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The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

ObjectiveTo assess the experience of moral distress among intensive care unit (ICU) professionals in the UK.DesignMixed methods: validated quantitative measure of moral distress followed by purposive sample of respondents who underwent semistructured interviews.SettingFour ICUs of varying sizes and specialty facilities.ParticipantsHealthcare professionals working in ICU.Results227 questionnaires were returned and 15 interviews performed. Moral distress occurred across all ICUs and professional demographics. It was most commonly related to providing care perceived as futile or against the patient’s wishes/interests, followed by resource constraints compromising care. Moral distress score was independently influenced by profession (p=0.02) (nurses 117.0 vs doctors 78.0). A lack of agency was central to moral distress and its negative experience could lead to withdrawal from engaging with patients/families. One-third indicated their intention to leave their current post due to moral distress and this was greater among nurses than doctors (37.0% vs 15.0%). Moral distress was independently associated with an intention to leave their current post (pConclusionsMoral distress is widespread among UK ICU professionals and can have an important negative impact on patient care, professional wellbeing and staff retention, a particularly concerning finding as this study was performed prior to the COVID-19 pandemic. Moral distress due to resource-related issues is more severe than comparable studies in North America. Interventions to support professionals should recognise the individualistic nature of coping with moral distress. The value of close-knit teams and supportive environments has implications for how intensive care services are organised.

Visceral leishmaniasis is an infectious parasitic disease caused by the protozoan parasites Leishmania donovani and Leishmania infantum. The drugs currently used to treat visceral leishmaniasis suffer from toxicity and the emergence of parasite resistance, and so a better solution would be the development of an effective subunit vaccine; however, no approved vaccine currently exists. The comparative testing of a large number of vaccine candidates requires a quantitative and reproducible experimental murine infection model, but the parameters that influence infection pathology have not been systematically determined. To address this, we have established an infection model using a transgenic luciferase-expressing L. donovani parasite and longitudinally quantified the infections using in vivo bioluminescent imaging within individual mice. We examined the effects of varying the infection route, the site of adjuvant formulation administration, and standardised the parasite preparation and dose. We observed that the increase in parasite load within the liver during the first few weeks of infection was directly proportional to the parasite number in the initial inoculum. Finally, we show that immunity can be induced in pre-exposed animals that have resolved an initial infection. This murine infection model provides a platform for systematic subunit vaccine testing against visceral leishmaniasis.

The Toronto Addis Ababa Academic Collaboration in Emergency Medicine (TAAAC-EM) is an educational global health partnership established 10 years ago to support the growth of EM in Ethiopia. In-person global health partnership activities were disrupted by the COVID-19 pandemic. We describe our five-step process for transitioning our global health partnership to a virtual space. Each step was conducted in collaboration between the University of Toronto and Addis Ababa University EM physicians: (1) risk identification and needs assessment, (2) discussing mitigation strategies, (3) crafting and piloting an approach, (4) revising based on pilot results, 5) implementation with continuous evaluation and revision. Teaching was modified iteratively in response to feedback. Our experience shows that virtual teaching, while not a replacement for in-person engagement, can be a valuable tool both to supplement partnership activities when travel is not possible, and to enhance global health partnerships long term. This approach can also inform the transition of other forms of medical education to the virtual space.RéSUMé: La Toronto Addis-Ababa collaboration universitaire en médecine d’urgence (TAAAC-EM) est un partenariat mondial en éducation à la santé établi il y a 10 ans pour soutenir la croissance de la médecine d’urgence en Éthiopie. Les activités du partenariat mondiale pour la santé en personne ont été perturbées par la pandémie de COVID-19. Nous décrivons notre processus en cinq étapes pour la transition de notre partenariat mondial pour la santé vers un espace virtuel. Chaque étape a été menée en collaboration entre les médecins d’urgences de l’Université de Toronto et de l’Université d’Addis-Ababa : 1) identification des risques et évaluation des besoins, 2) discussion des stratégies d’atténuation, 3) élaboration et pilotage d’une approche, 4) révision basée sur les résultats des projets pilotes, 5) mise en œuvre avec évaluation et révision continues. L’enseignement a été modifié de manière itérative en réponse aux commentaires. Notre expérience montre que l’enseignement virtuel, bien qu’il ne remplace pas l’engagement en personne, peut être un outil précieux à la fois pour compléter les activités de partenariat lorsque les déplacements ne sont pas possibles, et pour renforcer les partenariats mondiaux pour la santé à long terme. Cette approche peut également faire apprendre la transition d’autres formes de formation médicale vers l’espace virtuel.

Visceral leishmaniasis is an infectious parasitic disease caused by the protozoan parasites Leishmania donovani and Leishmania infantum. The drugs currently used to treat visceral leishmaniasis suffer from toxicity and the emergence of parasite resistance, and so a better solution would be the development of an effective subunit vaccine; however, no approved vaccine currently exists. The comparative testing of a large number of vaccine candidates requires a quantitative and reproducible experimental murine infection model, but the parameters that influence infection pathology have not been systematically determined. To address this, we have established an infection model using a transgenic luciferase-expressing L. donovani parasite and longitudinally quantified the infections using in vivo bioluminescent imaging within individual mice. We examined the effects of varying the infection route, the site of adjuvant formulation administration, and standardised the parasite preparation and dose. We observed that the increase in parasite load within the liver during the first few weeks of infection was directly proportional to the parasite number in the initial inoculum. Finally, we show that immunity can be induced in pre-exposed animals that have resolved an initial infection. This murine infection model provides a platform for systematic subunit vaccine testing against visceral leishmaniasis.

Supplemental Digital Content is Available in the Text., Objective: To describe our experience using the anterior internal pelvic fixator (INFIX) for treating pelvic ring injuries. Design: Case Series. Setting: Level 1 Trauma Center. Patients: Eighty-three patients with pelvic ring injuries were treated with INFIX. Follow-up average was 35 months (range 12–80.33). Intervention: Surgical treatment of pelvic ring injuries included reduction, appropriate posterior fixation, and INFIX placement. Outcome Measurements: Reduction using the pelvic deformity index and pubic symphysis widening, Majeed functional scores, complications; infection, implant failure, heterotopic ossification (HO), nerve injury, and pain. Results: All patients healed in an appropriate time frame (full weight bearing 12 weeks postoperation). The average pelvic deformity index reduction (injury = 0.0420 ± 0.0412, latest FU = 0.0254 ± 0.0243) was 39.58%. The average reduction of pubic symphysis injuries was 56.92%. The average Majeed score of patients at latest follow-up was 78.77 (range 47–100). Complications were 3 infections, 1 case of implant failure, 2 cases implantation too deep, 7 cases of lateral femoral cutaneous nerve irritation, and 3 cases of pain associated with the device. HO was seen in >50% of the patients, correlated with increased age (P < 0.007), injury severity score (P < 0.05) but only 1 case was symptomatic. Conclusions: The pelvic injuries had good functional and radiological outcomes with INFIX and the appropriate posterior fixation. The downside is removal requiring a second anesthetic, there is a learning curve, HO often occurs, the lateral femoral cutaneous nerve may get irritated which often resolves once the implants are removed. Surgery-specific implants need to be developed. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

BackgroundAntibiotic overuse has promoted growing rates of antimicrobial resistance and secondary antibiotic-associated infections such asClostridium difficile(C. difficile). Antimicrobial stewardship programs (ASPs) are effective in reducing antimicrobial use in the inpatient setting; however, the unique environment of the emergency department (ED) lends itself to challenges for successful implementation. Front-line ownership (FLO) methodology has been shown to be a potentially effective strategy for the implementation of inpatient ASPs through an iterative multi-pronged approach driven by front-line providers.ObjectiveTo determine whether a FLO approach to antimicrobial stewardship in the ED can alter antimicrobial usage.MethodsInterventions were driven by ED physicians and facilitated by Infectious Diseases Division physicians from the hospital’s ASP using FLO principles. Measured end points included antibiotic usage in the ED as measured by defined daily doses, and rates of urine culture sent from the ED.ResultsThere was a step-wise significant reduction in the use of azithromycin (p=0.006), ceftriaxone (p=0.045), ciprofloxacin (p=0.034), and moxifloxacin (p=0.008). There was also a significant reduction in rates of urine cultures (pConclusionsFLO offers a promising approach to successful implementation of an ASP in the ED. Future studies would be important to evaluate the generalizability of the FLO approach to ASP development in other EDs and to determine strategies to improve the sustainability of reductions in antimicrobial use.

The purpose of this study is to compare INFIX to plating in the treatment of unstable pelvic ring injuries with disruption of the symphysis. Twenty-four patients treated with INFIX were compared to 28 patients fixed by plating. All patients had anterior and posterior fixation. Injuries were classified using the Young and Burgess and AO/OTA classification systems. Reductions of the pelvic ring were assessed using the pelvic deformity index (PDI) and symphyseal widening. Patients were contacted to get functional outcomes using the Majeed scoring system and complications were tabulated . INFIX was inferior to plating at reducing symphyseal widening (INFIX 10.72± 5.0 Plates 6.97 ± 3.39 P = 0.012) but similar in reducing the pelvic deformity index. (INFIX 0.0221± .015 Plates 0.0190 ± .0105 P = 0 .38). Majeed scores were similar 83.95 ± 15.2 (median 89, range 51-100) for INFIX and 77.67± 16.7 (median 79, range 54-100) for plating. Complications included infection (1 (4%) INFIX , 4 (14%) plates), improper hardware placement or failure (2 (8%) INFIX, 3 (11%) plates), and heterotopic ossification (11 (46%) INFIX, 16 (57.1%) plates). Infection in the plated patients was related to urological injury in 3/4 cases. Plating provides better reduction of the pubic symphysis and requires only one surgery. Outcomes scores were similar. INFIX may be preferable in obese patients, young women of childbearing age or those with urological injury.

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p

Mortality in patients sustaining pelvic fractures has been reported to be 4% to 15%. We sought to investigate the cause of death based on timing and evaluate if type of fracture and Injury Severity Score have an influence on the survival time.Sixty-nine patients of eight hundred sixty seven with a pelvic fracture who died during their hospital admission were included. Fractures were classified using the Arbeitsgemeinschaft Osteosynthesefragen/Orthopaedic Trauma Association system. Cause determined by autopsy in 48/69.The leading cause of death within 6 hours was abdominal and pelvic hemorrhage; 6 to 24 hours head injury, and greater than 24 hours multiple organ dysfunction syndrome. Survival time did not correlate between fracture type (P.12) or Injury Severity Score. Only 2 patients died of isolated pelvic hemorrhage.Despite the advances made in acute management of the traumatized patient in the emergency department, mortality is unavoidable in a small group of patients with hemorrhage being the commonest cause of early death but isolated pelvic hemorrhage rare.

The soundscape plays a key, if often overlooked, role in the construction of public urban space. Street music – a conscious deliberate propagation of sound in public space – opens an entryway into comprehending the role of sound in the city, and what it reveals about the city’s inhabitants. Ethnographic fieldwork in Brussels and Stockholm focuses on street musicians of all kinds, exploring how their music is shaped by their personal motivations, how their practices negotiate meaning in sound and in space, and how their rhythms shape, and are shaped by, the city. These explorations give reason to question R. Murray Schafer’s philosophies on soundscape studies, particularly in the urban context. Drawing from Henri Lefebvre’s notions of the production of space, and rhythmanalysis as an analytical tool, the urban soundscape is understood as an ongoing negotiation of individual actions, where dynamics of power, identity, and ideology become audible. Street musicians and their sound cultures feature not just as a topic worthy of study, but also as a guide of how and why to listen to and analyze the rhythms of the city.

The dire state of Cuban internet connectivity has inspired local informal innovations. One such innovation is El Paquete, a weekly distribution of downloaded content spread through an informal network. Taking a postcolonial approach, I investigate through user experiences how this network operates in a resource-poor environment. This investigation articulates a model of El Paquete centered on social interactions, which inform the system’s function but also shape El Paquete’s design and role in society. Based on this model, a set of speculative design exercises probe possibilities to streamline El Paquete’s compilation, involve consumer preferences in its design directions, or act as a disruption tolerant network. In uncovering the technical possibilities of El Paquete, these designs illuminate how its current design serves Cuban communities by embodying realities and limitations of Cuban society. El Paquete’s embodiment of informal innovation serves as a call to designers to continuously rethink development design processes, centering communities and their knowledge and technical practices. Det kritiska tillståndet för den kubanska internetanslutningen har inspirerat flertalet informella lokala innovationer. Ett exempel på en sådan innovation är El Paquete, vars lösning går ut på distribution av nedladdat innehåll som sprids veckovis genom ett informellt nätverk. Jag har undersökt hur detta nätverk fungerar i en resursfattig miljö genom att undersöka användarupplevelser ur ett postkolonialt perspektiv. I denna undersökning framförs en modell av El Paquete som inriktas på sociala interaktioner, vilket utgör systemets funktioner men som också formar El Paquete’s design och samhällsroll. Baserat på denna modell undersöks möjligheterna till att effektivisera El Paquete’s sammanställning, genom ett antal olika spekulativa designövningar som inkluderar konsumentpreferenser i designinriktning, eller som ett avbrottstolerant nätverk. Dessa designer belyser hur dagens tekniska möjligheter med El Paquete är till nytta för kubanska samhällen genom förkroppsligandet av deras verklighet och begränsningar. El Paquete’s förkroppsligande av informell innovation fungerar som en uppmaning till designers att kontinuerligt ompröva utvecklingen av designprocesser som fokuserar på samhällets kunskap och tekniska praxis.