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Background: SMA1, a rapidly progressing disease, results in muscle weakness, respiratory failure, hospitalization, and early death. This study highlights the value of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Methods: Twelve SMA1 patients received a one-time intravenous proposed therapeutic dose of AVXS-101 (CL-101; NCT02122952). Event-free survival (no death/permanent ventilation), pulmonary/nutritional interventions, swallow function, hospitalization rates, CHOP-INTEND, motor milestones, and safety were assessed (2-year follow-up). Results: By study end, all 12 patients survived event-free; 7 did not require non-invasive ventilation; 11 had stable/improved swallowing function (6 exclusively fed by mouth); 11 spoke. On average, patients experienced 1.4 (SD=0.41, range=0–4.8) respiratory hospitalizations/year. The mean proportion of time hospitalized was 4.4% (range=0–18.3%); mean unadjusted rate of hospitalization/year was 2.1 (range=0–7.6), with a mean hospital stay of 6.7 (range=3–12.1) days. CHOP-INTEND increased by 9.8 (SD=3.9) and 15.4 (SD=6.4) points at 1- and 3-months post-treatment. At long-term follow-up, 11 patients sat unassisted, 4 stood with assistance, and 2 walked. Adverse events included elevated serum aminotransferase levels, which were attenuated by prednisolone. Conclusions: AVXS-101 in CL-101 resulted in dramatic survival and motor function improvements. The reduced healthcare utilization in treated infants could decrease cost and alleviate patient, caregiver, and societal burden.
Introduction: Renal colic is one of the most common presentations to the emergency department (ED), and often requires complex interdisciplinary collaboration between emergency physicians and urology surgeons. Previous literature has shown that adoption of interdisciplinary rapid referral clinics can improve both timeliness of care and patient outcomes. However, these Acute Care Surgery models have not yet been commonly adopted for urology care in the ED. Methods: In July 2016, we adopted the intervention of an Acute Care Urology (ACU) model through the creation of a rapid referral clinic dedicated to ED patient referrals, the addition of an ACU surgeon, and enhanced use of daytime OR blocks. We conducted a manual chart review of 579 patients presenting to the ED with a complaint of renal colic. Patient data was collected in two separate time periods to analyze trends before implementation of the ACU model (pre-intervention, September - November 2015), to examine the model's impact (post-intervention, September - November 2016). Secondary methods of evaluation included a survey of 20 ED physicians to capture subjective feedback through Likert scale data. Results: Of the evaluated 579 patients with a complaint of renal colic,194 patients were discharged from ED with an diagnosis of obstructing kidney stone and were referred to urology for outpatient care. The ED-to-clinic time was significantly lower for those in the ACU model (p <0.001). The mean time to clinic was 15.76 days (SD = 15.47, range 1-93) pre-intervention versus 4.17 days (SD = 2.33, range = 1-12) post-intervention. Furthermore, the ACU clinic allowed significantly more patients to be referred for outpatient care (p = 0.0004). There was also higher likelihood that patients would successfully obtain an appointment following referral (p = 0.0055). Decreasing trends were shown in mean ED wait time, in addition to time from assessment to procedure. Results of the qualitative survey were overwhelmingly positive. All 20 surveyed ED physicians were more confident that outpatients would be seen in a timely manner (85% strongly agree, 15% agree). Qualitative feedback included the belief that follow-up is more accessible, that ED physicians are less likely to page the on-call urologist, and that they are able to discharge patients sooner. Conclusion: The ACU model for patients with renal colic may be beneficial in reducing ED-to-clinic time, ensuring proper follow-up after ED diagnosis, and improving patient care within the ED.
OBJECTIVES/SPECIFIC AIMS: To establish an effective team of researchers working towards developing and validating prognostic models employing use of image analyses and other numerical metadata to better understand pediatric undernutrition, and to learn how different approaches can be brought together collaboratively and efficiently. METHODS/STUDY POPULATION: Over the past 18 months we have established a transdisciplinary team spanning three countries and the Schools of Medicine, Engineering, Data Science and Global Health. We first identified two team leaders specifically a pediatric physician scientist (SS) and a data scientist/engineer (DB). The leaders worked together to recruit team members, with the understanding that different ideas are encouraged and will be used collaboratively to tackle the problem of pediatric undernutrition. The final data analytic and interpretative core team consisted of four data science students, two PhD students, an undergraduate biology major, a recent medical graduate, and a PhD research scientist. Additional collaborative members included faculty from Biomedical Engineering, the School of Medicine (Pediatrics and Pathology) along with international Global Health faculty from Pakistan and Zambia. We learned early on that it was important to understand what each of the member’s motivation for contributing to the project was along with aligning that motivation with the overall goals of the team. This made us help prioritize team member tasks and streamline ideas. We also incorporated a mechanism of weekly (monthly/bimonthly for global partners) meetings with informal oral presentations which consisted of each member’s current progress, thoughts and concerns, and next experimental goals. This method enabled team leaders to have a 3600 mechanism of feedback. Overall, we assessed the effectiveness of our team by two mechanisms: 1) ongoing team member feedback, including team leaders, and 2) progress of the research project. RESULTS/ANTICIPATED RESULTS: Our feedback has shown that on initial development of the team there was hesitance in communication due to the background diversity of our various member along with different cultural/social expectations. We used ice-breaking methods such as dedicated time for brief introductions, career directions, and life goals for each team member. We subsequently found that with the exception of one, all other team members noted our working environment professional and conducive to productivity. We also learnt from our method of ongoing constant feedback that at times, due to the complexity of different disciplines, some information was lost due to the difference in educational backgrounds. We have now employed new methods to relay information more effectively, with the use of not just sharing literature but also by explaining the content. The progress of our research project has varied over the past 4-6 months. There was a steep learning curve for almost every member, for example all the data science students had never studied anything related to medicine during their education, including minimal if none exposure to the ethics of medical research. Conversely, team members with medical/biology backgrounds had minimal prior exposure to computational modeling, computer engineering and the verbage of communicating mathematical algorithms. While this may have slowed our progress we learned that by asking questions and engaging every member it was easier to delegate tasks effectively. Once our team reached an overall understanding of each member’s goals there was a steady progress in the project, with new results and new methods of analysis being tested every week. DISCUSSION/SIGNIFICANCE OF IMPACT: We expect that our on-going collaboration will result in the development of new and novel modalities to understand and diagnose pediatric undernutrition, and can be used as a model to tackle several other problems. As with many team science projects, credit and authorship are challenges that we are outlining creative strategies for as suggested by International Committee of Medical Journal Editors (ICMJE) and other literature.
Advances in material science and semiconductor technology have enabled a variety of inventions to be implemented in electronic systems and devices used in the medical, telecommunications, and consumer electronics sectors. In this paper, a wireless charging system is described as a wearable body heater that uses a chair as a transmitter (Tx). This system incorporates the widely accepted Qi wireless charging standard. Alignment conditions of a linear three-element coil arrangement and a 3 × 3 coil matrix array are investigated using voltage induced in a coil as a performance indicator. The efficiency obtained is demonstrated to be up to 80% for a voltage of over 6.5 Volts and a power transfer of over 5 Watts. Our results and proposed approach can be useful for many applications. This is because the wireless charging system described herein can help design seating areas for the elderly and disabled, commercial systems, consumer electronics, medical devices, electronic textiles (e-textiles), and other electronic systems and devices.
Some patients are more willing to see a behavioral health provider within primary care. The purpose of this study was to evaluate the patients’ perspectives of having access to a psychologist within primary care and to investigate whether mental health stigma affected preferences. In total, 36 patients completed questionnaires after seeing a psychologist in primary care. Patients were satisfied with having a primary care psychologist involved in their care. Most patients were more likely to see the psychologist in primary care and those who preferred this indicated higher levels of mental health stigma. The overarching theme for why patients saw a psychologist in primary care was convenience. Mental health stigma may also have played a role. Results suggest that providing integrated services may reach patients who may not have otherwise sought services in a behavioral health clinic. Findings from this study encourage the continued integration of behavioral health services.
Transcatheter right ventricle decompression in neonates with pulmonary atresia and intact ventricular septum is technically challenging, with risk of cardiac perforation and death. Further, despite successful right ventricle decompression, re-intervention on the pulmonary valve is common. The association between technical factors during right ventricle decompression and the risks of complications and re-intervention are not well described.
This is a multicentre retrospective study among the participating centres of the Congenital Catheterization Research Collaborative. Between 2005 and 2015, all neonates with pulmonary atresia and intact ventricular septum and attempted transcatheter right ventricle decompression were included. Technical factors evaluated included the use and characteristics of radiofrequency energy, maximal balloon-to-pulmonary valve annulus ratio, infundibular diameter, and right ventricle systolic pressure pre- and post-valvuloplasty (BPV). The primary end point was cardiac perforation or death; the secondary end point was re-intervention.
A total of 99 neonates underwent transcatheter right ventricle decompression at a median of 3 days (IQR 2–5) of age, including 63 patients by radiofrequency and 32 by wire perforation of the pulmonary valve. There were 32 complications including 10 (10.5%) cardiac perforations, of which two resulted in death. Cardiac perforation was associated with the use of radiofrequency (p=0.047), longer radiofrequency duration (3.5 versus 2.0 seconds, p=0.02), and higher maximal radiofrequency energy (7.5 versus 5.0 J, p<0.01) but not with patient weight (p=0.09), pulmonary valve diameter (p=0.23), or infundibular diameter (p=0.57). Re-intervention was performed in 36 patients and was associated with higher post-intervention right ventricle pressure (median 60 versus 50 mmHg, p=0.041) and residual valve gradient (median 15 versus 10 mmHg, p=0.046), but not with balloon-to-pulmonary valve annulus ratio, atmospheric pressure used during BPV, or the presence of a residual balloon waist during BPV. Re-intervention was not associated with any right ventricle anatomic characteristics, including pulmonary valve diameter.
Technical factors surrounding transcatheter right ventricle decompression in pulmonary atresia and intact ventricular septum influence the risk of procedural complications but not the risk of future re-intervention. Cardiac perforation is associated with the use of radiofrequency energy, as well as radiofrequency application characteristics. Re-intervention after right ventricle decompression for pulmonary atresia and intact ventricular septum is common and relates to haemodynamic measures surrounding initial BPV.
The advancement of human retinal pigment epithelial cell (hRPE) replacement therapy is partly dependent on optimization of cell culture, cell preservation, and storage medium. This study was undertaken to search for a suitable storage temperature and storage medium for hRPE. hRPE monolayer sheets were cultured under standard conditions at 37°C and then randomized for storage at six temperatures (4, 16, 20, 24, 28, and 37°C) for 7 days. After revealing a suitable storage temperature, hRPE sheets were subsequently stored with and without the silk protein sericin added to the storage medium. Live/dead assay, light microscopy, pH, and phenotypic expression of various proteins were used to assess cell cultures stored at different temperatures. After 7 days of storage, hRPE morphology was best preserved at 4°C. Addition of sericin to the storage medium maintained the characteristic morphology of the preserved cells, and improved pigmentation and levels of pigmentation-related proteins in the cultured hRPE sheets following a 7-day storage period at 4°C.
Poor growth with underweight for age, decreased length/height for age, and underweight-for-height are all relatively common in children with CHD. The underlying causes of this failure to thrive may be multifactorial, including innate growth potential, severity of cardiac disease, increased energy requirements, decreased nutritional intake, malabsorption, and poor utilisation of absorbed nutrition. These factors are particularly common and severe in low- and middle-income countries.
Although nutrition should be carefully assessed in all patients, failure of growth is not a contraindication to surgical repair, and patients should receive surgical repair where indicated as soon as possible.
Close attention should be paid to nutritional support – primarily enteral feeding, with particular use of breast milk in infancy – in the perioperative period and in the paediatric ICU. This nutritional support requires specific attention and allocation of resources, including appropriately skilled personnel.
Thereafter, it is essential to monitor growth and development and to identify causes for failure to catch-up or grow appropriately.
The initial assessment of epistaxis patients commonly includes: first aid measures, observations, focused history taking, and clinical examinations and investigations. This systematic review aimed to identify evidence that informs how the initial assessment of these patients should be conducted.
A systematic review of the literature was performed using a standardised methodology and search strategy.
Seventeen articles were included. Factors identified were: co-morbidity, intrinsic patient factors, coagulation screening and ice pack use. Hypertension and anticoagulant use were demonstrated to adversely affect outcomes. Coagulation screening is useful in patients on anticoagulant medication. Four studies could not be accessed. Retrospective methodology and insufficient statistical analysis limit several studies.
Sustained ambulatory hypertension, anticoagulant therapy and posterior bleeding may be associated with recurrent epistaxis, and should be recorded. Oral ice pack use may decrease severity and can be considered as first aid. Coagulation studies are appropriate for patients with a history of anticoagulant use or bleeding diatheses.
B-cell non-Hodgkin lymphoma (B-cell NHL) is the second commonest malignancy in the stomach. We determined the distribution of Helicobacter pylori outer membrane protein Q (HopQ) allelic type, cytotoxin-associated gene (cag)-pathogenicity activity island (cag-PAI) and vacuolation activating cytotoxin A (vacA) genes, respectively, in patients with B-cell NHL. We also compared them with their distribution in non-ulcer dyspepsia (NUD). H. pylori was cultured from gastric biopsy tissue obtained at endoscopy. Polymerase chain reaction was performed. Of 170 patients enrolled, 114 (63%) had NUD and 56 (37%) had B-cell NHL. HopQ type 1 was positive in 66 (58%) in NUD compared with 46 (82%) (P = 0·002) in B-cell NHL; HopQ type 2 was positive in 93 (82%) with NUD compared with 56 (100%) (P < 0·001) in B-cell NHL. Multiple HopQ types were present in 46 (40%) in NUD compared with 46 (82%) (P < 0·001) in B-cell NHL. CagA was positive in 48 (42%) in NUD vs. 50 (89%) (P < 0·001) in B-cell NHL; cagT was positive in 35 (31%) in NUD vs. 45 (80%) (P < 0·001) in B-cell NHL; left end of the cagA gene (LEC)1 was positive in 23 (20%) in NUD vs. 43 (77%) (P < 0·001) in B-cell NHL. VacAs1am1 positive in B-cell NHL in 48 (86%) (P < 0·001) vs. 50 (44%) in NUD, while s1am2 was positive in 20 (17%) in NUD vs. 46 (82%) (P < 0·001) in B-cell NHL. H. pylori strains with multiple HopQ allelic types, truncated cag-PAI evidenced by expression of cagA, cagT and cag LEC with virulent vacAs1 alleles are associated with B-cell NHL development.
The aim of this feasibility trial was to evaluate the feasibility and acceptability of the locally adapted Group Problem Management Plus (PM+) intervention for women in the conflict affected settings in Swat, Pakistan.
This mixed-methods study incorporated a quantitative component consisting of a two arm cluster randomised controlled feasibility trial, and qualitative evaluation of the acceptability of the Group PM+ to a range of stakeholder groups. For the quantitative component, on average from each of the 20 Lady Health Workers (LHWs) catchment area (20 clusters), six women were screened and recruited for the trial with score of >2 on the General Health Questionnaire and score of >16 on the WHO Disability Assessment Schedule. These LHW clusters were randomised on a 1 : 1 allocation ratio using a computer-based software through a simple randomisation method to the Group PM+ intervention or Enhanced Usual Care. The Group PM+ intervention consisted of five weekly sessions of 2 h duration delivered by local non-specialist females under supervision. The primary outcome was individual psychological distress, measured by levels of anxiety and depression on the Hospital Anxiety and Depression Scale at 7th week after baseline. Secondary outcomes include symptoms of depression, post-traumatic stress disorder (PTSD), general psychological profile, levels of functioning and generalised psychological distress. Intervention acceptability was explored through in-depth interviews.
The results show that lay-helpers with no prior mental health experience can be trained to achieve the desired competency to successfully deliver the intervention in community settings under supervision. There was a good intervention uptake, with Group PM+ considered useful by participants, their families and lay-helpers. The outcome evaluation, which was not based on a large enough study to identify statistically significant results, indicated statistically significant improvements in depression, anxiety, general psychological profile and functioning. The PTSD symptoms and depressive disorder scores showed a trend in favour of the intervention.
This trial showed robust acceptance in the local settings with delivery by non-specialists under supervision by local trained females. The trial paves the way for further adaptation and exploration of the outcomes through larger-scale implementation and definitive randomised controlled trials in the local settings.
Early sexual debut is of major concern because it is a correlate for health and economic shocks experienced in adulthood. In South Africa, this concern has provided impetus for research directed at the HIV and AIDS epidemic, teenage pregnancy and the effect of adolescent sexual behaviour on persistence in school. Of interest to the present study is high school completion, which is a well-established empirical barometer of adult socioeconomic opportunities. Using data from the five waves of the Cape Area Panel Study (CAPS), this paper examines the association between sexual behaviours initiated in pre- and early adolescence and high school completion rates. The CAPS study is a longitudinal survey that was designed to investigate young people’s (aged 14–22 years) educational attainment and sexual behaviours in Cape Town, South Africa. The sample was constituted from 3213 individuals who had initiated sex during their teenage years and the analysis was undertaken when the youngest cohort was aged 21, an age at which they should have completed high school if they were on time. Logistic regression models were fitted separately for males and females. Overall, the results reveal that early sexual debut is correlated with long-term negative educational outcomes. Individuals who experience early sexual debut are less likely to complete high school than their counterparts who make their sexual debut later on in life. This effect is worse for Africans, who also disproportionately have an earlier sexual debut than other race groups. Apart from race however, the findings also reinforce the effect of other demographic factors on high school completion, namely, place of residence and family socioeconomic status as measured by parental education and household income. Hence, early sexual debut adds another layer of inequality and worsens the plight of Africans, females, those living in rural areas and those who come from low-income families.
In 2014, over a million people were internally displaced after the launch of a military operation in North Waziristan, a tribal region on Pakistan's side of the Durand Line. Despite security concerns and restrictions, a collaborative mental health and psychosocial support initiative was undertaken in the district of Bannu. Monthly mental health camps were conducted for a period of 6 months by a multidisciplinary mental health team. The initiative also helped to assess mental health needs and plan training for primary care staff to strengthen existing resources.
As part of this initiative, Mental Health Gap Action Programme (mhGAP) training was conducted for physicians and psychosocial staff in the affected district. This marked the first instance of implementing these guidelines in Pakistan following a humanitarian crisis. This paper describes the training process including the adaptation of the mhGAP curriculum, training of trainers, training workshops for primary care staff and an analysis of results of pre- and post-testing of their knowledge about common mental disorders using a 25-item questionnaire.
The gaps in knowledge of primary care physicians in recognizing and managing common mental disorders were clearly identified. The mean pre- and post-test scores of the participants were 15.43, 62% (p value 0.000, s.d. 4.05) and 19.48, 78% (p value 0.000, s.d. 3.13) respectively, which showed significant improvement.
Despite the challenges of a humanitarian crisis, mhGAP guidelines can be successfully implemented to train primary care physicians in in low- and middle-income countries such as Pakistan. However, the dearth of primary care resources can hinder the complete integration of mental health services into primary healthcare.
Lead poisoning is a stealthy threat to human physiological systems as chronic exposure can remain asymptomatic for long periods of time before symptoms manifest. We presently review the biophysical mechanisms of lead poisoning that contribute to male infertility. Environmental and occupational exposure of lead may adversely affect the hypothalamic−pituitary−testicular axis, impairing the induction of spermatogenesis. Dysfunction at the reproductive axis, namely testosterone suppression, is most susceptible and irreversible during pubertal development. Lead poisoning also appears to directly impair the process of spermatogenesis itself as well as sperm function. Spermatogenesis issues may manifest as low sperm count and stem from reproductive axis dysfunction or testicular degeneration. Generation of excessive reactive oxygen species due to lead-associated oxidative stress can potentially affect sperm viability, motility, DNA fragmentation, membrane lipid peroxidation, capacitation, hyperactivation, acrosome reaction, and chemotaxis for sperm-oocyte fusion, all of which can contribute to deter fertilization. Reproductive toxicity has been tested through cross-sectional analysis studies in humans as well as in vivo and in vitro studies in animals.
Background: Planning for neurology training necessitated a reflection on the experience of graduates. We explored practice characteristics, and training experience of recent graduates. Methods: Graduates from 2010-2014 completed a survey. Results: Response rate was 37% of 211. 56% were female. 91% were adult neurologists. 65% practiced in an outpatient setting. 63% worked in academics. 85% completed subspecialty training (median 1 year). 36% work 3 days a week or less. 82% took general call (median 1 night weekly). Role preparation was considered very good or excellent for most; however poor or fair ratings were 17% in advocacy and 8% in leadership. Training feedback was at least “good” for 87%. Burnout a few times a week or more was noted by 5% (6% during residency, particularly PGY1 and 5). 64% felt overly burdened by paperwork. Although most felt training was adequate, it was poor or fair at preparing for practice management (85%) and personal balance (55%). Most conditions were under-observed in training environment. Many noted a need for more independent practice development and community neurology. Conclusions: Although our training was found to be very good, some identified needs included advocacy training, and more training in general neurology in the longitudinal outpatient/community settings.
Phenotype of cultured ocular epithelial transplants has been shown to affect clinical success rates following transplantation to the cornea. The purpose of this study was to evaluate the relationship between cell nucleus morphometry and phenotype in three types of cultured epithelial cells. This study provides knowledge for the development of a non-invasive method of determining the phenotype of cultured epithelium before transplantation. Cultured human conjunctival epithelial cells (HCjE), human epidermal keratinocytes (HEK), and human retinal pigment epithelial cells (HRPE) were analyzed by quantitative immunofluorescence. Assessments of nucleus morphometry and nucleus-to-cytoplasm ratio (N/C ratio) were performed using ImageJ. Spearman’s correlation coefficient was employed for statistical analysis. Levels of the proliferation marker PCNA in HCjE, HEK, and HRPE correlated positively with nuclear area. Nuclear area correlated significantly with levels of the undifferentiated cell marker ABCG2 in HCjE. Bmi1 levels, but not p63α levels, correlated significantly with nuclear area in HEK. The N/C ratio did not correlate significantly with any of the immunomarkers in HCjE (ABCG2, CK7, and PCNA) and HRPE (PCNA). In HEK, however, the N/C ratio was negatively correlated with levels of the undifferentiated cell marker CK14 and positively correlated with Bmi1 expression. The size of the nuclear area correlated positively with proliferation markers in all three epithelia. Morphometric indicators of phenotype in cultured epithelia can be identified using ImageJ. Conversely, the N/C ratio did not show a uniform relationship with phenotype in HCjE, HEK, or HRPE. N/C ratio therefore, may not be a useful morphometric marker for in vitro assessment of phenotype in these three epithelia.
We studied the prevalence of Helicobacter pylori virulence markers, e.g. cytotoxin associated gene (cagA), cagA promoter, vacuolating associated cytotoxin A (vacA) alleles induced by contact with epithelium (iceA type), and outer membrane protein Q (hopQ) in expatriates and compared them with those in local residents. Gastric biopsies were obtained at endoscopy for culture, histology and PCR for virulence marker and hopQ. Of 309 patients, 236 (76%) were males with a mean age of 45 years. A total of 102 patients were expatriates. hopQ type 1 was present in 98 (47%) local residents compared to 88 (86%) expatriates (P < 0·001), while hopQ type 2 was present in 176 (85%) local residents, compared to 60 (59%) expatriates (P < 0·001). H. pylori virulence marker cagA was positive in 97 (47%) local residents compared to 86 (84%) expatriates (P < 0·001) while cagA-P was positive in 72 (35%) local residents compared to 87 (85%) expatriates (P < 0·001). iceA type 1 was positive in 157 (76%) local residents compared to 45 (44%) expatriates (P < 0·001), while iceA type 2 was positive in 81 (39%) local residents compared to 86 (84%) expatriates (P < 0·001). Distribution of H. pylori cagA, cagA promoter, iceA and hopQ type in local residents and expatriates was different. H. pylori virulence markers were associated with severe pathology in expatriates.