Lack of ApoE inhibits ADan amyloidosis in a mouse model of familial Danish dementia.

The Apolipoprotein E-ε4 allele (APOE-ε4) is the strongest genetic risk factor for late onset Alzheimer disease (AD). ApoE plays a critical role in amyloid-ß (Aß) accumulation in AD, and genetic deletion of the murine ApoE gene in mouse models results in a decrease or inhibition of Aß deposition. The association between the presence of ApoE and amyloid in amyloidoses suggests a more general role for ApoE in the fibrillogenesis process. However, whether decreasing levels of ApoE would attenuate amyloid pathology in different amyloidoses has not been directly addressed. Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease characterized by the presence of widespread parenchymal and vascular Danish amyloid (ADan) deposition and neurofibrillary tangles. A transgenic mouse model for FDD (Tg-FDD) is characterized by parenchymal and vascular ADan deposition. To determine the effect of decreasing ApoE levels on ADan accumulation in vivo, we generated a mouse model by crossing Tg-FDD mice with ApoE KO mice (Tg-FDD+/-/ApoE-/-). Lack of ApoE results in inhibition of ADan deposition up to 18 months of age. Additionally, our results from a genetic screen of Tg-FDD+/-/ApoE-/- mice emphasize the significant role for ApoE in neurodegeneration in FDD via glial-mediated mechanisms. Taken together, our findings suggest that the interaction between ApoE and ADan plays a key role in FDD pathogenesis, in addition to the known role for ApoE in amyloid plaque formation in AD.

Tobramycin Systemic Absorption in Lung Transplant Recipients Treated With Inhaled Tobramycin: A Cohort Study.

Inhaled tobramycin treatment has been associated with nephrotoxicity in some case reports, but limited data are available about serum levels and its possible systemic absorption in lung transplant recipients (LTR). We conducted a single-center, observational and retrospective study of all adult (>18 years old) LTR treated with inhaled tobramycin for at least 3 days between June 2019 and February 2022. Trough serum levels were collected and >2 µg/mL was considered a high drug level. The primary outcome assessed the presence of detectable trough levels, while the secondary outcome focused on the occurrence of acute kidney injury (AKI) in individuals with detectable trough levels. Thirty-four patients, with a median age of 60 years, were enrolled. The primary indications for treatment were donor bronchial aspirate bacterial isolation (18 patients) and tracheobronchitis (15 patients). In total, 28 patients (82%) exhibited detectable serum levels, with 9 (26%) presenting high levels (>2 µg/mL). Furthermore, 9 patients (26%) developed acute kidney injury during the treatment course. Median trough tobramycin levels were significantly elevated in invasively mechanically ventilated patients compared to non-ventilated individuals (2.5 µg/mL vs. 0.48 µg/mL) (p < 0.001). Inhaled tobramycin administration in LTRs, particularly in those requiring invasive mechanical ventilation, may result in substantial systemic absorption.

Curricular and pedagogical approaches for physical activity prescription training: a mixed-methods study of the "Exercise is Medicine" workshops in Colombia.

BACKGROUND: The physical activity (PA) prescription workshop for physicians, through the global health initiative "Exercise is Medicine" (EIM), has trained more than 4000 health care professionals (HCPs) in Latin America. It has shown to be effective in increasing PA prescription knowledge and awareness among HCPs. The purpose of this paper is to evaluate the curricular and pedagogical approach used by EIM Colombia at the PA prescription workshops implemented between 2014 and 2015. METHODS: A mixed methods study, with a sequential explanatory design was implemented among a convenience sample of HCPs attending twenty-six PA prescription workshops. HCPs health status, PA personal habits, and medical practices were collected using a questionnaire at baseline among 795 participants (pre-test measurement), and subsequently quantitatively analyzed. A workshop satisfaction survey was administered after the completion of the workshop among 602 HCPs. The curricular and pedagogical approach of the workshop, the designers' and students' contextual factors, and perceptions about the workshop were measured using qualitative methods (analysis of the procedures manual, two workshop observations, three semi-structured interviews, and one focus group including 8 HCPs). RESULTS: The workshop is student-centered and guided by an expert with an academic and clinical background. Learning was achieved with theoretical and practical components using authentic performance and collaborative learning. An active teaching and learning approach was used with strategies such as interactive lectures, hands-on elements, and role-playing (patient-counselor). The workshop emphasized an individual approach when prescribing PA integrating in clinical practice not only health benefits but also patient´s beliefs, motivations, needs, and barriers. CONCLUSIONS: Evidence-based practices and authentic performance were the most salient pedagogical elements used by EIM Colombia at the PA prescription workshop. A knowledge assessment that includes the practical aspect is suggested for future workshops. The curricular and pedagogical approach of the PA prescription workshop implemented in Colombia is well received by the medical community and a useful continuing medical education intervention with a potential contribution to current, and future health promotion needs.

Isavuconazole use and TDM in real-world pediatric practice.

Isavuconazole (ISA) is approved for treating invasive aspergillosis and mucormycosis in adults, but its use in children remains off-label. We report on the use of ISA in real-world pediatric practice with 15 patients receiving ISA for treatment of invasive fungal infections. Therapeutic drug monitoring (TDM) was performed in all patients, with 52/111 (46.8%) Ctrough determinations out of range, thus supporting the need for TDM in children, especially those receiving extracorporeal membrane oxygenation (ECMO).

Psychometric analysis of the cross-cultural Spanish version of the diabetes management questionnaire.

Evaluation of the degree of adherence to self-care among Spanish type 1 diabetes (T1DM) pediatric population lacks of a validated tool. PURPOSE: To cross-culturally adapt and determine the psychometric properties of the Spanish version of the Diabetes Management Questionnaire to assess the degree of adherence to self-care among children with T1DM. METHODS: Translation, back-translation, and patient suggestions, were considered to obtain the Spanish version (DMQ-Sp). A cross-sectional study was conducted with 323 children (aged 8-18 years) with T1DM and their parents to determine internal reliability, structural validity, and external validity. Responsiveness to change was analyzed through a prospective longitudinal study involving 102 newly diagnosed T1DM patients. Psychometrics were evaluated for the entire sample and stratified by age (8-12 and 13-18 years). RESULTS: A total of 323 children with T1DM [49.8% female; age 13.3 ± 2.8 years; 155 aged 8-12; glycated hemoglobin (HbA1c) value 7.7 ± 1.0%] answered the Spanish final version. The internal consistency Cronbach's alpha was 0.76 and intraclass correlation coefficient 0.84. Test-retest reliability was r = 0.84 (p < 0.001). Fit index of structural validity was >0.7. External validity correlated inversely with HbA1c (r = -0.39; p < 0.001). The DMQ-Sp score increased significantly after 6 months of receiving the full therapeutic education program (TEP) (baseline 57.07 ± 10.81 vs. 6 months 78.80 ± 10.31; p < 0.001). CONCLUSION: The DMQ-Sp is reliable, valid, and sensitive to change in a large sample of children (aged 8-18 years) with T1DM and their parents. PRACTICE IMPLICATIONS: DMQ-Sp can be a useful tool for diabetes teams to identify adherence to different tasks and to evaluate TEPs.

Nebulized Micafungin Treatment for Scopulariopsis/Microascus Tracheobronchitis in Lung Transplant Recipients.

Scopulariopsis/Microascus isolates cause infections with high mortality in lung transplant recipients. Treatment is challenging due to antimicrobial resistance. We describe two cases of Scopulariopsis/Microascus tracheobronchitis in lung transplant recipients successfully treated with nebulized micafungin. This antifungal was well tolerated and achieved high concentrations in epithelial lining fluid up to 14 h after nebulization without significant plasma concentrations. Nebulized micafungin may be a safe and effective option for the treatment of fungal tracheobronchitis.

Pneumocystis jirovecii genetic diversity in a Spanish tertiary hospital.

Pneumocystis jirovecii is associated with non-noxious colonization or severe pneumonia in immunocompromised hosts. Epidemiological investigations have been hampered by the lack of a standardized typing scheme. Thus, only partial molecular data on Spanish P. jirovecii cases are available. Recently, a new ISHAM consensus multilocus sequence typing scheme (MLST) targeting ß-TUB, mt26S, CYB, and SOD with a publicly accessible database has been launched to overcome this problem. The molecular epidemiology of P. jirovecii from immunocompromised patients either colonized (n = 50) or having pneumonia (n = 36) seen between 2014 and 2018 at a single center in Barcelona, Spain, was studied. The new ISHAM consensus MSLT scheme was used to investigate the local epidemiology and identify possible unnoticed outbreaks. Mutations in the DHPS gene, not included in the scheme but giving information about potential sulfa treatment failure, were also studied. The study assigned 32 sequence types (ST) to 72.2% pneumonia and 56% colonization cases. The most frequent STs were ST21 (18.5%), ST22 (14.8%), and ST37(14.8%). For non-unique STs, ST3, ST30 and ST31 were found only in pneumonia cases, whereas ST27 was associated exclusively to colonizations. Despite 38 patients sharing similar STs, only two were involved in a potential cross transmission event. No DHPS mutations were identified. The new consensus typing scheme was useful to ascertain the molecular epidemiology of P. jirovecii in our center revealing a high genetic diversity and the potential association of specific STs to colonization and pneumonia cases. LAY SUMMARY: A newly described MLST scheme aims at providing a standardized tool to study and compare Pneumocystis jirovecii epidemiology. A high diversity among P. jirovecii isolates from patients in Barcelona, Spain, and a potential association between specific STs and infection/colonization were identified.

Impact of elite soccer coaching change on team performance according to coach- and club-related variables.

A coaching change is an extreme, but frequently occurring phenomenon in elite soccer with its impact on team success debatable. The aim of the current study was twofold: (i) to compare team's performance when coached by new and old coaches; and (ii) to investigate the impact of a coaching change on team's performance according to coach- and club-related factors. All in-season coaching changes from the 2010-11 to 2017-18 seasons within the Spanish, French, English, German and Italian professional leagues were examined. Team performance was assessed as points awarded from match outcome over 1-20 matches prior to and following the coaching change. Four independent variables (coach's experience, team's budget, whether the coach had been an elite former player or not, and whether the coach was a novice or not) were included into linear regression modelling. The main results showed that team's short-term performance was improved significantly with a change to a new coach with this impact declining in the longer term (> 10 matches). Specifically, the number of points (1.15-1.32 vs. 0.37-1.03, p < 0.05) and the moving average of points (1.19-1.31 vs. 0.37-1.04, p < 0.05) awarded per match were significantly greater after the coaching change. Further, the winning effect due to the new coach was independent of coach-related factors such as coaching experience or the new coach being a former elite player. A critical organisational decision to change coaches may provide an essential stimulus for future team success in elite soccer.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

Lung transplantation in two cystic fibrosis patients infected with previously pandrug-resistant Burkholderia cepacia complex treated with ceftazidime-avibactam.

We describe two cystic fibrosis patients infected with pandrug-resistant Burkholderia cepacia complex, with the exception of ceftazidime-avibactam, who received prophylaxis with this antibiotic during lung transplantation. Although both patients had a post-operative relapse of respiratory infection, one with positive blood cultures, ceftazidime-avibactam treatment yielded a favourable outcome. 12 months after transplantation, one patient presented an excellent clinical outcome. However, the other patient died 10 months later due to severe B. cepacia sinusitis with intracranial invasion.

High-Dose Daptomycin Is Effective as an Antibiotic Lock Therapy in a Rabbit Model of Staphylococcus epidermidis Catheter-Related Infection.

Long-term catheter-related bloodstream infections (CRBSIs) involving coagulase-negative staphylococci are associated with poor patient outcomes, increased hospitalization, and high treatment costs. The use of vancomycin lock therapy has been an important step forward in treatment of these biofilms, although failures occur in 20% of patients. In this study, we report that a high dose of daptomycin lock therapy may offer a therapeutic advantage for these CRBSIs in just 24 h of treatment.

Clinical Characteristics and Outcome of Lung Transplant Recipients with Respiratory Isolation of Corynebacterium spp.

Although chronic respiratory disease and immunosuppression are risk factors for Corynebacterium species respiratory infection, data are scarce regarding this disease in lung transplantation. Our aim was to describe the clinical characteristics and outcomes of lung transplant recipients (LTR) with respiratory isolation of Corynebacterium spp. This was a retrospective observational study performed at a referral center in Barcelona, Spain (2014 to 2016). We included all LTR in whom Corynebacterium spp. were isolated in at least one good-quality lower respiratory tract specimen. Overall, 24 of 527 (4.6%) LTR at risk during the study period were included. The main epidemiological, clinical, and microbiological data were analyzed. The most frequently isolated species were C. striatum (11/24), C. pseudodiphtheriticum (3/24), and C. amycolatum (3/24). All 19 (76%) patients who underwent bronchoscopy showed abnormalities, mainly mucosal plaques at the bronchial suture and purulent secretions. Clinical cure was achieved in 8/12 (67%) patients who fulfilled the CDC definition of lower respiratory tract infection (LRTI). To assess the clinical relevance of Corynebacterium spp., only patients with monomicrobial isolation (n = 18) were evaluated. LRTI was diagnosed in 9, and a nonsignificant association was found with a significant number of Corynebacterium sp. CFU/ml (7/9 LRTI versus 2/9 non-LRTI, P = 0.057). Persistent infection was associated with metallic bronchial stent implantation (4/4 versus 2/14, P = 0.005). The isolation of Corynebacterium spp. in respiratory specimens of lung transplant recipients may herald a respiratory tract infection or bronchial suture damage. Bronchial stent implantation is a risk factor for the persistence of Corynebacterium species infection.

Developing collaborative works for faster progress on fungal respiratory infections in cystic fibrosis.

Cystic fibrosis (CF) is the major genetic inherited disease in Caucasian populations. The respiratory tract of CF patients displays a sticky viscous mucus, which allows for the entrapment of airborne bacteria and fungal spores and provides a suitable environment for growth of microorganisms, including numerous yeast and filamentous fungal species. As a consequence, respiratory infections are the major cause of morbidity and mortality in this clinical context. Although bacteria remain the most common agents of these infections, fungal respiratory infections have emerged as an important cause of disease. Therefore, the International Society for Human and Animal Mycology (ISHAM) has launched a working group on Fungal respiratory infections in Cystic Fibrosis (Fri-CF) in October 2006, which was subsequently approved by the European Confederation of Medical Mycology (ECMM). Meetings of this working group, comprising both clinicians and mycologists involved in the follow-up of CF patients, as well as basic scientists interested in the fungal species involved, provided the opportunity to initiate collaborative works aimed to improve our knowledge on these infections to assist clinicians in patient management. The current review highlights the outcomes of some of these collaborative works in clinical surveillance, pathogenesis and treatment, giving special emphasis to standardization of culture procedures, improvement of species identification methods including the development of nonculture-based diagnostic methods, microbiome studies and identification of new biological markers, and the description of genotyping studies aiming to differentiate transient carriage and chronic colonization of the airways. The review also reports on the breakthrough in sequencing the genomes of the main Scedosporium species as basis for a better understanding of the pathogenic mechanisms of these fungi, and discusses treatment options of infections caused by multidrug resistant microorganisms, such as Scedosporium and Lomentospora species and members of the Rasamsonia argillacea species complex.

Scedosporium and Lomentospora: an updated overview of underrated opportunists.

Species of Scedosporium and Lomentospora are considered as emerging opportunists, affecting immunosuppressed and otherwise debilitated patients, although classically they are known from causing trauma-associated infections in healthy individuals. Clinical manifestations range from local infection to pulmonary colonization and severe invasive disease, in which mortality rates may be over 80%. These unacceptably high rates are due to the clinical status of patients, diagnostic difficulties, and to intrinsic antifungal resistance of these fungi. In consequence, several consortia have been founded to increase research efforts on these orphan fungi. The current review presents recent findings and summarizes the most relevant points, including the Scedosporium/Lomentospora taxonomy, environmental distribution, epidemiology, pathology, virulence factors, immunology, diagnostic methods, and therapeutic strategies.

A case of respiratory toxigenic diphtheria: contact tracing results and considerations following a 30-year disease-free interval, Catalonia, Spain, 2015.

In May 2015, following a 30-year diphtheria-free interval in Catalonia, an unvaccinated 6-year-old child was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae. After a difficult search for equine-derived diphtheria antitoxin (DAT), the child received the DAT 4 days later but died at the end of June. Two hundred and seventeen contacts were identified in relation to the index case, and their vaccination statuses were analysed, updated and completed. Of these, 140 contacts underwent physical examination and throat swabs were taken from them for analysis. Results were positive for toxigenic C. diphtheriae in 10 contacts; nine were asymptomatic vaccinated children who had been in contact with the index case and one was a parent of one of the nine children. Active surveillance of the 217 contacts was initiated by healthcare workers from hospitals and primary healthcare centres, together with public health epidemiological support. Lack of availability of DAT was an issue in our case. Such lack could be circumvented by the implementation of an international fast-track procedure to obtain it in a timely manner. Maintaining primary vaccination coverage for children and increasing booster-dose immunisation against diphtheria in the adult population is of key importance.

The virtual patient as a learning tool: a mixed quantitative qualitative study.

BACKGROUND: The use of simulation in medical education has been widely accepted. There are different types of medical simulators that vary in both accuracy to emulate the real world (fidelity) and cost of development or acquisition. There is significant evidence that supports the use of high-fidelity simulators (i.e. mannequins or dummies) to prepare students for clinical environments, less attention has been given to low-fidelity simulators. This article aims to present evidence regarding the effectiveness of a low-fidelity simulator: Virtual Patient (VP), which develops several interactive computer-based clinical scenarios, seeking to promote an alternative learning environment and the development of necessary medical skills such as clinical reasoning in students of medicine. METHODS: A quasi-experimental study was designed to investigate the results on the development of history taking and clinical reasoning skills in a group of undergraduate medical students, in a course devised under the concepts of constructivism in education, which used the Virtual Patient as the fundamental teaching tool. Results were measured through a mixed, quantitative and qualitative study, triangulating the results of the students' skills evaluation when facing a clinical case represented by an actor patient before and after the course. Additionally, the description of the students' and tool's performance was measured by way of a qualitative study. RESULTS: The comparison of the students' skills on the evaluation matrix before-and-after the course evidenced a statistically significant advance (p < 0.01) in all aspects (interview, physical exam, clinical judgment, relevance of medical exams, and presentation of case). Students described the VP as an easy-to-use and motivating tool for learning without stress, especially at the beginning of their career. VP allowed them to create logical and structured processes, to be wrong without consequences, and to review and reassess information available. From the professor perspective, it allowed a better follow-up of the students' learning process and favored reflections on the teaching-learning process. CONCLUSIONS: VP proved to be a valuable and useful tool for the development of clinical reasoning and history taking skills in medical students, as part of a constructivist learning course.

Aspergillus Species in Bronchiectasis: Challenges in the Cystic Fibrosis and Non-cystic Fibrosis Airways.

Bronchiectasis is a chronic irreversible airway abnormality associated with infectious agents that either cause or superinfect the airways. While the role of bacteria is well studied, much remains to be determined about fungi in both cystic fibrosis- and non-cystic fibrosis-related bronchiectasis. The airway is constantly exposed to inhaled ambient moulds of which Aspergillus represent the most ubiquitous. In a normal healthy host, this situation is of little consequence. The presence of anatomical or immunological abnormalities such as those in bronchiectasis leads to a range of fungal-related pathologies from asymptomatic airway colonization to fungal sensitization, allergic bronchopulmonary aspergillosis or chronic pulmonary aspergillosis. These entities are difficult to recognize, diagnose and treat due in part to a lack of validated biomarkers. Our true understanding of the complex relationships that regulate fungal-host interactions is still in its infancy and, several questions remain. This includes if fungal epidemiology in bronchiectasis is uniform across countries, and to what extent immunopathological mechanisms-related to fungal airway infections-occurs in different disease states. Specific triggers to allergic or infectious responses to Aspergillus require further exploration. How transition occurs between allergic and invasive phenotypes and their respective biomarkers is also important. Whether anti-fungal treatment is warranted in all cases and what the optimal management strategy is, particularly when treatment should commence and its expected duration remains unclear. Further research is clearly necessary and should be prioritized to better understand the clinical effects and impact of Aspergillus in the setting of bronchiectasis.

10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation.

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n-LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization. We performed an observational study including consecutive LTR recipients (2003-2013) undergoing n-LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow-up 2.56 years; IQR 1.01-4.65). Fifty-three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person-time incidence rates of Aspergillus spp. colonization and infection decreased (2003-2008, 0.19; 2009-2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003-2008, 38.1% vs 2009-2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28-41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long-term administration of prophylaxis with n-LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection.

Insulin/NFκB protects against ischemia-induced necrotic cardiomyocyte death.

In the heart, insulin controls key functions such as metabolism, muscle contraction and cell death. However, all studies have been focused on insulin action during reperfusion. Here we explore the cardioprotective action of this hormone during ischemia. Rat hearts were perfused ex vivo with an ischemia/reperfusion Langendorff model in absence or presence of insulin. Additionally, cultured rat cardiomyocytes were exposed to simulated ischemia in the absence or presence of insulin. Cytoprotective effects were measured by myocardial infarct size, trypan blue exclusion, released LDH and DNA fragmentation by flow cytometry. We found that insulin protected against cardiac ischemia ex vivo and in vitro. Moreover, insulin protected cardiomyocytes from simulated ischemia by reducing necrotic cell death. Protective effects of insulin were dependent of Akt and NFκB. These novel results show that insulin reduces ischemia-induced cardiomyocyte necrosis through an Akt/NF-κB dependent mechanism. These novel findings clarify the role of insulin during ischemia and further support its use in early GIK perfusion to treat myocardial infarction.