bluuebunny/crossref_metadata_2025 huggingface dataset:
Timelapse viability assay to detect division and death of primary multiple myeloma cells in response to drug treatments with single cell resolution
Authors: Mark Christina , Callander Natalie S , Chng Kenny , Miyamoto Shigeki , Warrick Jay
Published: June 2022

Heterogeneity among cancer cells and in the tumor microenvironment (TME) is thought to be a significant contributor to the heterogeneity of clinical therapy response observed between patients and can evolve over time. A primary example of this is multiple myeloma (MM), a generally incurable cancer where such heterogeneity contributes to the persistent evolution of drug resistance. However, there is a paucity of functional assays for studying this heterogeneity in patient samples or for assessing the influence of the patient TME on therapy response. Indeed, the population-averaged data provided by traditional drug response assays and the large number of cells required for screening remain significant hurdles to advancement. To address these hurdles, we developed a suite of accessible technologies for quantifying functional drug response to a panel of therapies in ex vivo three-dimensional culture using small quantities of a patient’s own cancer and TME components. This suite includes tools for label-free single-cell identification and quantification of both cell division and death events with a standard brightfield microscope, an open-source software package for objective image analysis and feasible data management of multi-day timelapse experiments, and a new approach to fluorescent detection of cell death that is compatible with long-term imaging of primary cells. These new tools and capabilities are used to enable sensitive, objective, functional characterization of primary MM cell therapy response in the presence of TME components, laying the foundation for future studies and efforts to enable predictive assessment drug efficacy for individual patients.
Continuous surveillance of drug-resistant TB burden in Rwanda: a retrospective cross-sectional study
Authors: Habimana-Mucyo Yves , Dushime Augustin , Migambi Patrick , Habiyambere Innocent , Semuto Ngabonziza Jean Claude , Decroo Tom
Published: June 2022

Background

Since the roll-out of the Xpert MTB/RIF assay, continuous surveillance can provide an estimate of rifampicin-resistant TB (RR-TB) prevalence, provided high drug susceptibility testing (DST) coverage is achieved. We use national data from Rwanda to describe rifampicin DST coverage, estimate the prevalence of RR-TB and assess its predictors.

Methods

Routinely collected DST data were entered into an electronic TB case-based surveillance system. DST coverage was calculated among all bacteriologically confirmed pulmonary TB patients notified from 1 July 2019 to 30 June 2020 in Rwanda. The prevalence of RR-TB was estimated among those with DST results. Univariable and multivariable analysis was performed to explore predictors for RR TB.

Results

Among 4066 patients with bacteriologically confirmed pulmonary TB, rifampicin DST coverage was 95.6% (4066/4251). RR-TB was diagnosed in 73 patients. The prevalence of RR-TB was 1.4% (53/3659; 95% CI 1.09 to 1.89%) and 4.9% (20/406; 95% CI 3.03 to 7.51%) in new and previously treated TB cases, respectively. Predictors of RR-TB were: (1) living in Kigali City (adjusted OR [aOR] 1.65, 95% CI 1.03 to 2.65); (2) previous TB treatment (aOR 3.64, 95% CI 2.14 to 6.19); and (3) close contact with a known RR-TB patient (aOR 11.37, 95% CI 4.19 to 30.82).

Conclusions

High rifampicin DST coverage for routine reporting allowed Rwanda to estimate the RR-TB prevalence among new and previously treated patients.
Cytokine response as a biomarker for early diagnosis and outcome prediction of stem cell transplant recipients and acute leukemia patients with invasive aspergillosis
Authors: Puerta-Alcalde Pedro , Ruiz-Camps Isabel , Gudiol Carlota , Salavert Miquel , Barba Pere , Morandeira Francisco , Jarque Isidro , Cuervo Guillermo , Ayats Josefina , Carratalà Jordi , Garcia-Vidal Carolina
Published: June 2022

We aimed to determine the role of serum cytokine expression in invasive aspergillosis (IA) diagnosis and outcome prediction in hematologic patients. In this multicenter study, serum cytokines (IL6, IL10, INF-gamma, IL12, IL4, TNF-alpha, IL17, and IL23) were prospectively recruited from all consecutive patients with hematologic malignances at IA diagnosis and compared to control patients matched by center, age, baseline disease, and therapeutic regimen. We included 36 patients with IA and 36 controls. Serum levels of IL6 and IL10 cytokines on day 0 were significantly increased in patients with IA when compared to controls (P = 0.001 and P = 0.025, respectively), even in those who were neutropenic. No differences were observed for the other cytokines. IL6 and IL10 predicted IA with an area under the ROC curve of 0.74 (95% CI 0.62–0.86) and 0.64 (95% CI 0.51–0.77), respectively. The best cutoff point in predicting IA was 20.85 pg/ml for IL6 (sensitivity 72.2%; specificity 77.8%; PPV 76.5% and NPV 73.7%), and 0.045 pg/ml for IL10 (sensitivity 62.9%; specificity 63.9%; PPV 62.9% and NPV 63.9%). IL6 levels were associated with increased mortality, with the best cutoff value being 65.59 pg/ml in mortality prediction. In conclusion, in addition to current tests in place, IL6 and IL10 levels—as measured in plasma—may help clinicians diagnose IA. High levels of IL6 at IA diagnosis are related with worse outcomes.

Lay summary

We evaluated the role of serum cytokine expression in invasive aspergillosis (IA) diagnosis and outcome. Serum levels of IL6 and IL10 are increased in patients with IA compared to controls, and IL6 levels are associated with mortality.
Star formation characteristics of CNN-identified post-mergers in the Ultraviolet Near Infrared Optical Northern Survey (UNIONS)
Authors: Bickley Robert W , Ellison Sara L , Patton David R , Bottrell Connor , Gwyn Stephen , Hudson Michael J
Published: June 2022

The importance of the post-merger epoch in galaxy evolution has been well documented, but post-mergers are notoriously difficult to identify. While the features induced by mergers can sometimes be distinctive, they are frequently missed by visual inspection. In addition, visual classification efforts are highly inefficient because of the inherent rarity of post-mergers (~1 per cent in the low-redshift Universe), and non-parametric statistical merger selection methods do not account for the diversity of post-mergers or the environments in which they appear. To address these issues, we deploy a convolutional neural network (CNN) that has been trained and evaluated on realistic mock observations of simulated galaxies from the IllustrisTNG simulations, to galaxy images from the Canada France Imaging Survey, which is part of the Ultraviolet Near Infrared Optical Northern Survey. We present the characteristics of the galaxies with the highest CNN-predicted post-merger certainties, as well as a visually confirmed subset of 699 post-mergers. We find that post-mergers with high CNN merger probabilities [p(x) > 0.8] have an average star formation rate that is 0.1 dex higher than a mass- and redshift-matched control sample. The SFR enhancement is even greater in the visually confirmed post-merger sample, a factor of 2 higher than the control sample.
Deep uGMRT observations of the ELAIS-North 1 field: statistical properties of radio–infrared relations up to z ∼ 2
Authors: Sinha Akriti , Basu Aritra , Datta Abhirup , Chakraborty Arnab
Published: June 2022

Comprehending the radio–infrared (IR) relations of the faint extragalactic radio sources is important for using radio emission as a tracer of star formation in high redshift (z) star-forming galaxies (SFGs). Using deep uGMRT observations of the ELAIS-N1 field in the 0.3–0.5 GHz range, we study the statistical properties of the radio–IR relations and the variation of the ‘q-parameter’ up to z = 2 after broadly classifying the faint sources as SFGs and AGN. We find the dust temperature (Tdust) to increase with z. This gives rise to $q_{\rm 24\,\mu m}$, measured at $24\, \mu$m, to increase with z as the peak of IR emission shifts towards shorter wavelengths, resulting in the largest scatter among different measures of q-parameters. $q_{\rm 70\,\mu m}$ measured at $70\, \mu$m, and qTIR using total-IR (TIR) emission are largely unaffected by Tdust. We observe strong, non-linear correlations between the radio luminosities at 0.4 and 1.4 GHz with $70\, \mu$m luminosity and TIR luminosity(LTIR). To assess the possible role of the radio-continuum spectrum in making the relations non-linear, for the first time we study them at high z using integrated radio luminosity (LRC) in the range 0.1–2 GHz. In SFGs, the LRC–LTIR relation remains non-linear with a slope of 1.07 ± 0.02, has a factor of 2 lower scatter compared to monochromatic radio luminosities, and $q^{\rm RC}_{\rm TIR}$ decreases with z as $q^{\rm RC}_{\rm TIR}= (2.27 \pm 0.03)\, (1+z)^{-0.12 \pm 0.03}$. A redshift variation of q is a natural consequence of non-linearity. We suggest that a redshift evolution of magnetic field strengths and/or cosmic ray acceleration efficiency in high-z SFGs could give rise to non-linear radio–IR relations.
Water observed in the atmosphere of τ Boötis Ab with CARMENES/CAHA
Authors: Webb Rebecca K , Gandhi Siddharth , Brogi Matteo , Birkby Jayne L , de Mooij Ernst , Snellen Ignas , Zhang Yapeng
Published: June 2022

Characterizing the atmospheres of hot Jupiters is important in understanding the formation and migration of these exotic planets. However, there are still many open questions about the chemical and physical properties of these atmospheres. Here, we confirm the detection of water vapour in thermal emission from the non-transiting hot Jupiter τ Boötis Ab with the high-resolution NIR CARMENES spectrograph. Combining over 17 h of observations (560 spectra) and using a Bayesian cross-correlation to log-likelihood approach, we measure a systemic velocity of $V_{\mathrm{sys}} = -11.51^{+0.59}_{-0.60}$  km s−1  and a radial velocity semi-amplitude of $K_{\mathrm{P}} = 106.21^{+1.76}_{-1.71}$  km s−1  for the planet, which results in an absolute mass of $M_{\mathrm{P}} = 6.24^{+0.17}_{-0.18}\, \mathrm{M_{J}}$ and an orbital inclination of $41.6^{+1.0}_{-0.9}$ degrees. Our retrieved Vsys shows a significant shift (+5  km s−1) from the literature value, which could be caused by an inaccurate time of periastron. Within the explored model grid, we measure a preference for solar water abundance (VMR  = 10−3) and find no evidence for additional minor species in the atmosphere. Given the extensive orbital coverage of the data, we searched for a phase dependency in the water signal but found no strong evidence of variation with orbital phase. This detection is at odds with recent observations from SPIRou/CFHT and their tight upper limit on water abundance. We recommend further observations of the atmosphere τ Boötis Ab to try and resolve these discrepancies.
Dispersal of protoplanetary discs: how stellar properties and the local environment determine the pathway of evolution
Authors: Coleman Gavin A L , Haworth Thomas J
Published: June 2022

We study the evolution and final dispersal of protoplanetary discs that evolve under the action of internal and external photoevaporation, and different degrees of viscous transport. We identify five distinct dispersal pathways, which are (i) very long-lived discs ($\gt 20\,$ Myr), (ii) inside-out dispersal where internal photoevaporation dominates and opens inner holes, (iii) outside-in dispersal where external photoevaporation dominates through disc truncation, and two intermediate regimes characterized by lingering material in the inner disc with the outer disc dispersed predominantly by either internal or external photoevaporation. We determine how the lifetime, relative impact of internal and external winds, and clearing pathway vary over a wide, plausible, parameter space of stellar/disc/radiation properties. There are a number of implications, for example, in high UV environments because the outer disc lifetime is shorter than the time-scale for clearing the inner disc, we do not expect transition discs to be common, which appears to be reflected in the location of transition disc populations towards the Orion Nebular Cluster. Irrespective of environment, we find that ongoing star formation is required to reproduce observed disc fractions as a function of stellar cluster age. This work demonstrates the importance of including both internal and external winds for understanding protoplanetary disc evolution.
Variations of cyclotron resonant scattering features in Vela X-1 revealed with Insight-HXMT
Authors: Liu Q , Wang W , Chen X , Ding Y Z , Lu F J , Song L M , Qu J L , Zhang S , Zhang S N
Published: June 2022

We present a detailed study of the high-mass X-ray binary Vela X-1, using observations performed by Insight-HXMT in 2019 and 2020, concentrating on timing analysis and spectral studies including pulse phase-resolved spectroscopy. The cyclotron line energy is found to be ∼21–27 and 43–50 keV for the fundamental and first harmonic, respectively. We present the evolution of spectral parameters and find that the two line centroid energy ratio E2/E1 evolved from ∼2 before MJD 58900 to ∼1.7 after that. The harmonic cyclotron line energy has no relation to the luminosity but the fundamental line energy shows a positive correlation with X-ray luminosity, suggesting that Vela X-1 is located in the sub-critical accreting regime. In addition, the pulse phase-resolved spectroscopy in Vela X-1 is performed. Both the cyclotron resonant scattering feature and continuum parameters show strong variability over the pulse phase with the ratio of two line energies about 2 near the peak phases and down to ∼1.6 around off-peak phases. Long-term significant variations of the absorption column density and its evolution over the pulse phase may imply the existence of the clumpy wind structure near the neutron star.
Host galaxy magnitude of OJ 287 from its colours at minimum light
Authors: Valtonen Mauri J , Dey Lankeswar , Zola S , Ciprini S , Kidger M , Pursimo T , Gopakumar A , Matsumoto K , Sadakane K , Caton D B , Nilsson K , Komossa S , Bagaglia M , Baransky A , Boumis P , Boyd D , Castro-Tirado A J , Debski B , Drozdz M , Escartin Pérez A , Fiorucci M , Garcia F , Gazeas K , Ghosh S , Godunova V , Gomez J L , Gredel R , Grupe D , Haislip J B , Henning T , Hurst G , Janík J , Kouprianov V V , Lehto H , Liakos A , Mathur S , Mugrauer M , Naves Nogues R , Nucciarelli G , Ogloza W , Ojha D K , Pajdosz-Śmierciak U , Pascolini S , Poyner G , Reichart D E , Rizzi N , Roncella F , Sahu D K , Sillanpää A , Simon A , Siwak M , Soldán Alfaro F C , Sonbas E , Tosti G , Vasylenko V , Webb J R , Zielinski P
Published: June 2022

OJ 287 is a BL Lacertae type quasar in which the active galactic nucleus (AGN) outshines the host galaxy by an order of magnitude. The only exception to this may be at minimum light when the AGN activity is so low that the host galaxy may make quite a considerable contribution to the photometric intensity of the source. Such a dip or a fade in the intensity of OJ 287 occurred in 2017 November, when its brightness was about 1.75 mag lower than the recent mean level. We compare the observations of this fade with similar fades in OJ 287 observed earlier in 1989, 1999, and 2010. It appears that there is a relatively strong reddening of the B− V colours of OJ 287 when its V-band brightness drops below magnitude 17. Similar changes are also seen in V− R, V− I, and R− I colours during these deep fades. These data support the conclusion that the total magnitude of the host galaxy is V = 18.0 ± 0.3, corresponding to MK = −26.5 ± 0.3 in the K-band. This is in agreement with the results, obtained using the integrated surface brightness method, from recent surface photometry of the host. These results should encourage us to use the colour separation method also in other host galaxies with strongly variable AGN. In the case of OJ 287, both the host galaxy and its central black hole are among the biggest known, and its position in the black hole mass–galaxy mass diagram lies close to the mean correlation.
Polarization properties of weakly magnetized neutron stars in low-mass X-ray binaries
Authors: Gnarini A , Ursini F , Matt G , Bianchi S , Capitanio F , Cocchi M , Farinelli R , Zhang W
Published: June 2022

X-ray polarimetry missions like Imaging X-ray Polarimetry Explorer will be able to measure for the first time the polarization properties of accreting, weakly magnetized neutron stars in low-mass X-ray binaries. In this work, we present simulations of the expected X-ray polarized signal, including the coronal emission for different geometries of the corona itself, i.e. a slab above the accretion disc and a spherical shell around the neutron star. The simulations are performed with the fully relativistic Monte Carlo code monk capable of computing the X-ray polarization degree and angle for various physical input parameters of the neutron star, disc, and corona. Different coronal geometries result in significantly different X-ray polarization properties, which can therefore be used to constrain the geometry of the systems.
Subjective symptoms contributing to the quality of life of rheumatoid arthritis patients with clinical remission from the IORRA database
Authors: Sakai Ryoko , Tanaka Eiichi , Inoue Eisuke , Sato Minako , Tanaka Masaru , Ikari Katsunori , Yamanaka Hisashi , Harigai Masayoshi
Published: June 2022

Objectives

To explore patient-reported outcomes (PROs) related to quality of life (QOL) in patients with rheumatoid arthritis (RA) who achieved clinical remission.

Methods

In the Institute of Rheumatology, Rheumatoid Arthritis dataset, RA patients >18 years old who met the simplified disease activity index (SDAI) remission criteria in April 2017 were enrolled in this analysis. Pain-visual analogue scale (pain-VAS) (0–100 mm), patient’s global assessment of disease activity (Pt-GA; 0–100 mm), Japanese version of the Health Assessment Questionnaire, duration of morning joint stiffness, and fatigue [Checklist Individual Strength 8R (CIS)] were the tools used to evaluate PROs. To assess the contribution of each PRO to the European QOL-5 Dimensions-5 Level (EQ-5D-5L) score, an analysis of variance was conducted.

Results

Among the 2443 patients with remission, the mean EQ-5D-5L was 0.9. The mean pain-VAS and Pt-GA were 7.2 and 7.4, respectively. Factors that significantly contributed to the EQ-5D-5L were pain-VAS (48.8%), CIS score (18.1%), and Pt-GA (15.6%). Around 82.5% of the variance in EQ-5D-5L was explained by the three PROs.

Conclusions

This study demonstrated that pain-VAS, CIS, and Pt-GA were significant contributors to the EQ-5D-5L score in patients with RA who achieved the simplified disease activity index remission criteria.
Use of biologics for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database
Authors: Narita Yusuke , Funatogawa Takashi , Mii Kazuma , Adachi Hiroki , Tamura Aya , Yamakido Shinji
Published: June 2022

Objectives

Limited information is available on the use of biologics in patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) in Japan. The types of biologics, treatment duration, treatment prior to biologics, concomitant treatment, and characteristics of patients receiving biologics were investigated.

Methods

We used a Japanese hospital claims database provided by Medical Data Vision Co. (2008–2021).

Results

In the database, 1186 of 34,207 SSc patients (3.5%) and 620 of 12,303 SSc-ILD patients (5.0%) received anti-interleukin-6 (anti-IL-6) drugs, anti-tumour necrosis factor (anti-TNF) drugs, abatacept, or rituximab. The most common were anti-IL-6 drugs [used in 35.5% of SSc patients and 38.5% of SSc-ILD patients (tocilizumab, 34.5% and 36.6%)], followed by anti-TNF drugs [31.3% and 26.5% (etanercept, 10.5% and 9.0%; others, <8%)], abatacept (17.5% and 20.6%), and rituximab (15.7% and 14.4%). Among SSc and SSc-ILD patients treated with anti-IL-6 drugs, anti-TNF drugs, or abatacept, the most common immunosuppressive drugs prior to initiation of biologics were methotrexate and tacrolimus. Approximately half of patients receiving anti-IL-6 drugs, anti-TNF drugs, or abatacept continued treatment beyond 1 year.

Conclusions

Our study indicates that off-label biologics have been used in a certain number of SSc or SSc-ILD patients in Japan, with tocilizumab the most common.
Phase II study of alisertib as a single agent for treating recurrent or progressive atypical teratoid/rhabdoid tumor
Authors: Upadhyaya Santhosh A , Campagne Olivia , Billups Catherine A , Orr Brent A , Onar-Thomas Arzu , Tatevossian Ruth G , Mostafavi Roya , Myers Jason R , Vinitsky Anna , Moreira Daniel C , Lindsay Holly B , Kilburn Lindsay , Baxter Patricia , Smith Amy , Crawford John R , Partap Sonia , Bendel Anne E , Aguilera Dolly G , Nichols Kim E , Rampersaud Evadnie , Ellison David W , Klimo Paul , Patay Zoltan , Robinson Giles W , Broniscer Alberto , Stewart Clinton F , Wetmore Cynthia , Gajjar Amar
Published: June 2022

Background

Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options.

Methods

We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged <22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1–7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks.

Results

SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h).

Conclusions

Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.
Aftersensations and Lingering Pain After Examination in Patients with Fibromyalgia Syndrome
Authors: Berwick Richard J , Andersson David A , Goebel Andreas , Marshall Andrew
Published: June 2022

Background

Fibromyalgia syndrome (FMS) is a chronic widespread pain condition with mixed peripheral and central contributions. Patients display hypersensitivities to a spectrum of stimuli. Patients’ blunt pressure pain thresholds are typically reduced, and sometimes (∼15%) gentle brushstroke induces allodynia. However, aftersensations after these stimuli have not, to our knowledge, been reported.

Methods

We examined the perception of blunt pressure and “pleasant touch” in FMS. Patients were first interviewed and completed standard psychometric questionnaires. We then measured their sensitivity to blunt pressure and perception of pleasant touch, including aftersensations; patients were followed up for 5 days to evaluate lingering pain from blunt pressure.

Results

We recruited 51 patients with FMS and 16 pain-free healthy controls (HCs) at a UK Pain Management Centre. Forty-four patients completed the aftersensation protocol. Most patients reported pain after the application of less mechanical pressure than the level of pressure at which HCs reported pain; median arm and leg thresholds for the patients with FMS were 167 kPa and 233 kPa, respectively. Eighty-four percent (31/37) of patients reported ongoing pain at the site of pressure application 1 day after testing, and 49% (18/37) still perceived pain at 5 days. Aftersensations after brushstroke were common in the FMS group, reported by 77% (34/44) of patients with FMS vs 25% (4/16) of HCs; 34% (15/44) of patients, but no HCs, perceived these aftersensations as uncomfortable. For patients with FMS who experienced aftersensations, brushstroke pleasantness ratings were reduced, and the skin was often an important site of pain.

Conclusion

Pain after blunt pressure assessment typically lingers for several days. Aftersensations after brushstroke stimulation are a previously unreported FMS phenomenon. They are associated with tactile anhedonia and might identify a clinically distinct subgroup.
Incidence and pattern of mycophenolate discontinuation associated with abnormal monitoring blood-test results: cohort study using data from the Clinical Practice Research Datalink Aurum
Authors: Nakafero Georgina , Grainge Matthew J , Card Tim , Mallen Christian D , Riley Richard , van der Windt Danielle , Fox Christopher P , Taal Maarten W , Aithal Guruprasad P , Williams Hywel C , Abhishek Abhishek
Published: June 2022

Objective

The aim was to examine the incidence and pattern of MMF discontinuation associated with abnormal monitoring blood-test results.

Methods

Data from people prescribed MMF for common inflammatory conditions in the Clinical Practice Research Datalink were used. Participants were followed from the first MMF prescription. The primary outcome was drug discontinuation with an associated abnormal blood-test result within 60 days. Secondary outcomes were drug discontinuation for any reason and discontinuation associated with severely abnormal blood-test results within 60 days. Multivariable Cox regression was used to examine factors associated with the primary outcome.

Results

The cohort included 992 participants (68.9% female, mean age 51.95 years, 47.1% with SLE) contributing 1885 person-years of follow-up. The incidence of MMF discontinuation associated with any (severely) abnormal blood-test results was 153.46 (21.07) per 1000 person-years in the first year of prescription and 32.39 (7.91) per 1000 person-years in later years. Of those patients prescribed MMF, 11.5% (1.7%) discontinued treatment with any (severely) abnormal blood-test results in the first year of prescription. After this period, a mean of 2.6% (0.7%) of patients discontinued treatment with any (severely) abnormal blood-test results per year. Increased serum creatinine and cytopenia were more commonly associated with MMF discontinuation than elevated liver enzymes. Chronic kidney disease stage 3 or higher was significantly associated with MMF discontinuation with any blood-test abnormalities [adjusted hazard ratio (95% CI) 2.22 (1.47, 3.37)].

Conclusion

MMF is uncommonly discontinued for blood-test abnormalities and even less often discontinued for severe blood-test abnormalities after the first year of prescription. Consideration can be given to less frequent monitoring after 1 year of treatment, especially in those without chronic kidney disease stage 3 or higher.
Central nervous system injury meets nanoceria: opportunities and challenges
Authors: Yang Wang , Zhang Maoting , He Jian , Gong Mingfu , Sun Jian , Yang Xiaochao
Published: June 2022

Central nervous system (CNS) injury, induced by ischemic/hemorrhagic or traumatic damage, is one of the most common causes of death and long-term disability worldwide. Reactive oxygen and nitrogen species (RONS) resulting in oxidative/nitrosative stress play a critical role in the pathological cascade of molecular events after CNS injury. Therefore, by targeting RONS, antioxidant therapies have been intensively explored in previous studies. However, traditional antioxidants have achieved limited success thus far, and the development of new antioxidants to achieve highly effective RONS modulation in CNS injury still remains a great challenge. With the rapid development of nanotechnology, novel nanomaterials provided promising opportunities to address this challenge. Within these, nanoceria has gained much attention due to its regenerative and excellent RONS elimination capability. To promote its practical application, it is important to know what has been done and what has yet to be done. This review aims to present the opportunities and challenges of nanoceria in treating CNS injury. The physicochemical properties of nanoceria and its interaction with RONS are described. The applications of nanoceria for stroke and neurotrauma treatment are summarized. The possible directions for future application of nanoceria in CNS injury treatment are proposed.
A qualitative study of factors resulting in care delays for adults with meningitis in Zambia
Authors: Elafros Melissa A , Bwalya Chiti , Muchanga Godfrey , Mwale Mwangala , Namukanga Nachizya , Birbeck Gretchen L , Chomba Mashina , Mugala-Mulenga Anchindika , Kvalsund Michelle P , Sikazwe Izukanji , Saylor Deanna R , Winch Peter J
Published: June 2022

Background

Meningitis causes significant mortality in regions with high comorbid HIV and TB. Improved outcomes are hindered by limited understanding of factors that delay adequate care.

Methods

In-depth interviews of patients admitted to the University Teaching Hospital with suspected meningitis, their caregivers, doctors and nurses were conducted. Patient/caregiver interviews explored meningitis understanding, treatment prior to admission and experiences since admission. Provider interviews addressed current and prior experiences with meningitis patients and hospital barriers to care. A conceptual framework based on the Three Delays Model identified factors that delayed care.

Results

Twenty-six patient/caregiver, eight doctor and eight nurse interviews occurred. Four delays were identified: in-home care; transportation to a health facility; clinic/first-level hospital care; and third-level hospital. Overcrowding and costly diagnostic testing delayed outpatient care; 23% of patients began with treatment inside the home due to prior negative experiences with biomedical care. Admission occurred after multiple clinic visits, where subsequent delays occurred during testing and treatment.

Conclusions

Delays in care from home to hospital impair quality meningitis care in Zambia. Interventions to improve outcomes must address patient, community and health systems factors. Patient/caregiver education regarding signs of meningitis and indications for care-seeking are warranted to reduce treatment delays.
Machine identification method of subway service quality based on smart card data
Authors: Li Maosheng , Tu Ci , Wang Pu
Published: June 2022

A new automatic evaluation method of subway service quality based on metro smart card data is proposed suitable for three different levels: station pair, railway line and subway network, which has merits of overcoming the previous lagging and subjective evaluation in the system of ‘questionnaire survey plus evaluation method’. First, passengers' travel time distribution for different operating periods in station OD pairs are introduced initially for service evaluation purposes and are classified into different groups in order to infer the station's operating characteristics at the different periods. Second, the classification is verified by K-means cluster analysis and K-S tests. Third, the service quality weight indicator is proposed to identify the service quality of the entire metro network from the dual perspectives of passengers and companies. Finally, the feasibility and rationality of the proposed method are verified by Shenzhen metro smart card data as an example. The new automated evaluation method of subway service quality is suitable for online and offline application.

Highlights

• A new machine identification method based on travel time distribution is proposed for estimating the service quality.

• The proposed model employs the K-means clustering method to distinguish passenger's travel time distribution into different modes.

• Characteristics of the different modes of passenger travel time distribution reflect different service levels of the urban subway system.

• The method provides automatically identification of service levels for urban subway operations.
Competition law as a catalyst for collective market governance: gauging the discursive benefits of intensified administrative action
Authors: Kuenzler Adrian
Published: June 2022

This article offers a novel perspective on competition law’s role in concentrated markets. While progressive views arguably flout just about anything that traditional legal doctrine esteems—advocating that competition law should be reconfigured to address a broader set of values beyond the welfare of consumers— established viewpoints hold that the subject of these attacks is the sheer size of digital platforms, although this overlooks their character as networked industries that overwhelmingly generate consumer benefits. Both views miss a crucial issue: they blur the vital role that competition law’s emphasis on consumers plays in producing welfare and prosperity when competition- and non-competition-related problems of market power are entwined. In particular, an intensified extent of administrative action helps to put in place the discursive benefits gained by advancing a proper dialogue between leading actors and consumers, and encourages a greater extent of integration of consumers’ views into the market.
Pharmacotherapies for Adults With Alcohol Use Disorders: A Systematic Review and Network Meta-analysis
Authors: Bahji Anees , Bach Paxton , Danilewitz Marlon , Crockford David , Devoe Daniel J. , el-Guebaly Nady , Saitz Richard
Published: June 2022

Background

We aimed to determine medications’ comparative efficacy and safety for adults with alcohol use disorders.

Methods

We searched eleven electronic data sources for randomized clinical trials with at least 4 weeks of treatment reporting on alcohol consumption (total abstinence and reduced heavy drinking), dropouts, and dropouts due to adverse events. We conducted network meta-analyses using random-effects, frequentist models, and calculated summary rate ratios (RRs) with 95% confidence intervals (CIs).

Results

We included 156 trials (N = 27,334). Nefazodone (RR = 2.11; 95% CI, 1.42–3.13), aripiprazole (RR = 1.97; 95% CI, 1.36–2.88), carbamazepine (RR = 1.85; 95% CI, 1.03–3.32), and nalmefene (RR = 1.17; 95% CI, 1.01–1.35) were associated with the most dropouts. Baclofen (RR = 0.83; 95% CI, 0.70–0.97) and pregabalin (RR = 0.63; 95% CI, 0.43–0.94) caused fewer dropouts than placebo. Nalmefene (RR = 3.26; 95% CI, 2.34–4.55), fluvoxamine (RR = 3.08; 95% CI, 1.59–5.94), and topiramate (RR=2.18; 95% CI, 1.36–3.51) caused more dropouts from adverse events over placebo. Gamma-hydroxy-butyrate (RR = 1.90; 95% CI, 1.03–3.53), baclofen (RR = 1.80; 95% CI, 1.39–2.34), disulfiram (RR = 1.71; 95% CI, 1.39–2.10), gabapentin (RR = 1.66; 95% CI, 1.04–2.67), acamprosate (RR = 1.33; 95% CI, 1.15–1.54), and oral naltrexone (RR = 1.15; 95% CI, 1.01–1.32) improved total abstinence over placebo (Fig. 3C). For reduced heavy drinking, disulfiram (RR = 0.19; 95% CI, 0.10–0.35), baclofen (RR = 0.72; 95% CI, 0.57–0.91), acamprosate (RR = 0.78; 95% CI, 0.70–0.86), and oral naltrexone (RR = 0.81; 95% CI, 0.73–0.90) were efficacious against placebo.

Conclusions

The current meta-analyses provide evidence that several medications for AUDs are effective and safe and encourage the expanded use of these medications in the clinical setting. Our review found that acamprosate (2–3 g/d), disulfiram (250–500 mg/d), baclofen (30 mg/d), and oral naltrexone (50 mg/d) had the best evidence for improving abstinence and heavy drinking for patients with AUD.

PROSPERO

CRD42020208946.
Determinants of School Diabetes Care Services and Quality Through the Lens of the School Nurse
Authors: An Ruopeng , Li Danyi , Cole Marjorie , Park Katherine , Lyon Aaron R. , White Neil
Published: June 2022

Schools play a critical role in students' diabetes management and ensure their safety and well-being. We conducted key informant interviews with 11 school nurses in Missouri to assess determinants for diabetes care implementation. Five themes and 29 subthemes were identified concerning school nurses, schools, external stakeholders, government, and the COVID-19 pandemic. A social-ecological model was developed to elucidate each level's barriers, facilitators, and resources, and their interplay. School nurses should lead diabetes management, emergency planning, and health education for students/staff. Multiple gray areas existed regarding school nurses' specific roles/responsibilities. Lacking funding, insurance, and communication with parents/physicians further challenged diabetes care.
Comprehension of an Over-the-Counter Drug Facts Label Prototype for a Mifepristone and Misoprostol Medication Abortion Product
Authors: Biggs M. Antonia , Ehrenreich Katherine , Morris Natalie , Blanchard Kelly , Bustamante Claudie Kiti , Choimorrow Sung Yeon , Hauser Debra , Hernandez Yamani , Kapp Nathalie , Kromenaker Tammi , Moayedi Ghazaleh , Perritt Jamila B. , Ralph Lauren , Raymond Elizabeth G. , Valladares Ena Suseth , White Kari , Grossman Daniel
Published: June 2022

OBJECTIVE:

To develop a drug facts label prototype for a combination mifepristone and misoprostol product and to conduct a label-comprehension study to assess understanding of key label concepts.

METHODS:

We followed U.S. Food and Drug Administration guidance, engaged a multidisciplinary group of experts, and conducted cognitive interviews to develop a drug facts label prototype for medication abortion. To assess label comprehension, we developed 11 primary and 13 secondary communication objectives related to indications for use, eligibility, dosing regimen, contraindications, warning signs, side effects, and recognizing the risk of treatment failure, with corresponding target performance thresholds (80–90% accuracy). We conducted individual structured video interviews with people with a uterus aged 12–49 years, recruited through social media. Participants reviewed the drug facts label and responded to questions to assess their understanding of each communication objective. After transcribing and coding interviews, we estimated the proportion of correct responses and exact binomial 95% CIs by age and literacy group.

RESULTS:

We interviewed 851 people (of 1,507 people scheduled); responses from 844 were eligible for analysis, and 35.7% (n=301) of participants were aged 12–17 years. The overall sample met performance criteria for 10 of the 11 primary communication objectives (93–99% correct) related to indications for use, eligibility for use, the dosing regimen, and contraindications; young people met nine and people with limited literacy met eight of the 11 performance criteria. Only 79% (95% CI 0.76–0.82) of the overall sample understood to contact a health care professional if little or no bleeding occurred soon after taking misoprostol, not meeting the prespecified threshold of 85.0%.

CONCLUSION:

Overall, high levels of comprehension suggest that people can understand most key drug facts label concepts for a medication abortion product without clinical supervision and recommend minor modifications.
Single-Dose, Bioadhesive Clindamycin 2% Gel for Bacterial Vaginosis
Authors: Mauck Christine , Hillier Sharon L. , Gendreau Judy , Dart Clint , Chavoustie Steven , Sorkin-Wells Valerie , Nicholson-Uhl Clifton , Perez Brandon , Jacobs Mark , Zack Nadene , Friend David
Published: June 2022

OBJECTIVE:

To assess efficacy and safety of a single-dose vaginal clindamycin gel for bacterial vaginosis treatment.

METHODS:

We conducted a double-blind, placebo-controlled, randomized study comparing clindamycin gel with placebo (2:1 ratio). Entry required clinical diagnosis of bacterial vaginosis, that is, all four Amsel's criteria, without other genital infections. Nugent scores of 7–10 were required for efficacy assessment, per updated 2019 U.S. Food and Drug Administration guidance. Patients were evaluated at screening, day 7–14, and day 21–30 (test of cure). Clinical cure was defined as resolution of three of four Amsel's criteria. Bacteriologic cure was defined as Nugent score lower than 4. Therapeutic cure was both clinical and bacteriologic cure. Primary outcome was clinical cure at the test-of-cure visit. Secondary endpoints were clinical cure at day 7–14, and bacteriologic and therapeutic cures at day 7–14 and test of cure. A sample size of 188 patients in the clindamycin group compared with 94 patients in the placebo group had 90% power to detect statistically significant difference (P=.05, 2-tailed).

RESULTS:

Participants were seen between July 9, 2020, and November 12, 2020. Of 307 randomized women, 56.0% were Black and 88.3% reported one or more previous bacterial vaginosis episodes. In the modified intention-to-treat population, 70.5% of patients in the clindamycin group and 35.6% in the placebo group achieved clinical cure at test of cure (primary outcome) (difference of 34.9, 95% CI 19.0–50.8), as did 77.5% of patients in the clindamycin group and 42.6% of patients in the placebo group in the per-protocol population (difference of 34.9, 95% CI 17.0–52.7). Statistically significant differences between groups were seen for all secondary endpoints. Clinical cure rate in patients in the clindamycin group with more than three bacterial vaginosis episodes in the prior year was 70.0%. Approximately 15% (15.3%) of patients in the clindamycin group experienced one or more treatment-emergent adverse events related to study treatment, as did 9.7% of patients in the placebo group. The most frequent treatment-related, treatment-emergent adverse event was vulvovaginal candidiasis.

CONCLUSION:

A new, single-dose clindamycin vaginal gel was highly effective, with excellent safety, in women disproportionately affected by bacterial vaginosis, with Nugent scores of 7–10 at study entry.

FUNDING SOURCE:

The study was funded by Daré Bioscience, Inc.

CLINICAL TRIALS REGISTRATION:

ClinicalTrials.gov, NCT04370548.
Distinguishing High-Performing From Low-Performing Hospitals for Severe Maternal Morbidity
Authors: Howell Elizabeth A. , Sofaer Shoshanna , Balbierz Amy , Kheyfets Anna , Glazer Kimberly B. , Zeitlin Jennifer
Published: June 2022

OBJECTIVE:

To investigate which organizational factors, policies, and practices distinguish hospitals with high compared with low risk-adjusted rates of severe maternal morbidity (SMM).

METHODS:

Using a positive deviance approach, this qualitative study included 50 semistructured interviews with health care professionals (obstetrics and gynecology chairs, labor and delivery medical directors, nurse managers, frontline nurses, physicians or nurses responsible for quality and safety, and chief medical officers) in four low-performing and four high-performing hospitals in New York City. Hospital performance was based on risk-adjusted morbidity metrics from previous research. Major topics explored were structural characteristics (eg, staffing, credentialing), organizational characteristics (eg, culture, leadership, communication, use of data), labor and delivery practices (eg, use of standardized, evidence-based practices, teamwork), and racial and ethnic disparities in SMM. All interviews were audiotaped, professionally transcribed, and coded using NVivo software. Researchers blinded to group assignment conducted qualitative content analysis. Researchers wrote analytic memos to identify key themes and patterns emerging from the interviews, highlight illustrative quotes, and draw qualitative comparisons between the two hospital clusters with different (but unrevealed) performance levels.

RESULTS:

Six themes distinguished high-performing from low-performing hospitals. High-performing hospitals were more likely to have: 1) senior leadership involved in day-to-day quality activities and dedicated to quality improvement, 2) a strong focus on standards and standardized care, 3) strong nurse–physician communication and teamwork, 4) adequate physician and nurse staffing and supervision, 5) sharing of performance data with nurses and other frontline clinicians, and 6) explicit awareness that racial and ethnic disparities exist and that racism and bias in the hospital can lead to differential treatment.

CONCLUSION:

Organizational factors, policies, and practices at multiple levels distinguish high-performing from low-performing hospitals for SMM. Findings illustrate the potential for targeted quality initiatives to improve maternal health and reduce obstetric disparities arising from delivery in low-performing hospitals.
Patterns of Sexual Activity and the Development of Sexual Pain Across the Menopausal Transition
Authors: Waetjen L. Elaine , Johnson Wesley O. , Xing Guibo , Hess Rachel , Avis Nancy E. , Reed Barbara D. , Dugan Sheila A. , Neal-Perry Genevieve , Gold Ellen B. ,   for the Study of Women's Health Across the Nation (SWAN)
Published: June 2022

OBJECTIVE:

To examine whether patterns of sexual intercourse frequency and demographic, menopausal status, genitourinary, health, and psychosocial factors are associated with developing sexual pain across the menopausal transition.

METHODS:

These were longitudinal analyses of questionnaire data from the multicenter, multiracial and ethnic prospective cohort SWAN (Study of Women's Health Across the Nation) (1995–2008). We used multivariable discrete-time proportional hazards models to examine whether incident sexual pain was associated with preceding long-term (up to 10 visits) or short-term (two and three visits) sexual intercourse frequency patterns or other factors (eg, menopause status, genitourinary symptoms, lifestyle factors, and mental health).

RESULTS:

Of the 2,247 women with no sexual pain at baseline, 1,087 (48.4%) developed sexual pain at least “sometimes” up to 10 follow-up visits over 13 years. We found no consistent association between prior patterns of sexual intercourse frequency and development of sexual pain. For example, neither decreases in intercourse frequency from baseline (adjusted hazard ratio [aHR] 0.93, 95% CI 0.73–1.19) nor decreases in frequency over three prior visits (aHR 1.00, 95% CI 0.72–1.41) were associated with incident pain. Reasons for interruptions in intercourse activity at the prior visit, including lack of interest (aHR 1.64, 95% CI 0.74–3.65) and relationship issues (aHR 0.36, 95% CI 0.04–2.88), were not associated with developing pain. Being postmenopausal using hormone therapy (aHR 3.16, 95% CI 1.46–6.85), and reported vaginal dryness (aHR 3.73, 95% CI 2.88–4.83) were most strongly associated with incident sexual pain.

CONCLUSION:

Long-term and short-term declines in sexual intercourse frequency across the menopausal transition were not associated with increased hazard of developing pain with intercourse. This empirical evidence does not support the common belief that a reduction in women's sexual frequency is responsible for their symptoms of sexual pain.