C-Abl inhibition; a novel therapeutic target for Parkinson’s disease

Parkinson’s disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of PD. However, recently, due to the ignorance of the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Currently, a huge amount of evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathology of PD. C-abl plays a role in PD pathology on the levels of parkin activation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-abl activation is involved in neuronal death and (2) c-abl inhibition shows neuroprotective effects and prevents dopaminergic neurons’ death. Current evidence from experimental studies and the first in-human trial shows that c-abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-abl in PD pathology and the findings of preclinical experiments and the first in-human trial. In addition, based on the lessons of the last decade and current preclinical evidence, we provide recommendations for future research in this area

Titanium elastic nails versus spica cast in pediatric femoral shaft fractures:A systematic review and meta-analysis of 1012 patients

Background: There is a general consensus on the management of femoral fractures in children younger than two years and adolescents older than sixteen years. The best treatment for patients younger than sixteen years of age is still debatable. Titanium Elastic Nails (TEN), is widely used with some evidence, nonetheless, we undertook a systematic meta-analysis to assess the efficacy of TEN compared to Spica cast for the management of femoral shaft fracture in children aged between 2 to 16 years old. Methods: A computer literature search of PubMed, Scopus, Web of Science, CINAHL and Cochrane Central was conducted using relevant keywords. We included clinical trials and observational studies that compared TEN versus Spica cast; Records were screened for eligible studies and data were extracted and synthesized using Review Manager version 5.3 for Windows. Our search found 573 unique articles. After screening the abstract and relevant full text, 12 studies with a total of 1012 patients were suitable for the final analysis. Results: In terms terms of union (in weeks), the reported effect sizes favoured the TEN group in two included studies only. Moreover, the overall standardized mean difference in sagittal (SMD -0.48, 95% CI [-0.70 to -0.26], P<0.001) and coronal angulations (SMD -0.66, 95% CI [-1.00 to -0.31], P<0.001) favored TEN fixation in management of femoral fractures younger than 16 years. The reported length of hospital stay was not consistent across studies. The overall risk ratio of malalignment (RR=0.39, 95% CI [0.27 to 0.57], P<0.001) favored the TEN as well as walking independently. Based on our analysis, TEN treatment is superior to traction and hip spica for femoral fractures in patients younger than 16 years old. Conclusion: Based on our analysis we recommend the use of TEN fixation in management of pediatric femoral fractures in patients younger than 16 years

Prevalence of spine surgery navigation techniques and availability in Africa: A cross-sectional study

Background: Africa has a large burden of spine pathology but has limited and insufficient infrastructure to manage these spine disorders. Therefore, we conducted this e-survey to assess the prevalence and identify the determinants of the availability of spine surgery navigation techniques in Africa. Materials and methods: A two-part questionnaire was disseminated amongst African neurological and orthopedic surgery consultants and trainees from January 24 to February 23, 2021. The Chi-Square, Fisher Exact, and Kruskal-Wallis tests were used to evaluate bivariable relationships, and a p-value \u3c0.05 was considered statistically significant. Results: We had 113 respondents from all regions of Africa. Most (86.7 %) participants who practiced or trained in public centers and centers had an annual median spine case surgery volume of 200 (IQR = 190) interventions. Fluoroscopy was the most prevalent spine surgery navigation technique (96.5 %), followed by freehand (55.8 %), stereotactic without intraoperative CT scan (31.9 %), robotic with intraoperative CT scan (29.2 %), stereotactic with intraoperative CT scan (8.8 %), and robotic without intraoperative CT scan (6.2 %). Cost of equipment (94.7 %), lack of trained staff to service (63.7 %), or run the equipment (60.2 %) were the most common barriers to the availability of spine instrumentation navigation. In addition, there were significant regional differences in access to trained staff to run and service the equipment (P = 0.001). Conclusion: There is a need to increase access to more advanced navigation techniques, and we identified the determinants of availability

Prevalence of spine surgery navigation techniques and availability in Africa: A cross-sectional study

Background: Africa has a large burden of spine pathology but has limited and insufficient infrastructure to manage these spine disorders. Therefore, we conducted this e-survey to assess the prevalence and identify the determinants of the availability of spine surgery navigation techniques in Africa. Materials and methods: A two-part questionnaire was disseminated amongst African neurological and orthopedic surgery consultants and trainees from January 24 to February 23, 2021. The Chi-Square, Fisher Exact, and Kruskal-Wallis tests were used to evaluate bivariable relationships, and a p-value \u3c0.05 was considered statistically significant. Results: We had 113 respondents from all regions of Africa. Most (86.7 %) participants who practiced or trained in public centers and centers had an annual median spine case surgery volume of 200 (IQR = 190) interventions. Fluoroscopy was the most prevalent spine surgery navigation technique (96.5 %), followed by freehand (55.8 %), stereotactic without intraoperative CT scan (31.9 %), robotic with intraoperative CT scan (29.2 %), stereotactic with intraoperative CT scan (8.8 %), and robotic without intraoperative CT scan (6.2 %). Cost of equipment (94.7 %), lack of trained staff to service (63.7 %), or run the equipment (60.2 %) were the most common barriers to the availability of spine instrumentation navigation. In addition, there were significant regional differences in access to trained staff to run and service the equipment (P = 0.001). Conclusion: There is a need to increase access to more advanced navigation techniques, and we identified the determinants of availability

Chloroquine and hydroxychloroquine for the prevention and treatment of COVID-19: A fiction, hope or hype? An updated review

In December 2019, the novel coronavirus disease pandemic (COVID-19) that began in China had infected so far more than 109,217,366 million individuals worldwide and accounted for more than 2,413,912 fatalities. With the dawn of this novel coronavirus (SARS-CoV-2), there was a requirement to select potential therapies that might effectively kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently available antiviral medications for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has been repurposed in China and was recommended by the National Health Commission, China in mid-February 2020. By this time, the selection of this regimen was based on its efficacy against the previous SARS-CoV-1 virus and its potential to inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive research effort has been made by several researchers worldwide to investigate whether this regimen is safe and effective for the management of COVID-19. In this review, we provided a comprehensive overview of the CQ/HCQ regimen, summarizing data from in vitro studies and clinical trials for the protection against or the treatment of SARS-CoV-2. Despite the initial promising results from the in vitro studies and the widespread use of CQ/HCQ in clinical settings during the 1st wave of COVID-19, current data from well-designed randomized controlled trials showed no evidence of benefit from CQ/HCQ supplementation for the treatment or prophylaxis against SARS-CoV-2 infection. Particularly, the two largest randomized controlled trials to date (RECOVERY and WHO SOLIDARITY trials), both confirmed that CQ/HCQ regimen does not provide any clinical benefit for COVID-19 patients. Therefore, we do not recommend the use of this regimen in COVID-19 patients outside the context of clinical trials

Global neurosurgery in the context of Global Public Health Practice - a literature review of case studies

Neurosurgical conditions are a substantial contributor to surgical burden in the world, with LMICs carrying a disproportionately large part. Policy initiatives such as the National Surgical, Obstetrics and Anesthesia Plans (NSOAPs) and CHYSPR have highlighted the need for an intersectoral approach, not just at the hospital level but on a large scale encompassing national public health strategies. This article aims to illustrate through case studies, how addressing this surgical burden is not limited to the clinical context but extends to public health strategies as well. For example, vitamin B12 and folic acid are micronutrients that, if not at adequate levels, can result in debilitating neurosurgical conditions. In Ethiopia, through coalesced efforts between neurosurgeons and policy makers, the government has made strides in implementing food fortification programs at a national level to address the neurosurgical burden. Traumatic brain injuries (TBIs) are another neurosurgical burden that unevenly affect LMICs. Countries such as Colombia and India have demonstrated the importance of legislation and enforcement, coupled with robust data collection and auditing systems and strong academic advocacy of neurosurgeons can drastically reduce TBIs. Despite the importance of public health efforts in addressing neurosurgical conditions, there is lack of neurosurgeon involvement in public health and lack of integration of neurosurgical burden in national health planning systems. It is imperative that neurosurgeons advocate for and are included in aspects of public health policy. Neurosurgery does not stop within the bounds of the hospital, and neither should the role of a neurosurgeon

Global Perspectives on Task Shifting and Task Sharing in Neurosurgery.

BACKGROUND: Neurosurgical task shifting and task sharing (TS/S), delegating clinical care to non-neurosurgeons, is ongoing in many hospital systems in which neurosurgeons are scarce. Although TS/S can increase access to treatment, it remains highly controversial. This survey investigated perceptions of neurosurgical TS/S to elucidate whether it is a permissible temporary solution to the global workforce deficit. METHODS: The survey was distributed to a convenience sample of individuals providing neurosurgical care. A digital survey link was distributed through electronic mailing lists of continental neurosurgical societies and various collectives, conference announcements, and social media platforms (July 2018-January 2019). Data were analyzed by descriptive statistics and univariate regression of Likert Scale scores. RESULTS: Survey respondents represented 105 of 194 World Health Organization member countries (54.1%; 391 respondents, 162 from high-income countries and 229 from low- and middle-income countries [LMICs]). The most agreed on statement was that task sharing is preferred to task shifting. There was broad consensus that both task shifting and task sharing should require competency-based evaluation, standardized training endorsed by governing organizations, and maintenance of certification. When perspectives were stratified by income class, LMICs were significantly more likely to agree that task shifting is professionally disruptive to traditional training, task sharing should be a priority where human resources are scarce, and to call for additional TS/S regulation, such as certification and formal consultation with a neurosurgeon (in person or electronic/telemedicine). CONCLUSIONS: Both LMIC and high-income countries agreed that task sharing should be prioritized over task shifting and that additional recommendations and regulations could enhance care. These data invite future discussions on policy and training programs

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112