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Abstract Background We developed a Next‐Generation‐Sequencing (NGS) protocol to screen the most frequent genetic variants related to lymphedema and a group of candidate genes. The aim of the study was to find the genetic cause of lymphedema in the analyzed patients. Methods We sequenced a cohort of 246 Italian patients with lymphatic malformations. In the first step, we analyzed genes known to be linked to lymphedema: 235 out of 246 patients tested negative for the most frequent variants and underwent testing for variants in a group of candidate genes, including the NOTCH1 gene, selected from the database of mouse models. We also performed in silico analysis to observe molecular interactions between the wild‐type and the variant amino acids and other protein residues. Results Seven out of 235 probands, five with sporadic and two with familial lymphedema, were found to carry rare missense variants in the NOTCH1 gene. Conclusions Our results propose that NOTCH1 could be a novel candidate for genetic predisposition to lymphedema.

Abstract In 2017, after a yearlong study of the conditions on Rikers Island, the Independent Commission on New York City Criminal Justice and Incarceration Reform (the Lippman Commission) released its [...]

This study measures the availability of menthol cigarettes in Oakland, California where such products were banned from the majority of tobacco retailers, except for those who sold a significant amount of tobacco (e.g., 60% gross income). Out of a total of 385 retailers in Oakland, only forty-eight retailers were exempt from this ban at the time of data collection. In February 2019, seven months after the ban went into effect, we selected a stratified random sample of 15 census tracts, based on race/ethnicity. In pairs, data collectors walked on opposite sides of the street and collected all discarded cigarette packs (n = 641) from the streets and sidewalks on weekdays. Overall, we found almost half (46.0%; 95% CI = 32.6%–59.3%) of the packs collected were menthol, with Newport as the dominant brand. We found at least one pack of menthol cigarettes in 14 of the 15 sampled census tracts. In predominantly black/African American census tracts, the proportion of menthol cigarettes collected was significantly higher (70.1%; 95% CI = 62.6%–77.7%) when compared to mixed race/ethnicity (55.9%; 95% CI = 41.0–70.9%) and white tracts (35.1%; 95% CI = 13.2%–57.1%). Finally, there was a moderate and negative correlation between distance to exempt tobacco retailer and menthol availability (r = −0.66, p

Abstract Background The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas. Methods We used next‐generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Results Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants—p.(Leu590His) and p.(Gly106Asp)—indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema.

Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer’s disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably, APOE2 was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of APOE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

Summary: A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

Purpose Across the UK and USA, postpartum smoking relapse rates are high, and rates of breastfeeding and physical activity are low. This project aimed to explore these interrelated health behaviours and technology use, for intervention development to support postpartum cancer prevention. Methods Focus groups and interviews with 26 purposively selected women (15 in Vermont, USA and 11 in Norfolk, UK). Recruitment was from deprived areas experiencing multiple disadvantage. Qualitative data were thematically analysed from dual cultural perspectives, underpinned by the social ecological model. Results Women negotiate interrelated lifestyle behaviours as part of managing an identity in transition, moving through stages of disturbance, adaptation, acceptance and integration towards “becoming” a new Mother. Technology was integral to women’s process of engagement with mothering identities. Intersectionality underpins complex patterns of interrelated behaviour. Conclusions There is scope to improve electronic/digital support for postpartum women cross-nationally to promote interrelated cancer-preventative lifestyle behaviours. Abbreviations CDC: Center for Disease Control, US; PA: Physical activity; SES: Socioeconomic status; SVI: Social Vulnerability Index; UK: UK; US: USA; WIC: Women infants and children office.

Background. ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation. Objective. The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema. Methods and Results. We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins. Conclusions. Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema.

The APOE ε4 allele is a strong genetic risk factor for Alzheimer’s disease, whereas the APOE ε2 allele is protective. Here the authors show that mice expressing the human APOE ε2/ε2 genotype have increased tau pathology and related behavioral deficits; they also find that the APOE ε2 allele is associated with an increased burden of tau pathology in postmortem human brains with progressive supranuclear palsy.

Greta Lila,1,2 Gjyle Mulliqi,1,2 Lul Raka,1,2 Arsim Kurti,2 Rrezarta Bajrami,1,2 Elvir Azizi3 1Department of Microbiology,Faculty of Medicine University of Pristina, Pristina, Kosovo; 2Department of Microbiology, National Institute of Public Health of Kosovo, Pristina, Kosovo; 3Food science and Technology, Faculty of Agriculture and Veterinary, University of Pristina, Pristina, Kosovo Background: Pseudomonas aeruginosa is an important opportunistic pathogen. It is frequently resistant to many commonly used antibiotics and develops easily resistant forms. Colonization with this organism often precedes infection, and its prevention is, therefore, critical. There is no information on molecular epidemiological investigation of outbreaks caused by P. aeruginosa in Kosovo. Materials and methods: The present investigation was carried out to enlighten molecular epidemiology of P. aeruginosa in University Clinical Center of Kosovo (UCCK) using pulsed-field gel electrophoresis (PFGE). During our study period, 80 isolates of P. aeruginosa were included. The overall antimicrobial susceptibility pattern showed a high level of resistance against aminoglycosides and the lowest against carbapenems. Forty isolates of P. aeruginosa were subjected to genotyping, of whom 31 (77.5%) were male patients and nine (22.5%) were female patients. Results: The most common diagnosis upon admission was polytrauma, sepsis, and coma cerebri. Majority of the patients were in mechanical ventilation (76.2%). Bacterial isolates were most frequently recovered from respiratory tract specimens (60%) and wounds (22.5%). Majority of the samples were recovered from intensive care unit (ICU) (47.5%). The length of ICU stay was higher compared to patients from other units. Genotype analysis of P. aeruginosa isolates identified seven distinct PFGE patterns, with the predominance of PFGE clone A (40%) and PFGE clone N (12.5%). All of these isolates were indistinguishable. The appearance of the indistinguishable genotypes supports the possibility of a cross and horizontal transmission of P. aeruginosa due to insufficient preventive measures. Conclusion: The results emphasize the need for strict infection control measures to prevent the nosocomial transmission of P. aeruginosa in our hospital. Keywords: genotyping, P. aeruginosa, pulsed-field gel electrophoresis, nosocomial infection, ICU

Abstract Background Promoting cultural competence of health professionals working with Aboriginal and Torres Strait Islander communities is key to improving health outcomes. Cultural Educators and Cultural Mentors (CE/ CMs) have critical roles in Australian general practice training, yet these are not well understood. Methods Guided by a CE/CM Network, our research team including experienced CE/CMs, used surveys and semi-structured interviews to explore these roles and investigate best practice in employment and support. Participants sampled from stakeholders involved in general practice education across Australia included CE/CMs, Medical Educators, General Practice Supervisors and Registrars, and representatives of Regional Training Organisations, Indigenous Health Training Posts and other key organisations. We undertook thematic analysis using a framework approach, refined further in team discussions that privileged views of CE/ CM members. Results Participants comprised 95 interviewees and 55 survey respondents. We organised our findings under three overarching themes: understandings about cultural education and mentoring; employment and support of CE/CMs; and delivery and evaluation of cultural education and mentoring. Our findings supported a central role for Aboriginal and Torres Strait Islander CE/CMs in face-to-face Registrar education about culture and history and related impacts on health and healthcare. Cultural education was reported to provide base-line learning as preparation for clinical practice whilst cultural mentoring was seen as longitudinal, relationship-based learning. Mentoring was particularly valued by Registrars working in Aboriginal and Torres Strait Islander communities. Challenges described with employment and support included difficulties in finding people with skills and authority to undertake this demanding work. Remuneration was problematic, particularly for CMs whose work-time is difficult to quantify, and who are often employed in other roles and sometimes not paid. Other improved support recommended included appropriate employment terms and conditions, flexibility in role definitions, and professional development. Recommendations concerning implementation and evaluation included valuing of cultural education, greater provision of mentoring, partnerships with Medical Educators, and engagement of CE/CMs in rigorous evaluation and assessment processes. Conclusions Our research highlights the importance of the unique CE/CM roles and describes challenges in sustaining them. Professional and organisational support is needed to ensure delivery of respectful and effective cultural education within general practitioner training.

Abstract Loss-of-function mutations in progranulin (GRN) and a non-coding (GGGGCC)n hexanucleotide repeat expansions in C9ORF72 are the two most common genetic causes of frontotemporal lobar degeneration with aggregates of TAR DNA binding protein 43 (FTLD-TDP). TMEM106B encodes a type II transmembrane protein with unknown function. Genetic variants in TMEM106B associated with reduced TMEM106B levels have been identified as disease modifiers in individuals with GRN mutations and C9ORF72 expansions. Recently, loss of Tmem106b has been reported to protect the FTLD-like phenotypes in Grn−/− mice. Here, we generated Tmem106b−/− mice and examined whether loss of Tmem106b could rescue FTLD-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity. Our results showed that neither partial nor complete loss of Tmem106b was able to rescue behavioral deficits induced by the expression of (GGGGCC)66 repeats (66R). Loss of Tmem106b also failed to ameliorate 66R-induced RNA foci, dipeptide repeat protein formation and pTDP-43 pathological burden. We further found that complete loss of Tmem106b increased astrogliosis, even in the absence of 66R, and failed to rescue 66R-induced neuronal cell loss, whereas partial loss of Tmem106b significantly rescued the neuronal cell loss but not neuroinflammation induced by 66R. Finally, we showed that overexpression of 66R did not alter expression of Tmem106b and other lysosomal genes in vivo, and subsequent analyses in vitro found that transiently knocking down C9ORF72, but not overexpression of 66R, significantly increased TMEM106B and other lysosomal proteins. In summary, reducing Tmem106b levels failed to rescue FTLD-like phenotypes in a mouse model mimicking the toxic gain-of-functions associated with overexpression of 66R. Combined with the observation that loss of C9ORF72 and not 66R overexpression was associated with increased levels of TMEM106B, this work suggests that the protective TMEM106B haplotype may exert its effect in expansion carriers by counteracting lysosomal dysfunction resulting from a loss of C9ORF72.

Abstract Background Accelerated treatment strategy, including tight disease control and early aggressive therapy with immunosuppressives (IS) and biological agents have become increasingly common in inflammatory bowel disease (IBD). The aim of the present study was to estimate the early treatment strategy and outcomes in newly diagnosed patients with Crohn’s disease (CD) between 2004 and 2008 and 2009–2015 in the whole IBD population in Hungary based on the administrative database of the National Health Insurance Fund (OEP). Methods We used the administrative database of the OEP, the only nationwide state-owned health insurance provider in Hungary. Patients were identified through previously reported algorithms using the ICD-10 codes for CD in the out-, inpatient (medical, surgical) non-primary care records and drug prescription databases between 2004 and 2015. Patients were stratified according to the year of diagnosis and maximum treatment steps during the first 3 years after diagnosis. Results A total of 6173 (male/female: 46.12%/53.87%) newly diagnosed CD patients with physician-diagnosed IBD were found in the period of 2004–2015. The use of 5-ASA and steroids remained common in the biological era, while immunosuppressives and biologicals were started earlier and became more frequent among patients diagnosed after 2009. The probability of biological therapy was 2.9%/6.4% and 8.4%/13.7% after 1 and 3 years in patients diagnosed in 2004–2008/2009–2015. The probability of hospitalization in the first 3 years after diagnosis was different before and after 2009, according to the maximal treatment step (overall 55.7%vs. 47.4% (p = 0.001), anti-TNF: 73%vs. 66.7% (p = 0.103), IS: 64.6% vs. 56.1% (p = 0.001), steroid: 44.2%vs. 36.8% (p

Background: Despite control program for Mycobacterium tuberculosis (MTB) and anti-tuberculosis (TB) drugs, MTB continues to be a major threat to global health; furthermore, it is the second leading cause of death worldwide. The distribution of TB in Kosovo has the highest rate in Europe. This study was designed to assess the performance of single-sputum GeneXpert MTB/ rifampicin (RIF) assay against the Ziehl-Neelsen smear, solid culture in diagnosing suspected pulmonary cases, and RIF resistance. Methods: A cross-sectional study was conducted to examine various diagnostic methods between 2014 and 2016 in the Department of Microbiology, the National Institute of Public Health, Kosovo, and the Lung Clinic. The present study compares diagnostic methods of MTBC and RIF resistance using Xpert MTB/RIF test in 813 samples from 760 patients suspected of TB by conventional smear microscopy and culture method. Results: Three hundred and ninety-six patients (52.1%) were male and the mean age was 48.6 ± 18.1 years. A total of 261 patients (32.6%) had underlying lung diseases. Of the 801 specimens investigated, 165 (20.5%) were MTBC-positive by culture, while 199 (28.3%) were positive by Xpert assay. Among the examined specimens, Two specimens with false negatives were shown in the Xpert method. Compared with culture, the Xpert assay achieved 82.3% (95% confidence interval [CI]: 65.5%–93.2%) sensitivity and 97.6% (95% CI: 91.5%–99.7%) specificity. GeneXpert could detect 11.7% and 50% additional positive cases as compared to Lowenstein–Jensen culture and smear microscopy, respectively. Three cases with resistance to RIF were detected from clinical isolates. Conclusions: According to the results obtained in this study, GeneXpert MTB/RIF assay can be used as a useful tool for rapid and efficient diagnosis of TB.

Background: Drug-resistant tuberculosis (TB) continues to threaten TB control and remains a major global public health concern. The poor patient adherence in TB treatment is the cornerstone of emerging multidrug-resistant TB (MDR-TB). The aim of this study was to evaluate the resistance of Mycobacterium tuberculosis to the first-line TB drugs among isolates from clinical specimens. Methods: A laboratory-based study was conducted in the Department of Microbiology, within the National Institute of Public Health of Kosovo, from January 2017 to September 2018. Sputum and other clinical specimens were obtained from patients with pulmonary and extrapulmonary TB. The specimens were stained with Ziehl–Neelsen, inoculated on Löwenstein–Jensen media for 6–8 weeks, and tested for sensitivity against the first-line TB drugs (isoniazid [INH], rifampicin [RIF], ethambutol [EMB], and streptomycin [SM]). Results: Of the 316 M. tuberculosis isolates collected, 31.6% showed resistance to first-line TB drugs. Among these resistant isolates, 31% showed resistance to at least one of the first-line TB drugs and 0.3% showed MDR. Resistance to EMB, INH, RIF, and SM was seen in 17%, 8%, 3%, and 72% of isolates, respectively. Polyresistance was seen in 3% of the isolates. Conclusion: Our study confirms that resistance to streptomycin was the most common phenomenon. The resistance pattern identified in this study could assist clinicians in providing appropriate treatment regimen to TB patients and improve their clinical outcome.

The current business environment demands the enablement of organization-wide use of analytics to support a fact-based decision making. Such movement within the organization require employees to take advantage of the self-service business analytics tools to independently fulfil their needs. However, assuming independence in data analytics requires employees to make sense of several elements which collectively contribute to the generation of required insights. Building on sense-making, self-service business analytics, and institutions literature, this paper explores the relationship between sense-making and self-service business analytics and how institutions influence and shape such relationship. By adopting a qualitative perspective and using 22 interviews, we have empirically investigated a model developed through our literature review and provided more understanding of the sense-making concept in a self-service business analytics context.

Digital business model innovation is discussed by bringing together systemic innovation and digital innovation. Applying the Rich Picture technique, the complexity transpiring in the digital innovation of the business models is illustrated. Further, a real world example is presented and discussed in relation to systemic innovation and digital innovation. This study further contributes by shedding light on the added complexity brought by digital innovation but also the need for a combined and mixed systems thinking approach.