standard deviation (SD), 28.07; P < 0.0001], 89.1% (SD, 25.77; P < 0.0001), and 56.0% (SD, 32.99; P < 0.0001), respectively. Improved clinical outcomes were observed with eculizumab regardless of IST changes during the OLE, and eculizumab's safety profile was similar in patients who used PRED, AZA, and MMF. Conclusions: Use of ISTs by patients with previously refractory gMG decreased during eculizumab treatment in the REGAIN OLE. Clinical improvements with eculizumab were maintained by patients in all groups, including those who decreased and/or stopped concomitant ISTs. Trial registration: www.clinicaltrials.gov: NCT01997229, NCT02301624.

Polyneuropathy Reveals Origins of Decade-long Gastrointestinal Symptoms in a Patient With Undiagnosed Mitochondrial Neurogastrointestinal Encephalopathy Caused by a Novel Mutation.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disease that manifests with multiorgan presentation characterized by gastrointestinal, extraocular, and both peripheral and central nervous system involvement. MNGIE is caused by mutation in the TYMP (thymidine phosphorylase) gene, resulting in loss of thymidine phosphorylase enzyme activity. This causes its substrates, thymidine and deoxyuridine, to accumulate in tissues and plasma, while also causing secondary alterations in mitochondrial DNA. To date, more than 80 mutations have been reported in this gene. We present herein the clinical, neuroimaging, electrodiagnostic, and molecular findings of a patient with MNGIE caused by a novel homozygous missense mutation (C1175T > G) of the TYMP gene.

Non-communicable diseases in Lebanon: results from World Health Organization STEPS survey 2017.

OBJECTIVES: Non-communicable diseases (NCDs) are a major global health problem. The objective of the study was to estimate the prevalence of common risk factors for NCDs in Lebanon, both among the Lebanese population and Syrian refugees, aged 18-69 years, residing in communities. STUDY DESIGN: Two national cross-sectional surveys using a two-stage cluster sampling design were conducted among the Lebanese and Syrian refugee adults. METHODS: We used the World Health Organization (WHO) STEPwise approach through questionnaire assessment and physical and biochemical measurements. All reported results were weighted to provide prevalence estimates at the population level. RESULTS: A total of 1899 Lebanese and 2134 Syrians adults participated in the survey. More than one-third of participants were current smokers at the time of the assessment, and 23% of Lebanese participants were current drinkers (almost all Syrian refugees were lifetime abstainers). Vegetable and fruit consumption was rated moderately low, in 73% and 93% of Lebanese and Syrian refugees, respectively. Many respondents did not meet WHO recommendations on physical activity. More than one-third of participants had raised blood pressure or were on antihypertensive medications. One in 10 participants had either raised blood glucose level or were currently on glycemic control medications. For all risk factors and in both samples, women consistently had lower prevalence of NCD risk factors. CONCLUSIONS: Prevalence of risk factors for NCDs is high in Lebanon, and given the recent rise in population size, the financial and social burden of NCDs will grow dramatically in the next years. The results highlight the need for interventions to address behavioral changes, including reduction in smoking, improvement of dietary habits, optimization of management of diabetes and cardiovascular diseases, and conducting continuous surveillance to monitor the trends in NCD prevalence, their risk factors, and treatments.

Carbazole derivatives containing chalcone analogues targeting topoisomerase II inhibition: First principles characterization and QSAR modelling.

Recently, a series of carbazole derivatives containing chalcone analogues (CDCAs) were synthetized as potent anticancer agents and apoptosis inducers. These compounds target the inhibition of topoisomerase II and present cytotoxic activities. After comparison to experiment, we validated the use of B3LYP, a density functional theory-based approach, to describe the structure and molecular properties of the carbazole subunit and CDCAs compounds of interest. Then, we derived relationships between the chemical descriptors and activity of these carbazole derivatives using multi-parameter optimization and quantitative structure activity relationships (QSAR) approaches. For the QSAR studies, we used multiple linear regression and artificial neural network statistical modelling. Our predicted activities are in good agreement with the experimental ones. We found that the most important parameter influencing the activity of the considered compounds is the octanol-water partition coefficient, highlighting the importance of flexibility as a key molecular parameter to favor cell membrane crossing and enhance the action of these CDCAs against topoisomerase II. Our results provide useful guidelines for designing new oral active CDCAs medicaments for cytotoxic inhibition.

Metabolic multistability and hysteresis in a model aerobe-anaerobe microbiome community.

Major changes in the microbiome are associated with health and disease. Some microbiome states persist despite seemingly unfavorable conditions, such as the proliferation of aerobe-anaerobe communities in oxygen-exposed environments in wound infections or small intestinal bacterial overgrowth. Mechanisms underlying transitions into and persistence of these states remain unclear. Using two microbial taxa relevant to the human microbiome, we combine genome-scale mathematical modeling, bioreactor experiments, transcriptomics, and dynamical systems theory to show that multistability and hysteresis (MSH) is a mechanism describing the shift from an aerobe-dominated state to a resilient, paradoxically persistent aerobe-anaerobe state. We examine the impact of changing oxygen and nutrient regimes and identify changes in metabolism and gene expression that lead to MSH and associated multi-stable states. In such systems, conceptual causation-correlation connections break and MSH must be used for analysis. Using MSH to analyze microbiome dynamics will improve our conceptual understanding of stability of microbiome states and transitions between states.

Publisher Correction: A quantitative sequencing framework for absolute abundance measurements of mucosal and lumenal microbial communities.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Minimal manifestation status and prednisone withdrawal in the MGTX trial.

OBJECTIVE: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG). METHODS: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups. RESULTS: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone. CONCLUSIONS: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone. CLINICALTRIALSGOV IDENTIFIER: NCT00294658. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.

Gamma-Ray and Radio-Frequency Radiation from Thunderstorms Observed from Space and Ground.

Terrestrial gamma ray flashes (TGFs) are a class of enigmatic electrical discharges in the Earth's atmosphere. In this study, we analyze an unprecedentedly large dataset comprised of 2188 TGFs whose signatures were simultaneously measured using space- and ground-based detectors over a five-year period. The Gamma-ray Burst Monitor (GBM) on board the Fermi spacecraft provided the energetic radiation measurements. Radio frequency (RF) measurements were obtained from the Global Lightning Dataset (GLD360). Here we show the existence of two categories of TGFs - those that were accompanied by quasi-simultaneous electromagnetic pulses (EMPs) detected by the GLD360 and those without such simultaneous EMPs. We examined, for the first time, the dependence of the TGF-associated EMP-peak-amplitude on the horizontal offset distance between the Fermi spacecraft and the TGF source. TGFs detected by the GBM with sources at farther horizontal distances are expected to be intrinsically brighter and were found to be associated with EMPs having larger median peak-amplitudes. This provides independent evidence that the EMPs and TGFs are produced by the same phenomenon, rather than the EMPs being from "regular" lightning in TGF-producing thunderstorms.