bluuebunny/crossref_metadata_2025 huggingface dataset:
Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
Authors: Wallander Karin , Thonberg Håkan , Nilsson Daniel , Tham Emma
Published: October 2021

Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.
Using motivational interviewing combined with digital shoe-fitting to improve adherence to wearing orthopedic shoes in people with diabetes at risk of foot ulceration: study protocol for a cluster-randomized controlled trial
Authors: Jongebloed-Westra M. , Bode C. , van Netten J. J. , ten Klooster P. M. , Exterkate S. H. , Koffijberg H. , van Gemert-Pijnen J. E. W. C.
Published: October 2021

Background

Diabetic foot ulcers have a high impact on mobility and daily functioning and lead to high treatment costs, for example, by hospitalization and amputation. To prevent (re)ulcerations, custom-made orthopedic shoes are considered essential. However, adherence to wearing the orthopedic shoes is low, and improving adherence was not successful in the past. We propose a novel care approach that combines motivational interviewing (MI) with a digital shoe-fitting procedure to improve adherence to orthopedic shoes. The aim of this trial is to assess the (cost-)effectiveness of this novel care approach compared to usual care (no MI and casting-based shoe-fitting) in promoting footwear adherence and ulcer prevention.

Methods

The trial will include people with diabetes, with IWGDF Risk categories 1–3, who have been prescribed orthopedic shoes. Participants will be randomized at the level of the podiatrist to the novel care approach or usual care. The primary outcome is the proportion of participants who adhere to the use of their orthopedic shoes, that is, who take at least 80% of their total daily steps with orthopedic shoes. A temperature microsensor will be built into the participants’ orthopedic shoes to measure wearing time continuously over 12 months. In addition, daily activity will be measured periodically using log data with an activity monitor. Data from the temperature microsensor and activity monitor will be combined to calculate adherence. (Re-)experienced complications after receiving orthopedic shoes will be registered. Questionnaires and interviews will measure the experiences of participants regarding orthopedic shoes, experiences of podiatrists regarding motivational interviewing, care consumption, and quality of life. Differences in costs and quality of life will be determined in a cost-effectiveness analysis.

Discussion

This trial will generate novel insights into the socio-economic and well-being impact and the clinical effectiveness of the novel care approach on adherence to wearing orthopedic shoes.

Trial registration

Netherlands Trial Register NL7710. Registered on 6 May 2019
Design, computational studies, synthesis and in vitro antimicrobial evaluation of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues
Authors: Noureldin Nada A. , Richards Jennifer , Kothayer Hend , Baraka Mohammed M. , Eladl Sobhy M. , Wootton Mandy , Simons Claire
Published: October 2021

Background

Two series of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues were designed and synthesised as novel antimicrobial drugs through inhibition of phenylalanyl-tRNA synthetase (PheRS), which is a promising antimicrobial target. Compounds were designed to mimic the structural features of phenylalanyl adenylate (Phe-AMP) the PheRS natural substrate.

Methods

A 3D conformational alignment for the designed compounds and the PheRS natural substrate revealed a high level of conformational similarity, and a molecular docking study indicated the ability of the designed compounds to occupy both Phe-AMP binding pockets. A molecular dynamics (MD) simulation comparative study was performed to understand the binding interactions with PheRS from different bacterial microorganisms. The synthetic pathway of the designed compounds proceeded in five steps starting from benzimidazole. The fourteen synthesised compounds 5a-d, 6a-c, 8a-d and 9a-c were purified, fully characterised and obtained in high yield.

Results

In vitro antimicrobial evaluation against five bacterial strains showed a moderate activity of compound 8b with MIC value of 32 μg/mL against S. aureus, while all the synthesised compounds showed weak activity against both E. faecalis and P. aeruginosa (MIC 128 μg/mL).

Conclusion

Compound 8b provides a lead compound for further structural development to obtain high affinity PheRS inhibitors.
Factors influencing mass drug administration adherence and community drug distributor opportunity costs in Liberia: a mixed-methods approach
Authors: Agboraw Efundem , Sosu Fred , Dean Laura , Siakeh Alice , Thomson Rachael , Kollie Karsor , Worrall Eve
Published: October 2021

Background

Preventive chemotherapy delivered via mass drug administration (MDA) is essential for the control of neglected tropical diseases (NTDs), including lymphatic filariasis (LF), schistosomiasis and onchocerciasis. Successful MDA relies heavily on community drug distributor (CDD) volunteers as the interface between households and the health system. This study sought to document and analyse demand-side (households) and supply-side (health system) factors that affect MDA delivery in Liberia.

Methods

Working in two purposively selected counties, we conducted a household MDA access and adherence survey; a CDD survey to obtain information on direct and opportunity costs associated with MDA work; an observational survey of CDDs; and key informant surveys (KIS) with community-level health workers. Data from the CDD survey and Liberian minimum wage rates were used to calculate the opportunity cost of CDD participation per MDA round. The observational data were used to calculate the time spent on individual household-level tasks and CDD time costs per house visited. KIS data on the organisation and management of the MDA in the communities, and researcher reflections of open-ended survey responses were thematically analysed to identify key demand- and supply-side challenges.

Results

More respondents were aware of MDA than NTD in both counties. In Bong, 39% (103/261) of respondents reported taking the MDA tablet in the last round, with “not being informed” as the most important reason for non-adherence. In Maryland, 56% (147/263) reported taking MDA with “being absent” at the time of distribution being important for non-adherence. The mean cost per CDD of participating in the MDA round was −$11.90 (median $5.04, range −$169.62 to $30.00), and the mean time per household visited was 17.14 min which equates to a mean opportunity cost of $0.03 to $0.05 per household visited. Thematic analysis identified challenges, including shortages of and delays in medicine availability; CDD frustration over costs; reporting challenges; and household concerns about drug side effects.

Conclusions

Improved adherence to MDA and subsequent elimination of NTDs in Liberia would be supported by an improved medicine supply chain, financial compensation for CDDs, improved training, healthcare workforce strengthening, greater community involvement, capacity building, and community awareness.

Graphical Abstract
Novel temporal and spatial patterns of metastatic colonization from breast cancer rapid-autopsy tumor biopsies
Authors: Huang Xiaomeng , Qiao Yi , Brady Samuel W. , Factor Rachel E. , Downs-Kelly Erinn , Farrell Andrew , McQuerry Jasmine A. , Shrestha Gajendra , Jenkins David , Johnson W. Evan , Cohen Adam L. , Bild Andrea H. , Marth Gabor T.
Published: October 2021

Background

Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood.

Methods

Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor’s evolution at subclonal resolution.

Results

The most unique, previously unreported aspect of the tumor’s evolution that we observed in this patient was the presence of “subclone incubators,” defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient’s metastases for effective clinical intervention.

Conclusions

Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.
Language of transducer manipulation 2.0: continuing to codify terms for effective teaching
Authors: End Bradley , Prats Michael I. , Minardi Joseph , Sharon Melinda , Bahner David P. , Boulger Creagh T.
Published: October 2021

Objectives

Accurate communication is an integral component of ultrasound education. In light of the recent global pandemic, this has become even more crucial as many have moved to virtual education out of necessity. Several studies and publications have sought to establish common terminology for cardinal ultrasound probe motions. To date, no studies have been performed to determine which of these terms have been adopted by the ultrasound community at large.

Methods

A survey was developed which asked respondents to describe videos of six common probe motions in addition to providing basic demographic and training data. The survey was disseminated electronically across various academic listservs and open access resources.

Results

Data were collected over a 6-week period and yielded 418 unique responses. Responses demonstrated significant variation in terminology related to all 6 cardinal probe motions. While some degree of difference in response can be accounted for by discipline of training, inter-group variation still exists in terminology to describe common probe motions. Of the survey respondents, 57.5% felt that inconsistent probe motion terminology made teaching ultrasound more difficult.

Conclusions

The results demonstrate that despite efforts to codify probe motions, variation still exists between ultrasound practitioners and educators in the description of cardinal probe motions. This lack of consensus can contribute to challenges in both virtual and in-person ultrasound education.
High sleep quality can increase the performance of CrossFit® athletes in highly technical- and cognitive-demanding categories
Authors: Klier Kristina , Dörr Selina , Schmidt Annette
Published: October 2021

Background

In current sports science, the important role of sleep quality for health and peak performance is well acknowledged. More precisely, it is evident that the negative combination of stressful factors, low resources, and bad sleep habits causes short-term performance losses as well as long-term health consequences. As the maximization of human performance consisting of multiple fixed workloads is the main motivation in CrossFit® (CF), the aim of the present study was to investigate the influence of high sleep quality on performance in CrossFit® athletes (CFA) and the different training categories that are addressed in CF.

Methods

In total, 149 CFA (81 females, 68 males; 32.01 ± 7.49 years old, 2.56 ± 1.77 active years in CF) filled in the online survey comprising the Pittsburgh Sleep Quality Index (PSQI) and CF performance-specific questions.

Results

It was found that CFA with high sleep quality reported higher values in all performance-related outcomes. Especially in Hero-/Girl-Workouts (χ2 = (1, n = 83) = 9.92, p = .002, φ = 0.37) and Gymnastics (χ2 = (1, n = 129) = 8.74, p = .003, φ = 0.28), performance differed significantly between good and poor sleeping CFA. Since those CF categories are highly technical- and cognitive-demanding high sleep quality seems to play a fundamental role in complex motor skill learning and performance development.

Conclusions

These results reveal for the first time the positive effects of high sleep quality for performance in CFA and could be used as basis for future studies. Future research should also develop and empirically test suitable interventions to foster high sleep quality in CFA.

Trial Registration: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of University of the Federal Armed Forces Munich, Germany (06/04/2018).
Controllability of higher-order fractional damped stochastic systems with distributed delay
Authors: Arthi G. , Suganya K. , Ma Yong-Ki
Published: October 2021

In this paper, the controllability analysis is proposed for both linear and nonlinear higher-order fractional damped stochastic dynamical systems with distributed delay in Hilbert spaces which involve fractional Caputo derivative of different orders. Based on the properties of fractional calculus, the fixed point technique, and the construction of controllability Gramian matrix, we establish the controllability results for the considered systems. Finally, examples are constructed to illustrate the applicability of obtained results.
Reflecting on perceived failure of entrepreneurship development initiatives to help ignite economic development in Malawi
Authors: Mwatsika Charles
Published: October 2021

This study reflects on the perceived failure of entrepreneurship development initiatives to help ignite economic development in Malawi. A cross-sectional survey of 337 enterprises collected top-of-the-mind definitions of entrepreneurship, and innovations and their values carried out. Content analyses, comparison of mean values, 2 independent samples tests and multiple linear regression analyses showed that entrepreneurship is perceived as starting and managing one’s own business; being self-employed. Carrying out innovations is low and of low value, but enterprises which carried out innovations had higher median values than those that did not. The study found opportunity-motivated, growth-oriented, limited liability enterprises in the medium-to-large size category to be productive types of enterprises, but there were very few. It is argued that initiatives fail to help ignite economic development because knowledge which guides entrepreneurship development misses the essence of entrepreneurship—carrying out innovations. Secondly, there are no initiatives to support SME innovation and growth through product development, investments in modern production facilities and access to export markets. It is encouraged that key stakeholders adjust their understanding of entrepreneurship to neoclassical economic perspectives, encourage innovative start-ups and provide support to grow the numbers of productive enterprises.
Differentiating brucella spondylitis from tuberculous spondylitis by the conventional MRI and MR T2 mapping: a prospective study
Authors: Guo Hui , Lan Siqin , He Yuanlin , Tiheiran Maijudan , Liu Wenya
Published: October 2021

Background

Brucella spondylitis (BS) and tuberculous spondylitis (TS), caused initially by bacteremia, are the two leading types of granulomatous spinal infections. BS is easy to miss or may be misdiagnosed as TS. Our purpose aims to differentiate BS from TS in conventional MR imaging and MR T2 mapping.

Methods

We performed on 26 BS and 27 TS patients conventional MR imaging and MR T2 mapping. We analyzed the features in conventional MR imaging and measured T2 values of the lesion vertebrae (LV) and unaffected adjacent vertebrae (UAV) in BS and TS patients, respectively.

Results

There were no significant differences in sex, age, national between BS and TS. There was significantly lower severity of vertebral destruction, vertebral posterior convex deformity, dead bone, and abscess scope in BS when compared to TS (p  <  0.001, p  =  0.048, p  <  0.001, p  <  0.001, respectively). The vertebral hyperplasia was significantly higher in BS when compared to TS (p  <  0.001). The T2 value of the LV with BS was markedly higher than that in the UAV with BS and that in the LV and UAV with TS (p  <  0.001, p  <  0.037, p  <  0.001, respectively). The T2 value of the LV with TS was significantly higher than that of the UAV in TS and BS (p  <  0.001, p  <  0.001, respectively). There were no significant differences in the T2 value of the UAV between BS and TS (p  =  0.568).

Conclusions

The qualitative and quantitative evaluation may differentiate BS from TS. The conventional MR imaging helps to distinguish BS from TS by several distinctive features. MR T2 mapping has the additional potential to provide quantitative information between BS and TS.
Revisiting nutrition–labor productivity link: new empirical evidence from farm households in Ethiopia
Authors: Berha Andu Nesrey , Mogess Yohannes Kefale , Wassie Mengistu Alamneh
Published: October 2021

Background

Among others, the productive use of surplus labor is a viable mechanism to transform the agricultural sector and thus the whole economy in low-income countries. It is critically important to understand the factors that condition labor productivity to design and deploy effective agricultural and labor market policies. A few studies confirm that, at low-income levels, improving nutrition can contribute to the labor productivity of households. These studies rely heavily on self-reported farm data, which are prone to systematic and random measurement errors. The empirical evidence on this topic remains inadequate and inconclusive for this reason. Here, we substantiate whether better nutritional status enhances the labor productivity of farm households using objective measures of plot-level data from a recent household survey in Ethiopia. We also employ alternative measures of nutrition status indicators known as, Food Consumption Score (FCS) and Household Dietary Diversity Score (HDDS), inter alia, to capture additional aspects of nutrition such as diet quality and diversity, which are overlooked by calorie intake data. To deal with possible endogeneity, we employ a panel fixed effect estimation technique with a rich set of household socioeconomic and plot characteristics.

Results

We observe that the impact of current nutritional status, as measured by HDDS, on labor productivity varies considerably depending on the initial level of diet quality and diversity with a stronger and positive effect for low-consumption households. In an alternative specification, we also observe a positive farm labor productivity effect of current nutritional status as measured by FCS with a homogenous effect across households. However, the effect of the outcome of past nutritional status as evaluated by the Activity of Daily Living Index (ADLI) seems negligible.

Conclusion

Our findings indicate that improving nutrition can contribute to farm labor productivity at least for households with low current diet quality and diversity. Also, based on the findings, we conclude that there is a possibility of a low consumption–low productivity trap in Ethiopia.
WHO/INRUD Core drug use indicators and commonly prescribed medicines: a National Survey from Sri Lanka
Authors: Galappatthy P. , Ranasinghe P. , Liyanage C. K. , Wijayabandara M. S. , Mythily S. , Jayakody R. L.
Published: October 2021

Background

Identification of internationally comparable indicators of medicines use are important for a country to implement strategies and regulations to improve usage of medicines. Sri Lanka established a new National Medicines Regulatory Authority in 2015 and this survey evaluated the medication use indicators in Sri Lanka, according to the International Network on Rational Use of Drugs (INRUD), prior to its implementation.

Methods

This descriptive-cross-sectional study was conducted in 80 pharmacies, representing all 25 districts of the country. Three pharmacy categories were included; privately owned pharmacies, ‘Rajya Osusala’ pharmacies operated by the State Pharmaceuticals Corporation (SPC) of Sri Lanka and SPC Franchisee pharmacy outlets. Selection of pharmacies from respective districts were done proportionate to estimated population. Data were collected to identify WHO/INRUD core drug use indicators and the commonly prescribed medicines.

Results

Total of 2328 prescriptions were included (‘Rajya Osusala 559; SPC Franchise 711; private pharmacies 1058). Altogether 7,255 medicines were prescribed, and the 3 most commonly prescribed medicines were atorvastatin, losartan and metformin. Average number of medicines per encounter was 3.1±1.9 (Median: 3; range 1-12) Highest average number of medicines per encounter was reported in prescriptions received at ‘Rajya Osusala’ pharmacies (3.6±2.2), significantly higher than in other categories of pharmacies (p<0.001). Percentage of medicines prescribed by generic name was only 35.5%, highest at the ‘Rajya Osusala’ pharmacies (40.6%), significantly higher than other categories of pharmacies. The overall percentage of medicines prescribed from essential medicine list (EML) was 68.8%, without any significant variation between different categories of pharmacies. The percentage of medicines actually dispensed and accurately labelled were 92.4 and 98.5% respectively.

Conclusions

The average number of medicines per encounter was higher than the WHO recommended value but the usage of antibiotic and injectable drugs were within recommended standards. Generic prescribing, was very much lower. The EML prescribing, labelling and percentage dispensed medicines fared much better although lower than the WHO recommended 100% compliance. This island wide study has provided national wide data before the implementation of key changes in regulation of medicines in Sri Lanka and a repeat survey will be useful to identify impact of the new legislations.
A multi-responsive coumarin–benzothiazole fluorescent probe for selective detection of biological thiols and hydrazine
Authors: Chen Kangni , Li Yanbo , Shang Jinyan , Li Heping
Published: October 2021

Biothiols play important roles in various physiological and biological processes, which closely related to many diseases. Hydrazine is widely used in the chemical industry, but it is harmful to humans and animals. Therefore, it is very important to develop a fluorescent probe that can simultaneously detect biological thiols and hydrazine. In this work, a new fluorescent probe (2E,4Z)-2-(benzo[d]thiazol-2-yl)-5-chloro-5-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)penta-2,4-dienenitrile (BCD) was synthesized by integrating coumarin and benzothiazole acetonitrile. Featured with four binding sites and different bonding mechanism between probe with biothiols and hydrazine, this probe exhibited fluorescent turn-on for distinguishing Cys, Hcy, GSH and hydrazine with 760-, 8-, 6- and 637-fold fluorescent intensity increase at 502, 479, 476 and 458 nm, respectively, through different excitation wavelengths. Research on the effect of pH on the fluorescent performance of BCD shows that the probe exhibits superior stability in a weakly alkaline to weakly acidic environment, which will facilitate the detection of biological thiols or hydrazine hydrate by BCD. Selectivity studies have shown that the probe has high specificity to biological thiols and hydrazine, which is of great significance to the application of BCD.
Magnetic resonance imaging of pure ovarian dysgerminoma: a series of eight cases
Authors: Cacioppa Laura Maria , Crusco Federico , Marchetti Francesco , Duranti Michele , Renzulli Matteo , Golfieri Rita
Published: October 2021

Background

Imaging findings have a prominent role in early and correct identification of ovarian dysgerminoma, the most common ovarian malignant germ cell tumor (OMGCT). Despite Computed Tomography (CT) is widely used, Magnetic Resonance Imaging (MRI) has proved to be superior in adnexal masses characterization. Limited data and small series are available concerning MRI aspects of dysgerminoma.

Case presentation

From January 2012 to December 2018, a database of solid ovarian masses was retrospectively reviewed. Eight patients with histologically proven pure ovarian dysgerminoma and complete imaging available were identified and analyzed. Imaging findings were evaluated separately by two radiologists expert in female genito-urinary MRI.

Conclusions

MRI findings of a lobulated, purely solid, encapsulated mass with hyper-intensity of lobules and hypo-intensity of septa on T2w images contribute to differentiate dysgerminomas from other ovarian neoplasms.
Shipping optimization systems (SOS) for tramp: stochastic cargo soft time windows
Authors: El Noshokaty Said
Published: October 2021

Cargo time windows have been discussed in the shipping literature in several ways and within several contexts. One way considers the hard time windows, where a fixed date is assigned to both the open and close laycan for the cargo loading and discharging ports. According to this way, the cargo is rejected if the ship cannot meet these time windows. Another way develops soft time windows, where the ship for an additional cost or a penalty may violate the cargo laycan. The context in the previous ways includes a tramp deterministic model. In this paper, the soft time windows are considered within a context of a tramp stochastic model, where both the cargo transport demand and the laycan dates are random variables. The objective is a gross-profit-per-day accompanied with realistic shipping elements embedded into decision support systems known as shipping optimization systems (SOS). The chance-constraint programming and the modified version of the Dantzig–Wolfe decomposition principle known as block-angular linear ratio programming solve the problem. A case study demonstrates that using stochastic soft time windows with stochastic cargo transport demand has considerably improved the gross profit-per-day better than trying to arrive on time by varying ship speed or being within a non-stochastic shipping context.
A workflow to generate patient-specific three-dimensional augmented reality models from medical imaging data and example applications in urologic oncology
Authors: Wake Nicole , Rosenkrantz Andrew B. , Huang William C. , Wysock James S. , Taneja Samir S. , Sodickson Daniel K. , Chandarana Hersh
Published: October 2021

Augmented reality (AR) and virtual reality (VR) are burgeoning technologies that have the potential to greatly enhance patient care. Visualizing patient-specific three-dimensional (3D) imaging data in these enhanced virtual environments may improve surgeons’ understanding of anatomy and surgical pathology, thereby allowing for improved surgical planning, superior intra-operative guidance, and ultimately improved patient care. It is important that radiologists are familiar with these technologies, especially since the number of institutions utilizing VR and AR is increasing. This article gives an overview of AR and VR and describes the workflow required to create anatomical 3D models for use in AR using the Microsoft HoloLens device. Case examples in urologic oncology (prostate cancer and renal cancer) are provided which depict how AR has been used to guide surgery at our institution.
Role of collagen degradation pathway in sphingomyelin synthase 2-deficient mouse skin
Authors: Hiranuma Takenaga , Watanabe Ken , Yamashita Tadashi , Okazaki Toshiro , Tokudome Yoshihiro
Published: October 2021

Background

Sphingomyelin synthase (SMS) is the only enzyme that synthesizes sphingomyelin from ceramide. The role of sphingomyelin synthase in epidermis is being understood, but there is no report on its role in the dermis. Quantitative and qualitative evaluation of collagen in SMS2-deficient mice reveals the role of SMS2 in collagen production.

Methods

SMS2-deficient mice were used for in this study. The dermis thickness was measured by Elastica van Gieson staining, the collagen fiber was observed by Scanning Electron Microscopy, the collagen content by ELISA, the ceramide and sphingomyelin content by Thin Layer Chromatography, the collagen-generating and metabolizing gene expression level by RT-PCR, and MMP13 protein level was measured by western blotting.

Results

Thinner dermis in these mice compared to wild-type mice. A reduced number of collagen fibers were observed, and decreased levels of type I collagen and sphingolipids. Gene expression levels of collagen production-related genes in the dermis were found to be unaltered. The expression of several genes related to collagen degradation was found to be affected. The expression level of TNFα and MMP13 and MMP13 protein levels were increased relative to those of wild-type mice, while the expression level of TIMP1 was decreased.

Conclusions

These results indicate that SMS is involved not only in maintaining the sphingolipid content of the epidermal barrier but also in maintaining collagen homeostasis. Further elucidation of the role of SMS2 in the skin may lead to SMS2 comprising a new target for the treatment of skin diseases and the development of functional cosmetics.
Influence of phosphorus and nitrogen co-doping of activated carbon from littered cigarette filters for adsorption of methylene blue dye from wastewater
Authors: Macchi Samantha , Alsebai Zane , Watanabe Fumiya , Ilyas Arooba , Atif Shiraz , Viswanathan Tito , Siraj Noureen
Published: October 2021

Global access to sanitary water is of utmost importance to human health. Presently, textile dye water pollution and cigarette pollution are both plaguing the environment. Herein, waste cigarette filters (CFs) are converted into useful carbon-based adsorbent materials via a facile, microwave-assisted carbonization procedure. The CFs are activated and co-doped with phosphorus and nitrogen simultaneously to enhance their surface characteristics and adsorbent capability by introducing chemisorptive binding sites to the surface. The doped carbonized CF (DCCF) and undoped carbonized CF (CCF) adsorbents are characterized physically to examine their surface area, elemental composition, and surface charge properties. The maximum adsorption capacity of synthesized adsorbents was determined via batch adsorption experiments and Langmuir modelling. Additionally, the influence of different parameters on the adsorption process was studied by varying the adsorption conditions such as adsorbent dosage, initial concentration, contact time, temperature, and pH. The DCCF adsorbent showed a maximum adsorption capacity of 303 mg g− 1. Adsorption of both adsorbents fit best to Langmuir model and pseudo-second order kinetics, indicating chemisorptive mechanism. Both adsorbents showed endothermic adsorption process which is indicated by increasing adsorption capacity with increased temperatures. DCCF exhibited greater adsorption capability than CCF at all temperatures from 25 to 55 °C. The pH of the solution significantly affected the adsorption capacity of CCF while DCCF adsorption is favorable at a wide pH range due to low value of the adsorbent’s point of zero charge. Reusability results showed that both adsorbents can be used over several cycles for removal of dye. Thus, results conclude that the waste DCCF-based adsorbent does not only show a profound potential as a sustainable solution to combat textile dye water pollution but also addresses the valuable use of the CF pollution simultaneously. This approach, which can target two major pollutants, is attractive due to its ease of preparation, negligible cost, and versatility in application.
Association of LH/FSH ratio with menstrual cycle regularity and clinical features of patients with polycystic ovary syndrome
Authors: Mitrašinović-Brulić Maja , Buljan Mihaela , Suljević Damir
Published: October 2021

Background

Understanding the global prevalence and phenotypic features of polycystic ovary syndrome (PCOS) is important as geographic factors and ethnic variations can significantly alter the clinical syndrome. The aim of this study was to determine and evaluate the luteinizing hormone/follicle-stimulating hormone ratio (LH/FSH) in women with PCOS during therapy on selected endocrine and biochemical parameters.

Results

Women with PCOS were included in the study and were classified into two groups: women without therapy (de novo) and women with therapy for PCOS. ESHERE/ASRM criteria that require the presence of two out of three criteria: ovulatory dysfunction, hyperandrogenism, and morphological PCOS detected by ultrasound diagnostics. Electrochemiluminescence immunoassay (ECLIA) was used for FSH and insulin analysis. The enzymatic method was used to analyze the biochemical profile. There was a significant difference between the two groups in terms of the LH/FSH ratio (2.56 vs. 2.41, P=0.043), glucose (6.23 vs. 5.12, P=0.003), insulin (19.21 vs. 7.35, P=0.000), IR (3.22 vs. 1.42, P=0.000), cholesterol (5.97 vs. 4.92, P=0.002), and LDL (3.56 vs. 2.56, P=0.001). The data suggest that patients with PCOS therapy have reduced hyperinsulinemia and insulin resistance. There was a significant correlation between the LH and FSH in the de novo group, as well as the correlation between hormone levels and LH/FSH ratio in both groups. Patients with PCOS therapy have a tendency for normal body weight and reduction of severe obesity compared to patients without therapy. Clinical features such as regular menstrual cycle and the prevalence of acne and hirsutism are not significantly different between groups.

Conclusion

PCOS cause irregularities of the menstrual cycle, the appearance of clinical manifestations, especially changes of LH/FSH ratio. Therapy for PCOS contributes to better regulation of endocrine and biochemical parameters, especially in the reduction of hyperinsulinemia, insulin resistance, and reduced LH/FSH ratio.
Learning from the “tail end” of de-implementation: the case of chemical castration for localized prostate cancer
Authors: Skolarus Ted A. , Forman Jane , Sparks Jordan B. , Metreger Tabitha , Hawley Sarah T. , Caram Megan V. , Dossett Lesly , Paniagua-Cruz Alan , Makarov Danil V. , Leppert John T. , Shelton Jeremy B. , Stensland Kristian D. , Hollenbeck Brent K. , Shahinian Vahakn , Sales Anne E. , Wittmann Daniela A.
Published: October 2021

Background

Men with prostate cancer are often treated with the suppression of testosterone through long-acting injectable drugs termed chemical castration or androgen deprivation therapy (ADT). In most cases, ADT is not an appropriate treatment for localized prostate cancer, indicating low-value care. Guided by the Theoretical Domains Framework (TDF) and the Behavior Change Wheel’s Capability, Opportunity, Motivation Model (COM-B), we conducted a qualitative study to identify behavioral determinants of low-value ADT use to manage localized prostate cancer, and theory-based opportunities for de-implementation strategy development.

Methods

We used national cancer registry and administrative data from 2016 to 2017 to examine the variation in low-value ADT use across Veterans Health Administration facilities. Using purposive sampling, we selected high- and low-performing sites to conduct 20 urology provider interviews regarding low-value ADT. We coded transcripts into TDF domains and mapped content to the COM-B model to generate a conceptual framework for addressing low-value ADT practices.

Results

Our interview findings reflected provider perspectives on prescribing ADT as low-value localized prostate cancer treatment, including barriers and facilitators to de-implementing low-value ADT. We characterized providers as belonging in 1 of 3 categories with respect to low-value ADT use: 1) never prescribe 2); willing, under some circumstances, to prescribe: and 3) prescribe as an acceptable treatment option. Provider capability to prescribe low-value ADT depended on their knowledge of localized prostate cancer treatment options (knowledge) coupled with interpersonal skills to engage patients in educational discussion (skills). Provider opportunity to prescribe low-value ADT centered on the environmental resources to inform ADT decisions (e.g., multi-disciplinary review), perceived guideline availability, and social roles and influences regarding ADT practices, such as prior training. Provider motivation involved goals of ADT use, including patient preferences, beliefs in capabilities/professional confidence, and beliefs about the consequences of prescribing or not prescribing ADT.

Conclusions

Use of the TDF domains and the COM-B model enabled us to conceptualize provider behavior with respect to low-value ADT use and clarify possible areas for intervention to effect de-implementation of low-value ADT prescribing in localized prostate cancer.

Trial registration

ClinicalTrials.gov, NCT03579680
Audit feedback interventions to address high-risk prescriptions in long-term care homes: a costing study and return on investment analysis
Authors: Thavorn Kednapa , Kumar Srishti , Reis Catherine , Lam Jonathan , Dobell Gail , Mulhall Cara , Grimshaw Jeremy M. , Ivers Noah
Published: October 2021

Background

Audit and feedback is a common implementation strategy, but few studies describe its costs. ‘MyPractice’ is a province-wide audit and feedback initiative to improve prescribing in nursing homes. This study sought to estimate the costs of ‘MyPractice’ and assess whether the financial benefit of ‘MyPractice’ offsets those costs.

Methods

We conducted a costing study from the perspective of the Ontario government. Total cost of ‘MyPractice’ was calculated as the sum of the costs of producing and disseminating the reports (covering three report releases) which were obtained from Ontario Health staff interviews and document reviews. Return on investment (ROI) was calculated as the ratio of net cost-savings and the intervention cost. Cost savings were based on the effectiveness of ‘MyPractice’ derived from a published cohort study. Cost-savings attributable to ‘MyPractice’ were estimated from the changes in the rates of antipsychotics over time between physicians who signed up and viewed the reports and those who did not sign up to the reports.

Results

Total intervention costs were C$223,691 (C$838 per physician and C$74,564 per release). Costs incurred during the development phase accounted for 74% of the total cost (C$166,117), while implementation costs for three report releases were responsible for 26% of the total costs (C$57,575). The ROI for every C$1 spent on the ‘MyPractice’ intervention was 1.02 (95% CI 0.51, 1.93) for three report releases.

Conclusion

‘MyPractice’ report offers a good return on investment and the value for money could improve with greater number of report releases.
Digital gangrene as an unusual paraneoplastic manifestation of hodgkins lymphoma—a rare case report
Authors: Deme Swaroopa , Kakarla Bhaskar , P. Venkateswar Rao , YSN Raju , M. Nageswara Rao
Published: October 2021

Background

Hodgkin’s lymphoma presenting with digital ischemia and gangrene is a rare manifestation. Paraneoplastic manifestations are rare in Hodgkin’s lymphoma but can occur in the form of paraneoplastic cerebellar degeneration (PCD) and dermatomyositis/polymyositis. This case report adds an exceptional presentation of Hodgkin's lymphoma as digital ischemia and gangrene.

Case presentation

We report a case of a 60-year-old male patient who presented with fever, cough, shortness of breath, the pain in the right middle finger. On examination bluish-black discoloration of the right middle finger, left middle finger, ring finger, and generalized lymphadenopathy was noted. On further evaluation, he was found to have anemia, eosinophilia, and severe thrombocytopenia with a normal coagulation profile and negative rheumatological workup. Arterial Doppler of both upper limbs showed the normal study. He was diagnosed to have Hodgkin’s lymphoma on the lymph node and bone marrow biopsy. He was started on chemotherapy with partial improvement in symptoms and was lost to follow-up after 2 cycles.

Conclusions

Digital ischemia can be a rare paraneoplastic manifestation of Hodgkin’s lymphoma.
Narrative exposure therapy for survivors of human trafficking: feasibility randomised controlled trial
Authors: Brady Francesca , Chisholm Amy , Walsh Eileen , Ottisova Livia , Bevilacqua Leonardo , Mason Claire , von Werthern Martha , Cannon Teresa , Curry Christina , Komolafe Kemi , Robert Rachel Elizabeth , Robjant Katy , Katona Cornelius
Published: October 2021

Background

Human trafficking is a grave human rights violation and a major public health concern. Survivors present with high rates of mental health problems including post-traumatic stress disorder (PTSD). Studies of effective treatments for PTSD in survivors of human trafficking are lacking. Narrative exposure therapy (NET) is an effective PTSD treatment for multiple, prolonged and complex trauma, but its efficacy has not been rigorously tested in survivors of human trafficking.

Aims

To test the feasibility and acceptability of a randomised controlled trial (RCT) offering NET as a treatment for PTSD in trafficking survivors with a history of multiple traumatic events, as well as providing preliminary evidence regarding its efficacy (trial registration: ISRCTN95136302).

Method

A single-blind RCT compared NET with a wait-list control in survivors of trafficking with PTSD (n = 25). In the NET arm of the study, participants attended a mean of 17 sessions.

Results

NET was well tolerated by participants. There were significant reductions in PTSD, depression and anxiety symptoms post-treatment in the NET group but no significant change in the wait-list group.

Conclusions

The results indicate that NET is a promising and acceptable treatment for trafficking survivors. Psychological therapy in an RCT design can be safely delivered to this vulnerable group, although modifications are required to ensure their holistic needs are properly addressed.
Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study
Authors: Al-Sawaf Othman , Zhang Can , Lu Tong , Liao Michael Z. , Panchal Anesh , Robrecht Sandra , Ching Travers , Tandon Maneesh , Fink Anna-Maria , Tausch Eugen , Schneider Christof , Ritgen Matthias , Böttcher Sebastian , Kreuzer Karl-Anton , Chyla Brenda , Miles Dale , Wendtner Clemens-Martin , Eichhorst Barbara , Stilgenbauer Stephan , Jiang Yanwen , Hallek Michael , Fischer Kirsten
Published: October 2021

PURPOSE

The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study.

PATIENTS AND METHODS

Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed.

RESULTS

Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred.

CONCLUSION

Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.