Usability and feasibility of E-nergEYEze: a blended vision-specific E-health based cognitive behavioral therapy and self-management intervention to reduce fatigue in adults with visual impairment.

BACKGROUND: Over 50% of adults with visual impairment experience severe fatigue. Therefore, we developed a guided E-health intervention based on cognitive behavioral therapy and self-management to reduce fatigue in this population. This pilot study evaluated the usability, feasibility, fidelity and potential effectiveness of E-nergEYEze. METHODS: E-nergEYEze was developed by a design team and customized by conducting a pilot study using an iterative development strategy. The intervention was first tested in a usability study among adults with visual impairment (n = 5). Participants were asked to think-aloud while exploring the intervention features and a semi-structured interview was performed afterwards. Subsequently, the enhanced intervention was tested in a feasibility study. Adults with visual impairment and severe fatigue (n = 10) followed the intervention partially with guidance from a social worker and one-time computer trainer support. Fatigue severity (Checklist Individual Strength), fatigue impact (Modified Fatigue Impact Scale) and cognitive behavioral therapy skills (Competencies of Cognitive Therapy Scale-Self Report) were measured at baseline and at three months follow-up and analyzed with the Wilcoxon signed-rank test. The intervention was evaluated through evaluation forms. RESULTS: The usability study resulted in adjustments to content and lay-out with regard to optically shortened text sentences, separate pages for information and assignments with one read-aloud audio and an additional descriptive explanation of page content. Digital challenges were overcome with mandatory computer training and e-platform modifications. The feasibility study showed a positive trend in reducing fatigue severity (Z -6.108; P < .001; SD 8.4), impact of fatigue (Z - 4.451; P < .001; SD 11.4) and cognitive behavioral therapy skills (Z -2.278; P = .023; SD 19.3). Participants gave useful feedback regarding accessibility, content and guidance, with an overall positive experience. The intervention was rated with a median score of 8 (range 7-10). CONCLUSION: We developed, evaluated and optimized E-nergEYEze by applying a user-centered and iterative approach. E-nergEYEze showed a promising trend to reduce fatigue severity and impact of fatigue and to increase cognitive behavioral therapy skills. The study methods were feasible and the fidelity of the intervention protocol was suitable. Performing a randomized controlled trial is warranted to give insight into whether E-nergEYEze is cost-effective in reducing severe fatigue in adults with visual impairment. TRIAL REGISTRATION: International Clinical Trial Registry Platform: NL7764. Date registered: 28-05-2019.

Preliminary Study on Open Labelled Randomized Controlled Trial of the Safety and Efficacy of Hydroxychloroquine and Chloroquine Phosphate for the Treatment of Persons Infected with 2019 Coronavirus Disease in Nigeria.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of COVID-19 is a leading cause of ill-health and deaths worldwide. Currently, COVID-19 has no known widely approved therapeutics. Thus, the need for effective treatment. OBJECTIVES: We investigated the safety and efficacy of two (2) therapeutic agents; chloroquine phosphate (CQ), 2- hydroxychloroquine (HCQ) and a control (standard supportive therapy) among hospitalized adults with COVID-19. METHODS: The clinical trial was done in accordance to the World Health Organization master protocol for investigational therapeutics for COVID-19. Atotal of 40 participants with laboratory-confirmed positive COVID-19 were enrolled. Blood samples and oropharyngeal (OP) swabs were obtained on days 1,3,15 and 29 for safety and efficacy assessments. RESULTS: The baseline demographics showed that the median ages in years (range) were 45 (31-57) in CQ, 45 (36.5-60.5) in HCQ, 43 (39.5-67.0) and 44.5 (25.3-51.3) in the control (P<0.042).At randomization, seven (7) participants were asymptomatic, thirty-three (33) had mild symptoms, eight (8) had moderate symptoms while three (3) had severe symptoms. The average day of conversion to negative COVID-19 was 15.5 days for CQ, 16 days for HCQ and 18 days for the control(P=0.036). CONCLUSION: The safety assessment revealed no adverse effect of the drugs in COVID-19 patients after treatment. These findings proved that chloroquine and hydroxychloroquine are effective for the treatment of COVID-19 among hospitalized adults. It also confirmed that they are safe.

CONTEXTE: Le coronavirus du syndrome respiratoire aigu sévère 2 (SARS-CoV-2),agentcausaldelaCOVID-19, est l'unedes principales causes demaladie et de décès dans le monde. À l'heure actuelle, il n'existe aucun traitement largement approuvé pour la COVID-19. Ainsi, ilya un besoin de traitement efficace. OBJECTIFS: Nous avons étudié l'innocuité et l'efficacité de deux (2) agents thérapeutiques, le phosphate de chloroquine (CQ) et l'hydroxychloroquine (HCQ), ainsi qu'un groupe témoin (traitement de soutien standard) chez des adultes hospitalisés atteints de la COVID-19.MÉTHODES: L'essai clinique a été mené conformément au protocole maître de l'Organisation mondiale de la santé pour les thérapeutiques à l'étude de la COVID-19. Au total, 40 participants atteints de la COVID-19, confirmée en laboratoire, ont été in scrits. Des échantillons de sang et des prélèvements oropharyngés (PO) ont été effectuésauxjours1,3,15et29pourévaluerl'innocuitéetl'efficacité. RÉSULTATS: Les données démographiques initiales ont révélé que l'âge médian en années (plage) était de 45 (31-57) pour le groupe CQ, de 45 (36,5-60,5) pour le groupe HCQ, de 43 (39,5-67,0) et de 44,5 (25,3-51,3) pour le groupe témoin (P<0,042). À la randomisation, sept (7) participants étaient asymptomatiques, trente-trois (33) présentaient des symptômes bénins, huit(8) avaient des symptômes modérés, tandis que trois(3) avaient des symptômes graves. Le jour moyende conversionentest COVID-19 négatif était de 15,5 jours pour le groupe CQ, de 16 jours pour le groupe HCQ et de 18 jours pourle groupe témoin (P=0,036). CONCLUSION: L'évaluation de la sécurité n'a révélé aucun effet indésirable des médicaments chez les patients atteints de la COVID-19 après le traitement. Ces conclusions ont prouvé que la chloroquine et l'hydroxychloroquine sont efficaces pour le traitement de la COVID-19 chez les adultes hospitalisés. Cela a également confirmé qu' ilssont sûrs. Mots-clés: COVID-19, SARS-CoV-2, essai clinique, innocuité, efficacité, thérapeutiques.

The effectiveness of motivational interviewing on adherence to wearing orthopedic shoes in people with diabetes at low-to-high risk of foot ulceration: A multicenter cluster-randomized controlled trial.

AIM: To evaluate the effectiveness of motivational interviewing (MI) performed by MI-trained podiatrists in improving adherence to wearing orthopedic shoes in comparison to usual care in people with diabetes at low-to-high risk of ulceration. METHODS: People with diabetes with loss of protective sensation and/or peripheral artery disease, and with orthopedic shoes prescription were allocated to receive one MI-consultation by a podiatrist randomized to MI training (n = 53) or usual care only (n = 68). Adherence was measured as the percentage of steps taken while wearing orthopedic shoes, determined using an insole temperature microsensor and wrist-worn activity tracker during one week at 3 and 6 months. RESULTS: The proportion of participants ≥80 % adherent to wearing their orthopedic shoes was higher in the control group than in the MI-intervention group at 3 months (30.9 % versus 15.1 %; p = 0.044), and not significantly different at 6 months (22.1 % versus 13.2 %; p = 0.210). Average adherence was also higher in the control group than the intervention group at both 3 months (60.9 % versus 50.9 %; p = 0.029) and 6 months (59.9 % versus 49.5 %; p = 0.025). CONCLUSIONS: One podiatrist-led MI-consultation in its current form did not result in higher adherence to wearing orthopedic shoes in people with diabetes 3 and 6 months after inclusion. TRIAL REGISTRATION: Netherlands Trial Register NL7710 (available on the International Clinical Trials Registry Platform).

Clinical predictors of Covid-19 mortality in a tertiary hospital in Lagos, Nigeria: A retrospective cohort study.

Background: The predictors of mortality among patients presenting with severe to critical disease in Nigeria are presently unknown. Aim: The aim of this study was to identify the predictors of mortality among patients with COVID-19 presenting for admission in a tertiary referral hospital in Lagos, Nigeria. Patients and Methods: The study was a retrospective study. Patients' sociodemographics, clinical characteristics, comorbidities, complications, treatment outcomes, and hospital duration were documented. Pearson's Chi-square, Fischer's Exact test, or Student's t-test were used to assess the relationship between the variables and mortality. To compare the survival experience across medical comorbidities, Kaplan Meir plots and life tables were used. Univariable and multivariable Cox-proportional hazard analyses were conducted. Results: A total of 734 patients were recruited. Participants' age ranged from five months to 92 years, with a mean ± SD of 47.4 ± 17.2 years, and a male preponderance (58.5% vs. 41.5%). The mortality rate was 9.07 per thousand person-days. About 73.9% (n = 51/69) of the deceased had one or more co-morbidities, compared to 41.6% (252/606) of those discharged. Patients who were older than 50 years, with diabetes mellitus, hypertension, chronic renal illness, and cancer had a statistically significant relationship with mortality. Conclusion: These findings call for a more comprehensive approach to the control of non-communicable diseases, the allocation of sufficient resources for ICU care during outbreaks, an improvement in the quality of health care available to Nigerians, and further research into the relationship between obesity and COVID-19 in Nigerians.

Attitudes and experiences towards the application of motivational interviewing by podiatrists working with people with diabetes at high-risk of developing foot ulcers: a mixed-methods study.

BACKGROUND: Podiatrists are key professionals in promoting adequate foot self-care for people with diabetes at high-risk of developing foot ulcers. However, merely informing patients about the advantages of foot self-care is insufficient to realise behavioural change. Motivational interviewing (MI) is a promising person-centred communication style that could help to create a working alliance between healthcare providers and patient to improve foot self-care. This study aims to observe and analyse the application of MI in consultations carried out by MI-trained and non-MI-trained podiatrists with their patients, and explore podiatrists' attitudes and experiences towards MI. METHODS: Eighteen podiatrists (median age: 28.5 years, 10 female and 8 male) followed a three-day basic training in MI and 4 podiatrists (median age: 38.5 years, 4 female) were not trained in MI. To observe and rate the MI-fidelity in daily clinical practice, audio recordings from the MI-trained and non-MI-trained podiatrists were scored with the Motivational Interviewing Treatment Integrity code. Individual, semi-structed, in-depth interviews were conducted with the MI-trained podiatrists to explore their attitudes towards and experiences with MI. These data sources were triangulated to describe the effect of training podiatrists in MI for their clinical practice. RESULTS: The MI-trained podiatrists scored significantly higher than the non-MI-trained podiatrists on two of four global MI-related communication skills (empathy, p = 0.008 and change talk, p = 0.008), on one of five core MI-adherent behaviours (affirmation, p = 0.041) and on one of the other behaviour counts (simple reflections, p = 0.008). The podiatrists mainly reported their attitudes and experiences regarding partnership and cultivating change talk, during the interviews. In addition, they also mentioned facilitators and barriers to using MI and indicated whether they experienced MI as having added value. CONCLUSIONS: The MI-trained podiatrists used the principles of MI at a solid beginner proficiency level in their clinical practice in comparison to the non-MI-trained podiatrists, who did not reach this level. This achievement is in accordance with the basic MI-training they received. This multi-method study reveals that podiatrists can be effectively trained in applying MI in daily clinical practice. TRIAL REGISTRATION: Netherlands Trial Register NL7710. Registered: 6 May 2019.

Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos.

INTRODUCTION: In vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS-CoV-2 viral replication, but questions remained as to in-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19. METHODS: We conducted a translational proof of concept randomized, double blind placebo controlled, dose response and parallel group study of IV efficacy in RT-polymerase chain reaction proven COVID 19 positive patients. Sixty-two patients were randomized to three treatment groups. (A) IV 6 mg regime, (B) IV 12 mg regime (given Q84 h for 2 weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care. RESULTS: The Days to COVID negativity (DTN) was significantly and dose dependently reduced by IV (P = 0.0066). The DTN for Control were, = 9.1+/-5.2, for A 6.0 +/- 2.9 and for B 4.6 +/-3.2. Two way repeated measures ANOVA of ranked COVID 19 +/- scores at 0, 84, 168 and252h showed a significant IV treatment effect (P = 0.035) and time effect (P < 0.0001). IV also tended to increase SPO2% compared to controls, P = 0.073, 95% CI-0.39 to 2.59 and increased platelet count compared to C (P = 0.037) 95%CI 5.55-162.55 × 103/ml. The platelet count increase was inversely correlated to DTN (r = -0.52, P = 0.005). No SAE was reported. CONCLUSIONS: 12mg IV regime given twice a week may have superior efficacy over 6mg IV given twice a week, and certainly over the non IV arm of the study. IV should be considered for use in clinical management of SARS-COV2, and may find applications in prophylaxis in high risk areas.

Using motivational interviewing combined with digital shoe-fitting to improve adherence to wearing orthopedic shoes in people with diabetes at risk of foot ulceration: study protocol for a cluster-randomized controlled trial.

BACKGROUND: Diabetic foot ulcers have a high impact on mobility and daily functioning and lead to high treatment costs, for example, by hospitalization and amputation. To prevent (re)ulcerations, custom-made orthopedic shoes are considered essential. However, adherence to wearing the orthopedic shoes is low, and improving adherence was not successful in the past. We propose a novel care approach that combines motivational interviewing (MI) with a digital shoe-fitting procedure to improve adherence to orthopedic shoes. The aim of this trial is to assess the (cost-)effectiveness of this novel care approach compared to usual care (no MI and casting-based shoe-fitting) in promoting footwear adherence and ulcer prevention. METHODS: The trial will include people with diabetes, with IWGDF Risk categories 1-3, who have been prescribed orthopedic shoes. Participants will be randomized at the level of the podiatrist to the novel care approach or usual care. The primary outcome is the proportion of participants who adhere to the use of their orthopedic shoes, that is, who take at least 80% of their total daily steps with orthopedic shoes. A temperature microsensor will be built into the participants' orthopedic shoes to measure wearing time continuously over 12 months. In addition, daily activity will be measured periodically using log data with an activity monitor. Data from the temperature microsensor and activity monitor will be combined to calculate adherence. (Re-)experienced complications after receiving orthopedic shoes will be registered. Questionnaires and interviews will measure the experiences of participants regarding orthopedic shoes, experiences of podiatrists regarding motivational interviewing, care consumption, and quality of life. Differences in costs and quality of life will be determined in a cost-effectiveness analysis. DISCUSSION: This trial will generate novel insights into the socio-economic and well-being impact and the clinical effectiveness of the novel care approach on adherence to wearing orthopedic shoes. TRIAL REGISTRATION: Netherlands Trial Register NL7710 . Registered on 6 May 2019.

Pro- and anti-inflammatory macrophages express a sub-type specific purinergic receptor profile.

Extracellular nucleotides act as danger signals that orchestrate inflammation by purinergic receptor activation. The expression pattern of different purinergic receptors may correlate with a pro- or anti-inflammatory phenotype. Macrophages function as pro-inflammatory M1 macrophages (M1) or anti-inflammatory M2 macrophages (M2). The present study found that murine bone marrow-derived macrophages express a unique purinergic receptor profile during in vitro polarization. As assessed by real-time polymerase chain reaction (PCR), Gαs-coupled P1 receptors A2A and A2B are upregulated in M1 and M2 compared to M0, but A2A 15 times higher in M1. The ionotropic P2 receptor P2X5 is selectively upregulated in M1- and M2-polarized macrophages. P2X7 is temporarily expressed in M1 macrophages. Metabotropic P2Y receptors showed a distinct expression profile in M1 and M2-polarized macrophages: Gαq coupled P2Y1 and P2Y6 are exclusively upregulated in M2, whereas Gαi P2Y13 and P2Y14 are overexpressed in M1. This consequently leads to functional differences between M1 and M2 in response to adenosine di-phosphate stimulation (ADP): In contrast to M1, M2 showed increased cytoplasmatic calcium after ADP stimulation. In the present study we show that bone marrow-derived macrophages express a unique repertoire of purinergic receptors. We show for the first time that the repertoire of purinergic receptors is highly flexible and quickly adapts upon pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.

Development and practice of laparoscopic surgery in a Nigerian tertiary hospital.

BACKGROUND: For the benefits of less postoperative pain, early recovery and discharge, and better cosmesis, laparoscopic surgery is rapidly gaining acceptance amongst surgeons as a better alternative to traditional open procedures. In January 2015, bookings for laparoscopic surgery became a more regular feature on our operation list. AIMS: We reported the indications, management outcome, and challenges in patients who had laparoscopic surgery in our institution. This is to document the trends in our surgical practice. METHODOLOGY: This is a descriptive study of 137 patients who had laparoscopic surgery for general surgical indications in our institution over a period of 5 years. Patients data as collected from the records department were evaluated for demographic characteristics, medical comorbidities, type of procedures done, and perioperative outcome. Data analysis was performed using Statistical Package for Social Sciences (SPSS). RESULTS: A total of 137 Patients had laparoscopic general surgery between January 2015 and December 2019. There were 48 males and 89 females with a male-to-female ratio of 1:1.9. The mean age of the patients was 38.8 ± 3.4 years (range 16-87 years). Laparoscopic cholecystectomy (35%) and laparoscopic appendicectomy (29.9%) were the most common procedures performed. Five (3.7%) cases were converted to open surgery. Superficial surgical site infection (5.8%) following laparoscopic appendicectomy was the most common postoperative complication. There was no 30-day postoperative mortality. CONCLUSION: Laparoscopic surgery is safe and can be applied to wide variety of general surgical conditions in developing countries. Minimal postoperative morbidity of laparoscopy is a major benefit to the patients.

Blood transfusion and ischaemic outcomes according to anemia and bleeding in patients with non-ST-segment elevation acute coronary syndromes: Insights from the TAO randomized clinical trial.

BACKGROUND: The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI). METHODS: The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a time-varying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status. RESULTS: 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p<0.01). This excess risk persisted after adjustment on GRACE score and nadir of hemoglobin (HR 3.36 95%CI 2.63-4.29 p<0.01). Subgroup analyses showed that blood transfusion was associated with a higher risk in patients without overt bleeding (adjusted HR 6.25 vs. 2.85; p-interaction 0.001) as well as in those with hemoglobin nadir > 9.0 g/dl (HR 4.01; p-interaction<0.0001). CONCLUSION: In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups.

Myocardial infarction type 1 is frequent in refractory out-of-hospital cardiac arrest (OHCA) treated with extracorporeal cardiopulmonary resuscitation (ECPR).

Extracorporeal cardiopulmonary resuscitation (ECPR) is a last resort treatment option for refractory cardiac arrest performed in specialized centers. Following consensus recommendations, ECPR is mostly offered to younger patients with witnessed collapse but without return of spontaneous circulation (ROSC). We report findings from a large single-center registry with 252 all-comers who received ECPR from 2011-2019. It took a median of 52 min to establish stable circulation by ECPR. Eighty-five percent of 112 patients with out-of-hospital cardiac arrest (OHCA) underwent coronary angiography, revealing myocardial infarction (MI) type 1 with atherothrombotic vessel obstruction in 70 patients (63% of all OHCA patients, 74% of OHCA patients undergoing coronary angiography). Sixty-six percent of 140 patients with intra-hospital cardiac arrest (IHCA) underwent coronary angiography, which showed MI type 1 in 77 patients (55% of all IHCA patients, 83% of IHCA patients undergoing coronary angiography). These results suggest that MI type 1 is a frequent finding and - most likely - cause of cardiac arrest (CA) in patients without ROSC, especially in OHCA. Hospital survival rates were 30% and 29% in patients with OHCA and IHCA, respectively. According to these findings, rapid coronary angiography may be advisable in patients with OHCA receiving ECPR without obvious non-cardiac cause of arrest, irrespective of electrocardiogram analysis. Almost every third patient treated with ECPR survived to hospital discharge, supporting previous data suggesting that ECPR may be beneficial in CA without ROSC. In conclusion, interventional cardiology is of paramount importance for ECPR programs.

Coloring of PLGA implants to better understand the underlying drug release mechanisms.

Different dyes and a colored vitamin (riboflavin) were used to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA)-based implants. The latter were prepared by hot melt extrusion (HME) or formed in-situ, upon solvent exchange when injecting a PLGA solution in N-methyl-pyrrolidone (NMP) into phosphate buffer pH 7.4. Methylene blue was used as water-soluble dye to stain the release medium, riboflavin as a yellow, water-soluble "model drug", and Sudan-III-red as poorly water-soluble dye, incorporated in the implant. In the case of pre-formed HME implants, the "orchestrating" role of polymer swelling for the control of drug release could be visualized: At early time points, only limited amounts of water penetrate into the system, insufficient for noteworthy drug dissolution and diffusion. However, bulk erosion starts, and once a critical polymer molecular weight threshold value is reached, substantial implant swelling sets on: Large amounts of water come in and allow for significant drug dissolution and diffusion. In the case of in-situ forming implants, the importance of the composition of the liquid formulation for the resulting inner implant structure could be visualized. The latter affects the rate and extent at which water penetrates into the system and, thus, the resulting drug release rate.

Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants.

Different types of poly(lactic-co-glycolic acid) (PLGA)- and poly(lactic acid) (PLA)-based implants for controlled dexamethasone release were prepared by hot melt extrusion (HME). The lactic acid:glycolic acid ratio was varied (50:50, 75:25, 100:0) as well as the drug loading (1-15%). Resomer RG 502H, RG 752H and R 202H (all with -COOH end groups) were studied. The implants were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C. Interestingly, in all cases polymer swelling seems to play an "orchestrating" role for drug release: At early time points, the amounts of water penetrating into the systems are limited (since the macromolecules are hydrophobic and highly entangled). Consequently, only small amounts of drug can dissolve and the dissolved drug molecules are not sufficiently mobile to diffuse out to a noteworthy extent (negligible dexamethasone release for up to 6 weeks). However, the water that is able to enter the implants at early time points cleaves the polyesters right from the beginning. Due to the newly generated -COOH end groups and decreased chain length, the macromolecules become more and more hydrophilic and less entangled. In addition, water-soluble polymer degradation products build up a steadily increasing osmotic pressure, attracting water into the system. Once a critical polymer molecular weight threshold range (around 8 kDa) is reached, substantial implant swelling starts: The systems' volume increases up to 600-1700% and the water contents exceeds 80-90% (partially approaching 100%). Under these fundamentally altered conditions, significant drug amounts can dissolve and the dissolved drug molecules are sufficiently mobile to diffuse out of the implants: Drug release sets on. In brief, polymer swelling "orchestrates" the involved mass transport phenomena: It enables drug release after a certain lag time by fundamentally changing the conditions for drug dissolution and diffusion. Note that in other types of implants, additional mass transport phenomena might be involved, e.g. no burst release was observed from the investigated, initially non-porous implants.

[New aspects of thrombolysis and thrombectomy in pulmonary embolism]. / Neues zu Thrombolyse und Thrombektomie bei Lungenembolie.

Pulmonary embolism is a potentially life-threatening disease, which can present with varying severity. Based on an emergency risk stratification, the initial treatment strategy should be chosen without delay. While patients with a low mortality risk can be treated in an outpatient setting, patients at high risk should proceed to immediate recanalization by thrombolysis or thrombectomy. Systemic thrombolysis is the first line therapy in the absence of contraindications. The dosing (low versus full dose) and application (systemic versus local via a catheter) of alteplase, the most frequently used agent, is the subject of a number of current studies with the goal to reduce the risk of bleeding. In the case of contraindications for systemic thrombolysis surgical or alternatively, interventional thrombectomy should be performed. This article discusses these procedures in the light of the currently available literature.

IgG4-related disease in patients with newly diagnosed idiopathic retroperitoneal fibrosis: a population-based Danish study.

Objectives: IgG4-related disease (IgG4-RD) may present as 'idiopathic' retroperitoneal fibrosis (IRPF). We aimed to determine the occurrence of IgG4-retroperitoneal fibrosis (IgG4-RPF) in a nationwide study on patients with newly diagnosed IRPF, and to compare histopathological, imaging, and clinical features in the IgG4-RPF and non-IgG4-RPF subsets. Method: The National Danish Pathology Register was searched for biopsy codes relating to retroperitoneal tissue from 1 January 2004 to 31 December 2013. Secondary causes of RPF were excluded. Among 724 candidate cases, 68 were identified with IRPF. Clinical, laboratory, and imaging recordings were reviewed, and tissue blocks were scrutinized for IgG4-RPF features according to international consensus. Results: Forty-two patients (28 males), median age 56 (25-74) years were included. Nineteen (45%) met the criteria for IgG4-RPF, seven with definite and 12 with possible IgG4-RPF, while 23 had non-IgG4-RPF. Local manifestations and laboratory measures did not differ between RPF subsets. Arterial hypertension (p = 0.037) and periaortic fibrosis (p = 0.024) were more common in IgG4-RPF vs non-IgG4-RPF. Plasma cell IgG4/total IgG ratios ≥ 40% were associated more with core histopathological features of IgG4-RD compared to ratios < 40% (p < 0.001). There was a positive correlation between tissue IgG4-positive plasma cells and eosinophil cell count in patients with IgG4-RPF (rho = 0.50, p = 0.043). Conclusion: Forty-five per cent of this nationwide study population with newly diagnosed IRPF could be reclassified with IgG4-RPF. The association between high numbers of IgG4-bearing plasma cells and histopathological features of IgG4-RPF supports IgG4-bearing plasma cells with a perturbed distribution between IgG4 and total IgG being implicated in the pathogenesis of IgG4-RPF.

Droplet digital PCR of serum miR-499, miR-21 and miR-208a for the detection of functionally relevant coronary artery disease.

BACKGROUND: microRNAs (miRNAs) have shown promise as potential new biomarkers for myocardial injury and myocardial ischemia. New digital polymerase chain reaction (PCR) techniques allow for highly precise and reliable absolute direct quantification. METHODS: In this pilot study we used droplet digital PCR (ddPCR) to assess if miRNAs might be released into circulation in patients with functionally relevant coronary artery disease (CAD). Blood samples for measurement of high-sensitivity cardiac troponin I (hs-cTnI) and miRNAs were obtained before, immediately after peak stress, and 2 h after stress testing in a blinded manner in consecutive patients referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT). ddPCR was used to directly quantify the serum concentrations of miR-21, miR-208a, and miR-499 as potential markers of myocardial injury/ischemia. Functionally relevant CAD was determined by expert interpretation of MPI-SPECT/CT, coronary angiography and fractional flow reserve, if performed. RESULTS: Overall, 200 patients were included and functionally relevant CAD was detected in 85 of them (42%). Neither miR-21, miR-208a, nor miR-499 concentrations differed at rest, stress, or 2-h after stress when comparing patients with versus without functionally relevant CAD, while hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (P < 0.001). Exercise-induced changes in miRNA or hs-cTnI concentrations did not have diagnostic utility and were similar in patients with versus without functionally relevant CAD. CONCLUSION: miR-208a, miR-21 and miR-499 concentrations at rest, after exercise and exercise-induced changes do not provide additional clinical value regarding the detection of functionally relevant CAD.

Treatment of a broncho-esophageal fistula complicated by severe ARDS.

INTRODUCTION: Broncho-esophageal fistula formation is a rare complication of tuberculosis, most often seen in immunocompromised patients. METHODS AND RESULTS: In this paper, we report the case of a young non-immunocompromised refugee from Somalia diagnosed with open pulmonary tuberculosis complicated by extensive osseous involvement and a broncho-esophageal fistula with consecutive aspiration of gastric contents. The patient rapidly developed a severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (ECMO) therapy for nearly 2 months. The fistula was initially treated by standard antituberculous combination therapy and implantation of an esophageal and a bronchial stent. Long-term antibiotic treatment was instituted for pneumonia and mediastinitis. 7 months later, discontinuity resection of the esophagus was performed and the bronchial fistula covered by an intercostal muscle flap. DISCUSSION: This case illustrates that tuberculosis should always be suspected in patients from high-incidence countries in case of lung involvement and that an interdisciplinary approach including long-term intensive care management can enable successful treatment of tuberculosis with severe, near-fatal complications.

In-situ forming PLGA implants for intraocular dexamethasone delivery.

Different types of in-situ forming implants based on poly(lactic-co-glycolic acid) (PLGA) and N-methyl-pyrrolidone (NMP) were prepared for controlled ocular delivery of dexamethasone. The impact of the volume of the release medium, initial drug content, polymer molecular weight and PLGA concentration on the resulting drug release kinetics were studied and explained based on a thorough physico-chemical characterization of the systems. This included for instance the monitoring of dynamic changes in the implants' wet and dry mass, morphology, PLGA polymer molecular weight, pH of the surrounding bulk fluid and water/NMP contents upon exposure to phosphate buffer pH 7.4. Importantly, the systems can be expected to be rather robust with respect to variations in the vitreous humor volumes encountered in vivo. Interestingly, limited drug solubility effects within the implants as well as in the surrounding aqueous medium play an important role for the control of drug release at a drug loading of only 7.5%. Furthermore, the polymer molecular weight and PLGA concentration in the liquid formulations are decisive for how the polymer precipitates during solvent exchange and for the swelling behavior of the systems. These features determine the resulting inner system structure and the conditions for mass transport. Consequently, they affect the degradation and drug release of the in-situ formed implants.