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Abstract Background Few implementation science (IS) measures have been evaluated for validity, reliability and utility – the latter referring to whether a measure captures meaningful aspects of implementation contexts. We present a real-world case study of rigorous measure development in IS that assesses Barriers and Facilitators in Implementation of Task-Sharing in Mental Health services (BeFITS-MH), with the objective of offering lessons-learned and a framework to enhance measurement utility. Methods We summarize conceptual and empirical work that informed the development of the BeFITS-MH measure, including a description of the Delphi process, detailed translation and local adaptation procedures, and concurrent pilot testing. As validity and reliability are key aspects of measure development, we also report on our process of assessing the measure’s construct validity and utility for the implementation outcomes of acceptability, appropriateness, and feasibility. Results Continuous stakeholder involvement and concurrent pilot testing resulted in several adaptations of the BeFITS-MH measure’s structure, scaling, and format to enhance contextual relevance and utility. Adaptations of broad terms such as “program,” “provider type,” and “type of service” were necessary due to the heterogeneous nature of interventions, type of task-sharing providers employed, and clients served across the three global sites. Item selection benefited from the iterative process, enabling identification of relevance of key aspects of identified barriers and facilitators, and what aspects were common across sites. Program implementers’ conceptions of utility regarding the measure’s acceptability, appropriateness, and feasibility clustered across several common categories. Conclusions This case study provides a rigorous, multi-step process for developing a pragmatic IS measure. The process and lessons learned will aid in the teaching, practice and research of IS measurement development. The importance of including experiences and knowledge from different types of stakeholders in different global settings was reinforced and resulted in a more globally useful measure while allowing for locally-relevant adaptation. To increase the relevance of the measure it is important to target actionable domains that predict markers of utility (e.g., successful uptake) per program implementers’ preferences. With this case study, we provide a detailed roadmap for others seeking to develop and validate IS measures that maximize local utility and impact.

Recent advances in the use of nano- and microparticles in drug delivery, cell therapy, and tissue engineering have led to increasing attention towards nanostructured microparticulate formulations for maximum benefit from both nano- and micron sized features. Scalable manufacturing of monodisperse nanostructured microparticles with tunable size, shape, content, and release rate remains a big challenge. Current technology, mainly comprises complex multi-step chemical procedures with limited control over these aspects. Here, we demonstrate a novel technique for high-yield fabrication of monodisperse monolayer and multilayer nanofibrous microparticles (MoNami and MuNaMi respectively). The fabrication procedure includes sequential electrospinning followed by micro-cutting at room temperature and transfer of particles for collection. The big advantage of the introduced technique is the potential to apply several polymer-drug combinations forming multilayer microparticles enjoying extracellular matrix (ECM)-mimicking architecture with tunable release profile. We demonstrate the fabrication and study the factors affecting the final three-dimensional structure. A model drug is encapsulated into a three-layer sheet (PLGA-pullulan-PLGA), and we demonstrate how the release profile changes from burst to sustain by simply cutting particles out of the electrospun sheet. We believe our fabrication method offers a unique and facile platform for realizing advanced microparticles for oral drug delivery applications.

Hydrogel based carriers have been predominantly investigated to combat the prominent challenges faced by oral biomacromolecule delivery. Several micromolding, microfluidic and photolithographic techniques have been described for the fabrication of non-spherical hydrogel based microcarriers. However, these techniques are unsuitable for loading biomacromolecules as integral part of the fabrication process due to the use of high temperatures, solvents and multiple processing steps. Here, we introduce UV-assisted punching as a novel two-step fabrication technique for the development of biocompatible microgel shapes for oral drug administration. Poly-ethylene glycol (PEG) microgel shapes with lateral dimensions of 25–100 μm and a height of 25 μm were fabricated on a flexible poly vinyl alcohol (PVA) substrate with a robust cycloolefin polymer (COP) stamp. The proposed process uses UV-initiated crosslinking of aqueous solutions at ambient temperatures, thereby providing a highly attractive method for the fabrication of biomacromolecule loaded hydrogel based carriers. For the proof-of-concept, the microgel shapes were loaded with the fluorescently labelled model biomacromolecule bovine serum albumin without any additional steps. The successful loading is demonstrated by fluorescence microscopy. In vitro studies are performed to quantify the macromolecular content and the release profile associated with the fabricated microgel shapes.

Background: Cutaneous adverse drug reactions (cADRs) constitute a significant cause of mortality and morbidity, adding to the economic burden for the patients. cADRs have varied and diverse presentations of morphology and severity. The present study aimed to explore the spectrum of cADRs reported in a tertiary care setup in Eastern India. Methods: A cross-sectional, single-center-based observational study was undertaken which included all the patients reporting with suspected cADRs. The patient details, ADR characteristics, and other relevant details were noted. Detailed pharmacovigilance workup, including causality, severity, and preventability assessment, was performed. Data were statistically analyzed. Results: 0.16% incidence of cADRs was observed, with the most common form being urticaria, followed by fixed drug eruption, maculopapular rash, and erythroderma. The most common drug class suspected to cause cADR was antimicrobials, followed by corticosteroids and nonsteroidal anti-inflammatory drugs. While most reactions were of moderate grade in severity, majority of the reactions were under “possible” causal category. 22.1% of the reported cADRs were not preventable. Conclusion: Proper diagnosis and optimum management of cutaneous ADRs are critically challenging and important.

As a non-narcotic antitussive, benzonatate has been effective in symptomatic relief of dry cough. Cough following recovery from acute COVID-19 has widely been treated with over-the-counter cough suppressants like benzonatate, guaifenesin, dextromethorphan etc. However, despite being an effective non-narcotic cough suppressant modality, benzonatate has been constrained by its poor safety profile. The present case series describes a very rare side effect of neck stiffness reported in patients who were prescribed benzonatate for dry cough suppression post COVID 19. Keywords: Benzonatate, Neck stiffness, Post-COVID complications, Cough

Abstract Background Research on the role of variations in the mitochondrial genome in pathogenesis of acute lymphoblastic leukemia (ALL) has been unfolding at a rapid rate. Our laboratory has previously described higher number of copies of the mitochondrial genomes per cell in pediatric ALL patients as compared to the healthy controls. In the current study, we evaluated the pattern of mitochondrial genome variations in 20 de-novo pediatric B-ALL cases and seven controls. Quantitative real-time Polymerase Chain Reaction was used for estimation of mitochondrial genomes’ copy number in bone marrow samples of each ALL patient and peripheral blood samples of controls. The complete mitochondrial genomes of all samples were sequenced using the Illumina platform. Results Sequencing data analysis using multiple mitochondrial genome databases revealed 325 variants in all 27 samples, out of which 221 variants were previously known while 104 were unassigned, new variants. The 325 variants consisted of 7 loss-of-function variants, 131 synonymous variants, 75 missense variants, and 112 non-coding variants. New, missense variants (n = 21) were identified in genes encoding the electron transport chain complexes with most of them encoding ND4, ND5 of complex I. Missense and loss-of-function variants were found to be deleterious by many predictor databases of pathogenicity. MuTect2 identified true somatic variants present only in tumors between patient-sibling pairs and showed overlap with missense and loss-of-function variants. Online MtDNA-server showed heteroplasmic and homoplasmic variants in mitochondrial genome. Conclusions The data suggest that some of these variations might have a deleterious impact on the expression of mitochondrial encoded genes with a possible functional relevance in leukemia.

Abstract Background There are increasing efforts for the integration of mental health services into primary care settings in low- and middle-income countries. However, commonly used approaches to train primary care providers (PCPs) may not achieve the expected outcomes for improved service delivery, as evidenced by low detection rates of mental illnesses after training. One contributor to this shortcoming is the stigma among PCPs. Implementation strategies for training PCPs that reduce stigma have the potential to improve the quality of services. Design In Nepal, a type 3 hybrid implementation-effectiveness cluster randomized controlled trial will evaluate the implementation-as-usual training for PCPs compared to an alternative implementation strategy to train PCPs, entitled Reducing Stigma among Healthcare Providers (RESHAPE). In implementation-as-usual, PCPs are trained on the World Health Organization Mental Health Gap Action Program Intervention Guide (mhGAP-IG) with trainings conducted by mental health specialists. In RESHAPE, mhGAP-IG training includes the added component of facilitation by people with lived experience of mental illness (PWLE) and their caregivers using PhotoVoice, as well as aspirational figures. The duration of PCP training is the same in both arms. Co-primary outcomes of the study are stigma among PCPs, as measured with the Social Distance Scale at 6 months post-training, and reach, a domain from the RE-AIM implementation science framework. Reach is operationalized as the accuracy of detection of mental illness in primary care facilities and will be determined by psychiatrists at 3 months after PCPs diagnose the patients. Stigma will be evaluated as a mediator of reach. Cost-effectiveness and other RE-AIM outcomes will be assessed. Twenty-four municipalities, the unit of clustering, will be randomized to either mhGAP-IG implementation-as-usual or RESHAPE arms, with approximately 76 health facilities and 216 PCPs divided equally between arms. An estimated 1100 patients will be enrolled for the evaluation of accurate diagnosis of depression, generalized anxiety disorder, psychosis, or alcohol use disorder. Masking will include PCPs, patients, and psychiatrists. Discussion This study will advance the knowledge of stigma reduction for training PCPs in partnership with PWLE. This collaborative approach to training has the potential to improve diagnostic competencies. If successful, this implementation strategy could be scaled up throughout low-resource settings to reduce the global treatment gap for mental illness. Trial registration ClinicalTrials.gov, NCT04282915 . Date of registration: February 25, 2020.

Abstract We explored the link between mitochondrial biogenesis and mitochondrial morphology using transmission electron microscopy (TEM) in lymphoblasts of pediatric acute lymphoblastic leukemia (ALL) patients and compared these characteristics between tumors and control samples. Gene expression of mitochondrial biogenesis markers was analysed in 23 ALL patients and 18 controls and TEM for morphology analysis was done in 15 ALL patients and 9 healthy controls. The area occupied by mitochondria per cell and the cristae cross-sectional area was observed to be significantly higher in patients than in controls (p-value = 0.0468 and p-value

Abstract Background Diabetes mellitus is a lingering hyperglycemic ailment resulting in several life-threatening difficulties. Enduring hyperglycemia often persuades the buildup of reactive oxygen species that are the significant pathological makers of diabetic complications. The mitochondrial dysfunction, with mitochondrial damage and too much production of reactive oxygen species, have been proposed to be convoluted in the progress of insulin resistance. Numerous studies advocate that agents that enhance the mitochondrial number and/or decrease their dysfunction, could be greatly helpful in management of diabetes and its complications. Main body Mitochondrial biogenesis is an extremely delimited procedure arbitrated by numerous transcription influences, in which mitochondrial fusion and fission happen in synchronization in a standard vigorous cell. But this synchronization is greatly disturbed in diabetic condition designated by modification in the working of several important transcription factors regulating the expressions of different genes. Numerous preclinical and clinical investigations have suggested that, the compromised functions of mitochondria play a significant protagonist in development of pancreatic β-cell dysfunction, skeletal muscle insulin resistance and several diabetic complications. However, there are several phytoconstituents performing through numerous alleyways, either unswervingly by motivating biogenesis or indirectly by constraining or averting dysfunction and producing a beneficial effect on overall function of the mitochondria. Conclusion This review describes standard mitochondrial physiology and anomalous modifications that transpire in answer to persistent hyperglycemia in diabetes condition. It also discusses about the different phytoconstituents that can affect the biogenesis pathways of mitochondria and thus can be used in the treatment and prevention of diabetes.

Background Prior research has indicated that posttraumatic growth (PTG) often co-occurs with symptoms of posttraumatic stress disorder (PTSD). However, it is yet unclear what longitudinal patterns of posttraumatic symptom levels may predict the development of PTG. Methods World Trade Center (WTC) rescue and recovery workers (2038 police and 2103 non-traditional responders) were assessed an average of 3, 6, 8, and 12 years post-9/11/2001. Responders’ WTC-related PTSD symptoms were characterized by No/Low Symptom, Worsening/Subtly Worsening, Steeply Worsening (only for non-traditional responders), Improving, and Chronic trajectories. PTSD symptom trajectories were examined as predictors of PTG, which was assessed using total scores on the Posttraumatic Growth Inventory-Short Form. Results Across both occupational groups, being female, older, Hispanic, and experiencing more post-9/11 traumatic events were independently associated with self-reported PTG. Among police responders, a greater number of WTC exposures and supportive family members while working at the WTC site were linked to higher PTG. Among non-traditional responders, Black race/ethnicity, less education, fewer pre-9/11 traumatic events, and the presence of support while working at the WTC site were additionally linked to higher PTG. Only the moderate PTSD symptom trajectories (ie, worsening and improving) for police responders and all symptomatic trajectories for non-traditional responders were associated with higher levels of PTG. Conclusions Symptomatic 12-year trajectories of PTSD symptoms and certain sociodemographic characteristics, stressor exposures, and supportive resources were associated with PTG in traditional and non-traditional WTC responders. Results provide insight into subgroups of WTC responders who may benefit from PTG-promoting interventions, as well as potentially modifiable targets to help foster PTG in this population.

Saccharomyces cerevisiae Vac8 is a vacuolar membrane protein, which functions in vacuole inheritance and fusion, nucleus-vacuole junctions, autophagy and the cytoplasm-to-vacuole-targeting pathway. Here, we analyzed Vac8 of the yeast Hansenula polymorpha . We show that Hp Vac8 localizes to the vacuolar membrane and concentrates in patches at nucleus-vacuole junctions. Analysis of a VAC8 deletion strain indicated that Hp Vac8 is required for vacuole inheritance and the formation of nuclear-vacuole junctions, but not for vacuole fusion. Previously, organelle proteomics resulted in the identification of Vac8 in peroxisomal fractions isolated from H. polymorpha and S. cerevisiae . However, deletion of H. polymorpha VAC8 had no effect on peroxisome biogenesis or peroxisome-vacuole contact sites.

Background: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy and in many centers, it is still a part of the diagnostic armamentarium. In this study, the histopathological spectrum of the nerve biopsies received is being revisited to analyze the various clinical and pathologic features and also to assess their relevance. Materials and Methods: Retrospective analysis of the data retrieved was done for 74 cases of nerve biopsies. Results: On the basis of the data and histopathological features, broad diagnoses were obtained in 52 cases and further categorized into biopsies being supportive for patient management (including acute and chronic axonopathies and demyelinating neuropathies) and biopsies considered essential for patient management (including vasculitic neuropathies, leprous neuropathies, hereditary neuropathies, and chronic inflammatory demyelinating neuropathies). Nine nerve biopsies did not show any abnormal histopathological features, while 13 nerve biopsies were found to be inadequate for diagnosis, both these groups were categorized as noncontributory. Conclusion: With advanced nerve conduction studies available, nerve biopsy is losing its relevance. However, in our experience, nerve biopsy did complement the clinical findings and nerve conduction studies, with which a close correlation is required to make the histopathology of nerve biopsy more relevant in terms of guiding further specific workup and management.

Background and Aim: Microvascular patterns (MVPs) and microvessel density (MVD) can influence the progression of glioblastomas. This study aims to study MVP and MVD using immunohistochemistry, and examine any correlation with the expression of matrix metalloproteinase-9 (MMP-9), p53, glial fibrillary acidic protein (GFAP), and Ki-67 labeling index (Ki-67 LI) in 24 cases of glioblastoma multiforme. Materials and Methods: MVPs and MVD were studied by a dual staining method using periodic acid–Schiff stain with CD34 (MVDCD34), CD31 (MVDCD31), von Willebrand factor (MVDvWF), and factor VIII (MVDFVIII). The expression of MMP-9, p53, GFAP, and Ki-67 LI was analyzed using immunohistochemistry. The Pearson coefficient of correlation and intraclass correlation were obtained using SPSS software. Results: Five distinct categories of MVP were found: Microvascular sprouting (MS)/simple vessels, vascular clusters (VCs), vascular garlands, glomeruloid tufts, and vasculogenic mimicry. Of the MVPs, MS was the most common pattern and was present in all cases. On calculating the Pearson's correlation coefficient, different MVPs gave varying results regarding their correlation with MMP-9, p53, GFAP, and Ki-67 LI. MSCD34, CD31, vWF showed significant correlation with MMP-9 and Ki-67 LI, while MSFVIII did not show any correlation with Ki-67 LI. Only VCCD34 had a correlation with Ki-67 LI. No correlation between any of the MVPs and GFAP and p53 was appreciated. MVD ranged from: CD34 (9.2–41.9/hpf), FVIII (6.05–40.5/hpf), CD31 (5.1–40.7/hpf), and vWF (8.7–35.5/hpf). MVDCD34 and MVDCD31 correlated with MMP-9 and Ki-67, whereas, MVDvWF and MVD FVIII correlated with MMP-9. Interobserver agreement was seen only in the assessment of MVD and the MS type of MVP. Conclusion: MVD and MVPs had correlation with MMP-9, p53, GFAP, and Ki-67. These results could impact the development of strategies using antiangiogenic therapies.

Microparticles are ubiquitous in applications ranging from electronics and drug delivery to cosmetics and food. Conventionally, non-spherical microparticles in various materials with specific shapes, sizes, and physicochemical properties have been fabricated using cleanroom-free lithography techniques such as soft lithography and its high-resolution version particle replication in non-wetting template (PRINT). These methods process the particle material in its liquid/semi-liquid state by deformable molds, limiting the materials from which the particles and the molds can be fabricated. In this study, the microparticle material is exploited as a sheet placed on a deformable substrate, punched by a robust mold. Drawing inspiration from the macro-manufacturing technique of punching metallic sheets, Micromechanical Punching (MMP) is a high-throughput technique for fabrication of non-spherical microparticles. MMP allows production of microparticles from prepatterned, porous, and fibrous films, constituting thermoplastics and thermosetting polymers. As an illustration of application of MMP in drug delivery, flat, microdisk-shaped Furosemide embedded poly(lactic-co-glycolic acid) microparticles are fabricated and Furosemide release is observed. Thus, it is shown in the paper that Micromechanical punching has potential to make micro/nanofabrication more accessible to the research and industrial communities active in applications that require engineered particles.

Microcontainers are reservoir-based advanced drug delivery systems (DDS) that have proven to increase the bioavailibity of the small-molecule drugs, targeting of biomolecules, protection of vaccines and improved treatment of Pseudomonas aeruginosa. However, high-throughput loading of these micron-sized devices with drug has been challenging. Hot punching is a new technique that is a fast, simple and single-step process where the microdevices are themselves used as mold to punch biocompatible and biodegradable drug-polymer films, thereby loading the containers. Here, we investigate the effect of hot punching on the drug distribution as well as drug release from the loaded drug-polymer matrices. Zero-order sustained drug release is observed for the model drug Furosemide embedded in biodegradable polymer, Poly-ε-caprolactone, which is attributed to the unique spatial distribution of Furosemide during the loading process.

This paper examines how short-short stories published on social media platforms such asFacebook and Twitter experiment with brevity. It examines the use of devices such as planned spaces between words, colors, and enjambments, a genre called twitter fiction, to deliver the literary after-taste of ‘byte-sized’ fiction. What are the ramifications, requirements, and results of this form of brevity? Since the works are written and published on/for the digital media, what other aids supplement the reading process, if any? What forms of innovation does this conciseness allow? Two platforms of reading and writing short-short stories (of 140 characters or less) will be used to examine these questions: Terribly Tiny Tales on Facebook and Very Short Story (@veryshortstory)on Twitter. Keywords: digital humanities, twitter fiction, brevity, short story, technology, social mediaThe six-word story by Ernest Hemingway, written in the 1920s, can be seen as an exemplary precursor to the recent burgeoning of short-short stories on Twitter and Facebook. To clearly define the term in the context of length is a complicated process as not only do short-short stories have different names, there is no fixity in terms of how short they must be or which style or form they deal with – ranging from myths and fables to serialized novels. However, works that are strictly 140 characters or less come under the subset of short-short stories and are popularly known as ‘140 stories,’ ‘short-shorts,’ and ‘very short stories.’ These are mostly published on social platforms like Twitter, Facebook, Tumblr and personal blogs to allow immediacy in writing, self-publishing, and reaching out to an audience. Restricting the work to this minimum character limit allows the writer to publish the work across different social platforms.Therefore, the underlining requirement of this form of literature is that it must be brief. This becomes the first and the most important prerequisite for the genre.

Microfabricated devices have been introduced as a promising approach to overcome some of the challenges related to oral administration of drugs and, thereby, improve their oral bioavailability. In this study, we fabricate biodegradable microcontainers with different polymers, namely poly-ɛ-caprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA) 50:50 and PLGA 75:25 by hot punching. The mucoadhesion of the microcontainers is assessed with an ex vivo retention model on porcine intestinal tissue. Finally, in vitro degradation studies of the biodegradable microcontainers are completed for six weeks in simulated intestinal medium with the addition of pancreatic enzymes. Through SEM inspection, the PLGA 50:50 microcontainers show the first signs of degradation already after two weeks and complete degradation within four weeks, while the other polymers slowly degrade in the medium over several weeks.