bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryopreservation of human cancers conserves tumour heterogeneity for single-cell multi-omics analysis
Authors: Wu Sunny Z. , Roden Daniel L. , Al-Eryani Ghamdan , Bartonicek Nenad , Harvey Kate , Cazet Aurélie S. , Chan Chia-Ling , Junankar Simon , Hui Mun N. , Millar Ewan A. , Beretov Julia , Horvath Lisa , Joshua Anthony M. , Stricker Phillip , Wilmott James S. , Quek Camelia , Long Georgina V. , Scolyer Richard A. , Yeung Bertrand Z. , Segara Davendra , Mak Cindy , Warrier Sanjay , Powell Joseph E. , O’Toole Sandra , Lim Elgene , Swarbrick Alexander
Published: May 2021

Background

High throughput single-cell RNA sequencing (scRNA-Seq) has emerged as a powerful tool for exploring cellular heterogeneity among complex human cancers. scRNA-Seq studies using fresh human surgical tissue are logistically difficult, preclude histopathological triage of samples, and limit the ability to perform batch processing. This hindrance can often introduce technical biases when integrating patient datasets and increase experimental costs. Although tissue preservation methods have been previously explored to address such issues, it is yet to be examined on complex human tissues, such as solid cancers and on high throughput scRNA-Seq platforms.

Methods

Using the Chromium 10X platform, we sequenced a total of ~ 120,000 cells from fresh and cryopreserved replicates across three primary breast cancers, two primary prostate cancers and a cutaneous melanoma. We performed detailed analyses between cells from each condition to assess the effects of cryopreservation on cellular heterogeneity, cell quality, clustering and the identification of gene ontologies. In addition, we performed single-cell immunophenotyping using CITE-Seq on a single breast cancer sample cryopreserved as solid tissue fragments.

Results

Tumour heterogeneity identified from fresh tissues was largely conserved in cryopreserved replicates. We show that sequencing of single cells prepared from cryopreserved tissue fragments or from cryopreserved cell suspensions is comparable to sequenced cells prepared from fresh tissue, with cryopreserved cell suspensions displaying higher correlations with fresh tissue in gene expression. We showed that cryopreservation had minimal impacts on the results of downstream analyses such as biological pathway enrichment. For some tumours, cryopreservation modestly increased cell stress signatures compared to freshly analysed tissue. Further, we demonstrate the advantage of cryopreserving whole-cells for detecting cell-surface proteins using CITE-Seq, which is impossible using other preservation methods such as single nuclei-sequencing.

Conclusions

We show that the viable cryopreservation of human cancers provides high-quality single-cells for multi-omics analysis. Our study guides new experimental designs for tissue biobanking for future clinical single-cell RNA sequencing studies.
Oxidant therapy improves adipogenic differentiation of adipose-derived stem cells in human wound healing
Authors: Ploner Christian , Rauchenwald Tina , Connolly Catherine E. , Joehrer Karin , Rainer Johannes , Seifarth Christof , Hermann Martin , Nagl Markus , Lobenwein Susanne , Wilflingseder Doris , Cappellano Giuseppe , Morandi Evi M. , Pierer Gerhard
Published: May 2021

Background

Adipose-derived stem cells (ASC) and adipocytes are involved in numerous physiological and pathophysiological conditions, which have been extensively described in subcutaneous and visceral fat depots over the past two decades. However, much less is known about ASC and adipocytes outside classical fat tissue depots and their necessity in tissue remodeling after injury. Therefore, we investigated the etiology of adipocytes in human granulation tissue and define their possible role wound healing.

Methods

Identification of human wound tissue adipocytes was determined by immunohistochemical staining of granulation tissue sections from patients undergoing surgical debridement. Stromal cell fractions from granulation tissue and subcutaneous fat tissue were generated by collagenase type II-based protocols. Pro- and anti-inflammatory wound bed conditions were mimicked by THP1- and CD14+ monocyte-derived macrophage models in vitro. Effects of macrophage secretome on ASC differentiation and metabolism were determined by immunoblotting, flow cytometry, and microscopy assessing early and late adipocyte differentiation states. Functional rescuing experiments were conducted by lentiviral transduction of wildtype PPARG, IL1RA, and N-chlorotaurine (NCT) treatment.

Results

Single and clustered adipocyte populations were detected in 11 out of 13 granulation tissue specimens and single-cell suspensions from granulation tissue showed adipogenic differentiation potential. Pro-inflammatory signaling by IFNG/LPS-stimulated macrophages (M (IFNG/LPS)) inhibited the maturation of lipid droplets in differentiated ASC. In contrast, anti-inflammatory IL4/IL13-activated macrophages (M (IL4/IL13)) revealed minor effects on adipocyte development. The M (IFNG/LPS)-induced phenotype was associated with a switch from endogenous fatty acid synthesis to glycolysis-dominated cell metabolism and increased pro-inflammatory cytokine production. Impaired adipogenesis was associated with increased, but seemingly non-functional, CEBPB levels, which failed to induce downstream PPARG and CEBPA. Neither transgenic PPARG overexpression, nor inhibition of IL1B was sufficient to rescue the anti-adipogenic effects induced by IFNG/LPS-activated macrophages. Instead, macrophage co-treatment during stimulation with NCT, a mild oxidant produced by activated granulocytes present in human wounds in vivo, significantly attenuated the anti-adipogenic effects.

Conclusions

In conclusion, the appearance of adipocytes in wound tissue indicates a prevailing anti-inflammatory environment that could be promoted by NCT treatment and may be associated with improved healing outcomes.

Graphical abstract
Non-invasive and minimally invasive glucose monitoring devices: a systematic review and meta-analysis on diagnostic accuracy of hypoglycaemia detection
Authors: Lindner Nicole , Kuwabara Aya , Holt Tim
Published: May 2021

Background

The use of minimally and non-invasive monitoring systems (including continuous glucose monitoring) has increased rapidly over recent years. Up to now, it remains unclear how accurate devices can detect hypoglycaemic episodes. In this systematic review and meta-analysis, we assessed the diagnostic accuracy of minimally and non-invasive hypoglycaemia detection in comparison to capillary or venous blood glucose in patients with type 1 or type 2 diabetes.

Methods

Clinical Trials.gov, Cochrane Library, Embase, PubMed, ProQuest, Scopus and Web of Science were systematically searched. Two authors independently screened the articles, extracted data using a standardised extraction form and assessed methodological quality using a review-tailored quality assessment tool for diagnostic accuracy studies (QUADAS-2). The diagnostic accuracy of hypoglycaemia detection was analysed via meta-analysis using a bivariate random effects model and meta-regression with regard to pre-specified covariates.

Results

We identified 3416 nonduplicate articles. Finally, 15 studies with a total of 733 patients were included. Different thresholds for hypoglycaemia detection ranging from 40 to 100 mg/dl were used. Pooled analysis revealed a mean sensitivity of 69.3% [95% CI: 56.8 to 79.4] and a mean specificity of 93.3% [95% CI: 88.2 to 96.3]. Meta-regression analyses showed a better hypoglycaemia detection in studies indicating a higher overall accuracy, whereas year of publication did not significantly influence diagnostic accuracy. An additional analysis shows the absence of evidence for a better performance of the most recent generation of devices.

Conclusion

Overall, the present data suggest that minimally and non-invasive monitoring systems are not sufficiently accurate for detecting hypoglycaemia in routine use.

Systematic review registration

PROSPERO 2018 CRD42018104812
Staff experiences of encountering and treating outpatients with substance use disorder in the psychiatric context: a qualitative study
Authors: Petersén Elisabeth , Thurang Anna , Berman Anne H.
Published: May 2021

Background

High comorbidity exists between mental illness and substance use disorders (SUD). Patients in psychiatry living with problematic alcohol or drug consumption can experience a sense of exclusion, where seeking help for SUD can be perceived as stigmatizing. The aim of this study is to illuminate staff experiences of encountering patients with SUD within the psychiatric outpatient context.

Methods

The study was exploratory, with a qualitative design. Interviews with outpatient psychiatry managers and focus groups with clinical staff focused on the experience of encountering patients with SUD. Data were evaluated using content analysis inspired by phenomenological-hermeneutic methodology.

Results

Three themes were identified and each illuminated by two sub-themes. Bridging the organizational gap included sub-themes of having an established collaboration and facing difficulties in the collaboration; Having beliefs about the patient you encounter included sub-themes of working with patients who are exposed to prejudicial thoughts and expressing prejudicial thoughts about the patient. Striving to achieve a therapeutic alliance included sub-themes of having a feeling of developing together and supporting the patient towards recovery.

Conclusion

A life-world perspective, used to interpret results, indicated that caring for patients with SUD in psychiatry was perceived as difficult, where collaboration between psychiatry and addiction care was often experienced as problematic. Based on these findings, we believe that the current gap between the psychiatry and addiction care could be reduced to some extent by offering patients digital treatment for SUD. In this way, patients could remain under the care of their regular psychiatric clinic without having to physically visit SUD services. Thus, a virtual bridge could be established to bring psychiatry and addiction care closer to each other for the patients’ benefit.
Novel chromosomal insertions of ISEcp1-blaCTX-M-15 and diverse antimicrobial resistance genes in Zambian clinical isolates of Enterobacter cloacae and Escherichia coli
Authors: Shawa Misheck , Furuta Yoshikazu , Mulenga Gillan , Mubanga Maron , Mulenga Evans , Zorigt Tuvshinzaya , Kaile Christone , Simbotwe Manyando , Paudel Atmika , Hang’ombe Bernard , Higashi Hideaki
Published: May 2021

Background

The epidemiology of extended-spectrum β-lactamases (ESBLs) has undergone dramatic changes, with CTX-M-type enzymes prevailing over other types.blaCTX-Mgenes, encoding CTX-M-type ESBLs, are usually found on plasmids, but chromosomal location is becoming common. Given thatblaCTX-M-harboring strains often exhibit multidrug resistance (MDR), it is important to investigate the association between chromosomally integratedblaCTX-Mand the presence of additional antimicrobial resistance (AMR) genes, and to identify other relevant genetic elements.

Methods

A total of 46 clinical isolates of cefotaxime-resistantEnterobacteriaceae(1Enterobacter cloacae, 9Klebsiella pneumoniae, and 36Escherichia coli) from Zambia were subjected to whole-genome sequencing (WGS) using MiSeq and MinION. By reconstructing nearly complete genomes,blaCTX-Mgenes were categorized as either chromosomal or plasmid-borne.

Results

WGS-based genotyping identified 58 AMR genes, including fourblaCTX-Malleles (i.e.,blaCTX-M-14,blaCTX-M-15,blaCTX-M-27, andblaCTX-M-55). Hierarchical clustering using selected phenotypic and genotypic characteristics suggested clonal dissemination ofblaCTX-Mgenes. Out of 45blaCTX-Mgene-carrying strains, 7 harbored the gene in their chromosome. In oneE. cloacaeand threeE. colistrains, chromosomalblaCTX-M-15was located on insertions longer than 10 kb. These insertions were bounded by ISEcp1at one end, exhibited a high degree of nucleotide sequence homology with previously reported plasmids, and carried multiple AMR genes that corresponded with phenotypic AMR profiles.

Conclusion

Our study revealed the co-occurrence of ISEcp1-blaCTX-M-15and multiple AMR genes on chromosomal insertions inE. cloacaeandE. coli, suggesting that ISEcp1may be responsible for the transposition of diverse AMR genes from plasmids to chromosomes. Stable retention of such insertions in chromosomes may facilitate the successful propagation of MDR clones among theseEnterobacteriaceaespecies.
Overexpression of Toll-like receptor 4 contributes to the internalization and elimination of Escherichia coli in sheep by enhancing caveolae-dependent endocytosis
Authors: Li Yao , Zhao Yue , Xu Xueling , Zhang Rui , Zhang Jinlong , Zhang Xiaosheng , Li Yan , Deng Shoulong , Lian Zhengxing
Published: May 2021

Background

Gram-negative bacterial infections have a major economic impact on both the livestock industry and public health. Toll-like receptor 4 (TLR4) plays a crucial role in host defence against Gram-negative bacteria. Exploring the defence mechanism regulated by TLR4 may provide new targets for treatment of inflammation and control of bacterial infections. In a previous study, we generated transgenic sheep overexpressing TLR4 by microinjection to improve disease resistance. The defence mechanism through which TLR4 overexpression protected these sheep against pathogens is still not fully understood.

Results

In the present study, we used Escherichia coli to infect monocytes isolated from peripheral blood of the animal model. The overexpression of TLR4 strongly enhanced the percentage of endocytosis and capacity of elimination in monocytes during the early stages of infection. This phenomenon was mainly due to overexpression of TLR4 promoting caveolae-mediated endocytosis. Pretreatment of the transgenic sheep monocytes with inhibitors of TLR4, Src signalling, or the caveolae-mediated endocytosis pathway reduced the internalization of bacteria, weakened the ability of the monocytes to eliminate the bacteria, and increased the pH of the endosomes.

Conclusion

Together, our results reveal the effects of TLR4 on the control of E. coli infection in the innate immunity of sheep and provide crucial evidence of the caveolae-mediated endocytosis pathway required for host resistance to invading bacteria in a large animal model, providing theoretical support for breeding disease resistance in the future. Furthermore, Src and caveolin 1 (CAV1) could be potentially valuable targets for the control of infectious diseases.
The authentication and repatriation of a ceremonial tsantsa to its country of origin (Ecuador)
Authors: Byron Craig D. , Kiefer Adam M. , Thomas Joanna , Patel Sagar , Jenkins Amy , Fratino Anthony L. , Anderson Todd
Published: May 2021

Tsantsas, commonly referred to as “shrunken heads”, are unique and valuable antiquities that were produced by the Shuar, Achuar, Awajún/Aguaruna, Wampís/Huambisa, and Candoshi-Shampra (SAAWC) peoples until the mid twentieth century. Originally used with ceremonial purpose during important social group functions, tsantsas became monetarily valuable as keepsakes and curios during the nineteenth century as a result of Western/European cultural encroachment. Unmet demand resulted in the production of convincing forgeries that created confusion about the authenticity of existing collections. Ceremonial tsantsas are both human remains and valuable cultural items. Their production and purpose were negatively influenced by colonialism and the outside curio market; as such many institutions may choose to repatriate them to their places of origin. Herein, we report on the authentication and repatriation of a ceremonial tsantsa recently rediscovered in a university’s natural history collection. The personal memoirs of the original collector describe that it originated in the Ecuadorean Amazon. In consultation with the government of Ecuador, it was determined that authentication was required prior to repatriation. The tsantsa was compared to a list of thirty-three distinct characteristics shared by ceremonial tsantsas. These criteria were taken from those provided by Ecuador’s National Cultural Heritage Institute and those found in prior studies from the academic literature; they include notable skin and hair features, structure and facial anatomy, and evidence of traditional fabrication and modification. We were able to affirm 30 of the 33 authenticating indicators. As part of our protocol the tsantsa was scanned with a CT-imaging system. The resulting 3D images were invaluable in discerning subtle and difficult-to-visualize characteristics regarding the skin and patterns of modification, although there are limitations related to the small size of filamentous structures. The results of the authentication were accepted by the Ecuadorean government, and the tsantsa was repatriated in June 2019. An additional benefit of CT-imaging is that data files can be generated in order to create rapid prototypes via 3D printing. In fact, as our work demonstrates, artifacts of value can be repatriated while simultaneously preserved as a volumetric replica for the purposes of a collection.
Characterization of okra seed flours, protein concentrate, protein isolate and enzymatic hydrolysates
Authors: Nnamezie Anastasia Amaka , Famuwagun Akinsola Albert , Gbadamosi Saka Olasunkanmi
Published: May 2021

The need to feed the increasing world population with high quality protein and the enormous post-harvest losses of okra fruits necessitated the research on okra seeds in this study. Whole flour (WF) of matured okra seed was processed to obtain defatted flour (DF), protein concentrate (PC) and protein isolate (PI), followed by hydrolysis of the protein isolate by three different proteases; pepsin (PHp), pancreatin (PHc) and trypsin (PHT) to produce hydrolysates. The okra seed flours, proteins and the hydrolysates were analyzed for changes in the functional groups using Fourier, Transform Infrared (FTIR), amino acid composition, solubility profile and some functional properties. The FTIR results showed the presence of N-H stretching, C=O stretching, C=N stretching N-H bending and C-N stretching in the samples. Protein hydrolysate had higher essential amino acids (51.32–53.01%) than unhydrolysed samples (36.31–37.99%). PI and WF had the highest water absorption and swelling capacities respectively. The solubility profiles of the samples were minimal at pH 2–4 and then increased after the isoelectric point. The PC was more soluble than PI between pH 2–8. The foaming properties of the samples was least in the absence of salt but high in the presence of 0.5 M sodium chloride. The emulsion capacity of the samples was least in the presence of 1.0 M NaCl. The in-vitro protein digestibility results showed that okra seed protein hydrolysates were more digestible (83.26–86.08%) than unhydrolyzed proteins (36.48–80.90%). The results of the antioxidant properties showed that PHp and PHT exhibited better radical scavenging and metal chelating activities respectively than the other samples. The study concluded that okra seed proteins and hydrolysates demonstrated potentials as ingredients in functional food preparation and this may be considered as a strategy to reducing the post-harvest losses of okra fruit and subsequently feeding the world with quality proteins.

Graphical abstract
Extended endoscopic frontal nasal sinus surgery in management of chronic and recurrent frontal sinus diseases
Authors: Abdelaal Ahmed Sobhi , Al Awady Mohamed Kamel , Elkholy Tawfik Abdelaty
Published: May 2021

Background

The anatomical variation of the frontal sinus and its intimate relation to the skull base and orbit makes its surgery demanding. The extended endoscopic frontal sinus surgery allows wide better drainage and preventing the recurrence of the disease. Fourteen patients underwent EEFSS from May 2017 to May 2019. These patients are nine patients presented by chronic recurrent frontal sinusitis, three patients presented by chronic recurrent fronto ethmoidal mucocele and two patients with chronic recurrent external frontal fistula. Draff III done for ten patients of them and Draff IIB done for four patients of them. This study is designed for evaluating the efficacy of the extended endoscopic frontal sinus surgery (E E F S S) in management of chronic and recurrent frontal sinus diseases.

Results

The neo opening of the restored frontal sinus was remained opened with Draff III with high success rate; two patients from four patients with Draff IIb were with closed nasofrontal duct. The main follow-up was 12 months; the patients were followed up post-operatively for many office visits without any other manifestations.

Conclusion

The chronic recurrent frontal sinus diseases can be treated successfully with extended endoscopic frontal sinus surgery (E E F S S). The extended endoscopic frontal sinus surgery (Draff III) provides good results with low morbidity and less post-operative care.
Animal welfare and other ethical implications of Precision Livestock Farming technology
Authors: Schillings Juliette , Bennett Richard , Rose David Christian
Published: May 2021

In this commentary, we explore the risks and challenges associated with Precision Livestock Farming technologies based on an online workshop with over 70 international animal welfare experts, policy-makers, NGO, students, farmers and industry staff.
ctDNA Predicts Overall Survival in Patients With NSCLC Treated With PD-L1 Blockade or With Chemotherapy
Authors: Zou Wei , Yaung Stephanie J. , Fuhlbrück Frederike , Ballinger Marcus , Peters Eric , Palma John F. , Shames David S. , Gandara David , Jiang Yuqiu , Patil Namrata S.
Published: May 2021

PURPOSE

Identification of predictors for overall survival (OS) allows timely detection of clinical efficacy signals and therefore facilitates treatment decisions. We assessed the association between circulating tumor DNA (ctDNA) metrics and the primary end point of OS in a subset of previously treated patients with locally advanced or metastatic non–small-cell lung cancer, who underwent atezolizumab or docetaxel treatment in the open-label randomized phase III OAK trial.

MATERIALS AND METHODS

Plasma from 94 patients at baseline and at subsequent cycles of therapy every 3 weeks was analyzed retrospectively for ctDNA. ctDNA was measured by allele frequency and mutant molecules per milliliter (MMPM). Concordance between various per-sample metrics and clinical outcome were assessed using C index.

RESULTS

Of all the ctDNA metrics tested, the association of median MMPM at 6 weeks with OS in patients treated with atezolizumab or docetaxel had a C index > 0.7. The OS hazard ratios relative to high ctDNA above median MMPM within each arm were 0.28 (95% CI, 0.11 to 0.75) for atezolizumab and 0.19 (95% CI, 0.08 to 0.48) for docetaxel. For patients who had ctDNA median MMPM levels of < 4.79, the median survival time was more than 17 months in docetaxel-treated patients and the median survival time was not reached in the atezolizumab-treated patients.

CONCLUSION

ctDNA MMPM levels measured at 6 weeks post-treatment are associated with OS in advanced non–small-cell lung cancer. Our results suggest that ctDNA has the potential for a noninvasive early liquid biopsy predictor for OS that warrants further studies to demonstrate its utility in clinical development.
Autosomal recessive osteopetrosis: mechanisms and treatments
Authors: Penna Sara , Villa Anna , Capo Valentina
Published: May 2021

Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Clinical manifestations include dense and brittle bones, anemia and progressive nerve compression, which hamper the quality of patients' lives and cause death in the first 10 years of age. This Review describes the pathogenesis of ARO and highlights the strengths and weaknesses of the current standard of care, namely hematopoietic stem cell transplantation (HSCT). Despite an improvement in the overall survival and outcomes of HSCT, transplant-related morbidity and the pre-existence of neurological symptoms significantly limit the success of HSCT, while the availability of human leukocyte antigen (HLA)-matched donors still remains an open issue. Novel therapeutic approaches are needed for ARO patients, especially for those that cannot benefit from HSCT. Here, we review preclinical and proof-of-concept studies, such as gene therapy, systematic administration of deficient protein, in utero HSCT and gene editing.
Changes in the US Gender Gap in Wages in the 1960s
Authors: Bailey Martha J. , Helgerman Thomas , Stuart Bryan A.
Published: May 2021

The 1960s witnessed landmark legislation that aimed to increase women's wages, including the Equal Pay Act of 1963, Title VII of the Civil Rights Act, and the 1966 amendments to the Fair Labor Standards Act. Although the gender gap in pay changed little at the mean/median during the decade, our distributional analysis shows that women's wages converged sharply on men's below but diverged above the median. However, the bulk of women's relative pay gains are not explained by changes in observed attributes. Our findings suggest an important role for legislation in narrowing the gender gap in the 1960s.
The Proximal Bootstrap for Finite-Dimensional Regularized Estimators
Authors: Li Jessie
Published: May 2021

We propose a proximal bootstrap that can consistently estimate the limiting distribution of sqrt(n)-consistent estimators with nonstandardasymptotic distributions in a computationally efficient manner by formulating the proximal bootstrap estimator as the solution to aconvex optimization problem, which can have a closed-form solution for certain designs. This paper considers the application to finite-dimensionalregularized estimators, such as the lasso, l1-norm regularized quantile regression, l1-norm support vector regression, and trace regression via nuclear norm regularization.
Minimum Grade Requirements for Economics Majors: Effects on Enrollments and Student Learning
Authors: Schmidt Stephen J.
Published: May 2021

This paper studies one college's policy requiring minimum grades in core courses for completion of the economics major. The policy reduced majors by approximately 6 percent. Grades of C-and D (requiring students to retake the course) dropped substantially, while grades of C (the minimum acceptable grade) did not change, and grades from C+ to B rose. Difference-in-difference analysis suggests that the policy caused the grade shift. Because C grades did not change and grades as high as B increased, I conclude that the policy caused increased effort by students who were below and somewhat above the performance standard.
Adaptive Correspondence Experiments
Authors: Avivi Hadar , Kline Patrick , Rose Evan , Walters Christopher
Published: May 2021

Correspondence experiments probe for discrimination by manipulating employer perceptions of applicant characteristics. We consider the gains from dynamically adapting the number and quality of fictitious applications each employer receives to their prior callback decisions. Calibrating employer behavior to experimental data from Nunley et al. (2015), we find that it is possible to cut the number of applications required to detect a fixed number of discriminators roughly in half relative to a benchmark design with a fixed number of applications per job. These gains are achieved primarily from abandoning jobs with very low callback probabilities and those that call back Black applicants.
Indigenous Self-Governance and Development on American Indian Reservations
Authors: Frye Dustin , Parker Dominic P.
Published: May 2021

The UN Declaration on the Rights of Indigenous People promotes self-governance as a matter of justice rather than economics. How will self-governance affect the incomes of indigenous people? To gain insight, we compare long-run income growth on American Indian reservations with and without federal oversight through the 1934 Indian Reorganization Act. Reservations with more autonomy had 12-15 percent higher income per capita in 2016, even conditional on 1930s income. However, these more autonomous reservations also experienced wider income variance with more downside risk. The findings are consistent with theory emphasizing the development trade-offs between local and centralized governance.
COVID-19 and Small- and Medium-Sized Enterprises: A 2021 “Time Bomb”?
Authors: Gourinchas Pierre-Olivier , Kalemli-Özcan Şebnem , Penciakova Veronika , Sander Nick
Published: May 2021

This paper assesses the prospects of a 2021 "time bomb" in small-and medium-sized enterprise (SME) failures triggered by the generous support policies enacted during the 2020 COVID-19 crisis. Policies implemented in 2020 do not on their own create a 2021 time bomb for SMEs. Rather, business failures and policy costs remain modest. By contrast, credit contraction poses significant risk. Such a contraction would disproportionately impact firms that could survive COVID-19 in 2020 without any fiscal support. Even in that scenario, most business failures would arise not from excessively generous 2020 policies but rather from the contraction of credit to the corporate sector.
Gender Bias in Assessments of Teacher Performance
Authors: Beg Sabrin , Fitzpatrick Anne , Lucas Adrienne M.
Published: May 2021

To measure whether principals exhibit gender bias when assessing teacher effectiveness, we compare principals' subjective evaluations against teachers' self-evaluations and objective effectiveness in Ghanaian primary schools. Female and male teachers rate themselves equivalently. Principals are 11 percentage points less likely to rate a female teacher as "more effective," but female teachers are objectively more effective based on student learning. Principals assess the least effective male teacher as more effective than the objectively most effective female teacher. We corroborate results with a survey experiment showing similar gender bias. This bias against female teachers has implications for promotion and student learning.
Mid-level health providers for primary healthcare: a rapid evidence synthesis
Authors: Moola Sandeep , Bhaumik Soumyadeep , Nambiar Devaki
Published: May 2021

Background: Healthcare services, in many countries, are increasingly being provided by cadres not trained as physicians, and these substitute health workers are referred to as mid-level health providers (MLHPs). The objective of this study was to rapidly synthesise evidence on the effectiveness of MLHPs involved in the delivery of healthcare, with a perspective on low- and middle-income countries.

Methods: The review team performed an overview of systematic reviews assessing various outcomes for participants receiving care from MLHPs. The team evaluated systematic reviews for methodological quality and certainty of the evidence. Also, the review team consulted relevant stakeholders in India.

Results: The final report included seven systematic reviews, with six assessed as moderate to high methodological quality. Mortality outcomes concerning pregnancy and childbirth care services showed no significant differences in care provided by MLHPs when compared with doctors. Pregnancy care provided by midwives was found to improve the quality of care slightly. The risk of failure or incomplete abortion for surgical abortion procedures provided by MLHPs was twice when compared to the procedures provided by doctors. Moderate to high certainty evidence showed that initiation and maintenance of antiretroviral therapy for HIV-infected patients by a nurse or clinical officer slightly reduced mortality. High certainty evidence showed that chronic disease management by non-medical prescribers reduced some important physiological measures compared to medical prescribing by doctors.

Conclusions: To date, this is the first rapid overview of the evidence on MLHPs. Low-quality evidence suggests that MLHPs might be suitable to deliver quality pregnancy care. Moderate and high-quality evidence from trials suggests that MLHPs are helpful for chronic disease management and initiation and maintenance of antiretroviral therapy in people with HIV/AIDS. However, the roles and subsequent training and regulation of MLHPs might be different for different care domains.
The need for standardisation in life science research - an approach to excellence and trust.
Authors: Hollmann Susanne , Kremer Andreas , Baebler Špela , Trefois Christophe , Gruden Kristina , Rudnicki Witold R. , Tong Weida , Gruca Aleksandra , Bongcam-Rudloff Erik , Evelo Chris T. , Nechyporenko Alina , Frohme Marcus , Šafránek David , Regierer Babette , D'Elia Domenica
Published: May 2021

Today, academic researchers benefit from the changes driven by digital technologies and the enormous growth of knowledge and data, on globalisation, enlargement of the scientific community, and the linkage between different scientific communities and the society. To fully benefit from this development, however, information needs to be shared openly and transparently. Digitalisation plays a major role here because it permeates all areas of business, science and society and is one of the key drivers for innovation and international cooperation. To address the resulting opportunities, the EU promotes the development and use of collaborative ways to produce and share knowledge and data as early as possible in the research process, but also to appropriately secure results with the European strategy for Open Science (OS). It is now widely recognised that making research results more accessible to all societal actors contributes to more effective and efficient science; it also serves as a boost for innovation in the public and private sectors. However  for research data to be findable, accessible, interoperable and reusable the use of standards is essential. At the metadata level, considerable efforts in standardisation have already been made (e.g. Data Management Plan and FAIR Principle etc.), whereas in context with the raw data these fundamental efforts are still fragmented and in some cases completely missing. The CHARME consortium, funded by the European Cooperation in Science and Technology (COST) Agency, has identified needs and gaps in the field of standardisation in the life sciences and also discussed potential hurdles for implementation of standards in current practice. Here, the authors suggest four measures in response to current challenges to ensure a high quality of life science research data and their re-usability for research and innovation.
Modular intervention to improve paternal involvement and support for better infant and young child feeding in a district of coastal South India: a randomized controlled trial protocol
Authors: Mithra Prasanna , Unnikrishnan Bhaskaran , Thapar Rekha , Kumar Nithin , Holla Ramesh , Rathi Priya
Published: May 2021

Background: The major determinant to the well-being of infants and young children (IYC) is their feeding practices. These practices are the responsibility of both parents, meaning that fathers have an equal role to mothers. Fathers’ involvement can have an impact on the overall health of the children. Despite this, paternal involvement towards IYC feeding (IYCF) have not been studied adequately.

Methods: This randomized control trial (n=120) will be conducted among fathers of infants (children aged <1 year) and young children (children aged 12-23 months) in selected households in Dakshina Kannada District of the southern Indian State of Karnataka. The study will be conducted after an initial baseline assessment on awareness, attitude and involvement of fathers in IYCF. Fathers with scores less than the 50th percentile in the practice component will be categorized as fathers with poor involvement and will be potential participants for the trial. A visual module will be developed and validated for improving paternal involvement in IYCF. Using a simple randomization technique, the participants will be allocated to modular intervention and control group (1:1 allocation). Each participant in the intervention arm will be visited once a month to implement the module, for six months on a one-to-one basis. Following the intervention, a post-test assessment will be done for both groups to measure the level of paternal involvement in IYCF.

Ethics and dissemination: Approval has been obtained from the Institutional Ethics Committee of Kasturba Medical College, Mangalore, India. The dissemination plans include scientific conferences and publication in scientific journals.

Registration: The study is registered with Clinical Trial Registry of India (CTRI/2017/06/008936).
Bayes Lines Tool (BLT): a SQL-script for analyzing diagnostic test results with an application to SARS-CoV-2-testing
Authors: Aukema Wouter , Malhotra Bobby Rajesh , Goddek Simon , Kämmerer Ulrike , Borger Peter , McKernan Kevin , Klement Rainer Johannes
Published: May 2021

The performance of diagnostic tests crucially depends on the disease prevalence, test sensitivity, and test specificity. However, these quantities are often not well known when tests are performed outside defined routine lab procedures which make the rating of the test results somewhat problematic. A current example is the mass testing taking place within the context of the world-wide SARS-CoV-2 crisis. Here, for the first time in history, laboratory test results have a dramatic impact on political decisions. Therefore, transparent, comprehensible, and reliable data is mandatory. It is in the nature of wet lab tests that their quality and outcome are influenced by multiple factors reducing their performance by handling procedures, underlying test protocols, and analytical reagents. These limitations in sensitivity and specificity have to be taken into account when calculating the real test results. As a resolution method, we have developed a Bayesian calculator, the Bayes Lines Tool (BLT), for analyzing disease prevalence, test sensitivity, test specificity, and, therefore, true positive, false positive, true negative, and false negative numbers from official test outcome reports. The calculator performs a simple SQL (Structured Query Language) query and can easily be implemented on any system supporting SQL. We provide an example of influenza test results from California, USA, as well as two examples of SARS-CoV-2 test results from official government reports from The Netherlands and Germany-Bavaria, to illustrate the possible parameter space of prevalence, sensitivity, and specificity consistent with the observed data. Finally, we discuss this tool’s multiple applications, including its putative importance for informing policy decisions.
Case Report: Breast cancer-associated paraneoplastic stiff person syndrome: anastrozole monotherapy insufficient for symptom improvement
Authors: Cordova Justin , Nelson Blessie , Brizendine Ashley , Pacheco David , Willis Maurice , Markowitz Avi
Published: May 2021

Stiff person syndrome (SPS) is a rare clinical disorder presenting with progressive muscle stiffness and painful spasms. Its ill-defined mechanism and variable presentation make diagnosis a challenge, though it is associated with a range of specific auto-antibodies. One particular antibody, anti-amphiphysin, is found in the presence of breast or lung malignancy and leads to a disorder termed paraneoplastic SPS (PSPS). Our patient, an 83-year-old woman, presented with bilateral leg weakness, spasms, and left clubfoot over a period of three months. She also reported a lump in her left breast for which she had not sought treatment over the past 10 years. Her ankle radiograph was negative for fractures and dislocations, while an MRI of the left leg was negative for plexopathies. Electromyography was suggestive of an SPS disorder and a positive anti-amphiphysin test indicated a diagnosis of PSPS. Her symptoms were managed with baclofen, diazepam, and five cycles of therapeutic plasma exchange (TPEX) over 10 days. Breast imaging revealed a 4.5-cm left breast lesion, later biopsy-confirmed as invasive ductal carcinoma (ER+, PR+, HER2−). The patient declined definitive surgical management, opting instead for once-daily anastrozole 1 mg as hormonal therapy. This regimen was not sufficient to lead to symptomatic improvement over a period of more than 30 days, and the patient expired less than 45 days after discharge. To our knowledge, this is the first case of PSPS to be treated in this manner. Our report illustrates that conservative management with anastrozole monotherapy was not sufficient to lead to symptomatic improvement in this form of paraneoplastic syndrome, suggesting the need for more aggressive pharmacological or definitive surgical intervention in order to produce symptom improvement and/or resolution.
COVID-19 lockdown and lifestyles: A narrative review
Authors: Doraiswamy Sathyanarayanan , Cheema Sohaila , Al Mulla Ahmad , Mamtani Ravinder
Published: May 2021

Background: The primary objective worldwide during the coronavirus disease 2019 (COVID-19) pandemic has been controlling disease transmission. However, lockdown measures used to mitigate transmission have affected human behavior and altered lifestyles, with a likely impact on chronic non-communicable diseases. More than a year into the pandemic, substantial peer-reviewed literature has emerged on altered lifestyles following the varying lockdown measures imposed globally to control the virus spread. We explored the impact of lockdown measures on six lifestyle factors, namely diet, physical activity, sleep, stress, social connectedness, and the use of tobacco, alcohol, or other harmful substances.

Methods: We comprehensively searched PubMed and the World Health Organization’s global literature database on COVID-19 and retrieved 649 relevant articles for the narrative review. A critical interpretative synthesis of the articles was performed.

Results: Most of the articles included in the review identified the negative effect of lockdown measures on each of the lifestyle factors in many parts of the world. Encouraging lifestyle trends were also highlighted in a few articles. Such trends can positively influence the outcome of lifestyle-related chronic diseases, such as obesity and diabetes.

Conclusions: The COVID-19 pandemic provides an opportunity to better understand the negative impact of strict lockdown measures on lifestyles. At the same time, it helps us identify and initiate positive behavioral changes, which, if consolidated, could improve chronic disease outcomes. It is up to governments, communities, and healthcare/academic entities to derive benefit from lessons learned from the pandemic, with the ultimate objective of better educating and promoting healthy lifestyles among communities.
Outcomes measures in current Danish pharmacoepidemiological research: a protocol for a systematic mapping review
Authors: Thor Petersen Charlotte , Jensen Kristoffer Jarlov , Rosenzweig Mary , Ankarfeldt Mikkel Zöllner , Kampen Gita , Petersen Janne
Published: May 2021

There is a growing interest in complementing the evidence on efficacy and safety of medicinal products gained by randomised clinical trials with real-world data and real-world evidence. Registries provide important sources of real-world data but are typically initiated for administrative purposes. The Danish national registries capture a wide range of information such as health care contacts, social, and economic data; and thereby offer unique possibilities for pharmacoepidemiological research. To gain insight into how registry-based outcome measures from mostly administrative databases are used in real-world evidence studies, the present literature review will investigate the current practice in registry-based studies using Danish health data. A systematic mapping review will be conducted using the literature databases PubMed®/MEDLINE and Scopus®. The search will include Danish registry-based studies aiming at evaluating the effectiveness or safety of medicinal products published from January 1st, 2018 to December 31st, 2019. Data extraction will include the Anatomical Therapeutic Chemical code level 2 of the medicinal product of interest, the outcome measures used, the registry of which the outcome measure has been obtained as well as how the quality of the outcome measure has been considered. The outcome measures extracted will be presented as a categorical overview. These categories will be associated with therapeutic exposure, registry of origin and refereed validation of the outcomes. This systematic mapping review will, as far as we know, be the first of its kind to map outcome measures from Danish national registries used for safety and efficacy studies.
Primary care-based models of care for osteoarthritis: a scoping review protocol
Authors: Cunningham Joice , Doyle Frank , Ryan Jennifer M. , Clyne Barbara , Cadogan Cathal , Cottrell Elizabeth , Smith Susan M. , French Helen P.
Published: May 2021

Background: The burden of osteoarthritis (OA) to individuals and health systems is substantial and is expected to increase due to population ageing and rising prevalence of obesity and multimorbidity. Primary care-based models of care (MoCs) are being increasingly developed in response to this growing burden. However, these MoCs have yet to be formally reviewed. A MoC can be defined as an ‘evidence-informed strategy, framework or pathway that outlines the optimal manner in which condition-specific care should be delivered to consumers within a local health system’.

Objective: To identify and describe the available research regarding the extent, nature and characteristics of MoCs for OA that have been developed or evaluated in primary care.

Methods: A scoping review will be conducted in accordance with the Arksey and O’Malley scoping review framework and the PRISMA-ScR guidelines. Systematic literature searches of MEDLINE, EMBASE, CINAHL, PsychINFO, Web of Science and LILACs will be conducted from 2010 to present, aligning with publication dates of recent clinical guidelines. A structured iterative search of grey literature will be conducted. Full-text original quantitative or mixed method studies which describe the development or evaluation of MoCs for OA in primary care will be considered. Data will be charted and synthesised and a narrative synthesis will be conducted.

Conclusions: This scoping review will provide a broad overview regarding the extent, nature and characteristics of the available literature on primary care based MoCs for OA. Findings will be used to identify gaps in the current evidence to identify areas for future research.