Increasing cell permeability of N-acetylglucosamine via 6-acetylation enhances capacity to suppress T-helper 1 (TH1)/TH17 responses and autoimmunity.

N-acetylglucosamine (GlcNAc) branching of Asn (N)-linked glycans inhibits pro-inflammatory T cell responses and models of autoimmune diseases such as Multiple Sclerosis (MS). Metabolism controls N-glycan branching in T cells by regulating de novo hexosamine pathway biosynthesis of UDP-GlcNAc, the donor substrate for the Golgi branching enzymes. Activated T cells switch metabolism from oxidative phosphorylation to aerobic glycolysis and glutaminolysis. This reduces flux of glucose and glutamine into the hexosamine pathway, thereby inhibiting de novo UDP-GlcNAc synthesis and N-glycan branching. Salvage of GlcNAc into the hexosamine pathway overcomes this metabolic suppression to restore UDP-GlcNAc synthesis and N-glycan branching, thereby promoting anti-inflammatory T regulatory (Treg) over pro-inflammatory T helper (TH) 17 and TH1 differentiation to suppress autoimmunity. However, GlcNAc activity is limited by the lack of a cell surface transporter and requires high doses to enter cells via macropinocytosis. Here we report that GlcNAc-6-acetate is a superior pro-drug form of GlcNAc. Acetylation of amino-sugars improves cell membrane permeability, with subsequent de-acetylation by cytoplasmic esterases allowing salvage into the hexosamine pathway. Per- and bi-acetylation of GlcNAc led to toxicity in T cells, whereas mono-acetylation at only the 6 > 3 position raised N-glycan branching greater than GlcNAc without inducing significant toxicity. GlcNAc-6-acetate inhibited T cell activation/proliferation, TH1/TH17 responses and disease progression in Experimental Autoimmune Encephalomyelitis (EAE), a mouse model of MS. Thus, GlcNAc-6-Acetate may provide an improved therapeutic approach to raise N-glycan branching, inhibit pro-inflammatory T cell responses and treat autoimmune diseases such as MS.

Evaluation of the impact of the ARC program on national nursing and midwifery regulations, leadership, and organizational capacity in East, Central, and Southern Africa.

BACKGROUND: The African Health Professions Regulatory Collaborative (ARC) was launched in 2011 to support countries in East, Central, and Southern Africa to safely and sustainably expand HIV service delivery by nurses and midwives. While the World Health Organization recommended nurse initiated and managed antiretroviral therapy, many countries in this region had not updated their national regulations to ensure nurses and midwives were authorized and trained to provide essential HIV services. For four years, ARC awarded annual grants, convened regional meetings, and provided technical assistance to country teams of nursing and midwifery leaders to improve national regulations related to safe HIV service delivery. We examined the impact of the program on national regulations and the leadership and organizational capacity of country teams. METHODS: Data was collected to quantify the level of participation in ARC by each country (number of grants received, number of regional meetings attended, and amount of technical assistance received). The level of participation was analyzed according to two primary outcome measures: 1) changes in national regulations and 2) improvements in leadership and organizational capacity of country teams. Changes in national regulations were defined as advancement of one "stage" on a capability maturity model; nursing and midwifery leadership and organizational capacity was measured by a group survey at the end of the program. RESULTS: Seventeen countries participated in ARC between 2012 and 2016. Thirty-three grants were awarded; the majority addressed continuing professional development (20; 61%) and scopes of practice (6; 18%). Fourteen countries (representing approximately two-thirds of grants) progressed at least one stage on the capability maturity model. There were significant increases in all five domains of leadership and organizational capacity (p < 0.01). The number of grants (Kendall's tau = 0.56, p = 0.02), duration of technical assistance (Kendall's tau = 0.50, p = 0.03), and number of learning sessions attended (Kendall's tau = 0.46, p = 0.04) were significantly associated with improvements in in-country collaboration between nursing and midwifery organizations. CONCLUSIONS: The ARC program improved national nursing regulations in participating countries and increased reported leadership, organizational capacity, and collaboration among national nursing and midwifery organizations. These changes help ensure national policies and professional regulations underpin nurse initiated and managed treatment for people living with HIV.

Scottish Bowel Screening Programme colonoscopy quality - scope for improvement?

AIM: The delivery of the Scottish Bowel Screening Programme (SBoSP) is rooted in the provision of a high quality, effective and participant-centred service. Safe and effective colonoscopy forms an integral part of the process. Additional accreditation as part of a multi-faceted programme for participating colonoscopists, as in England, does not exist in Scotland. This study aimed to describe the quality of colonoscopy in the SBoSP and compare this to the English national screening standards. METHODS: Data were collected from the SBoSP between 2007 and 2014. End-points for analysis were caecal intubation, cancer, polyp and adenoma detection, and complications. Overall results were compared with 2012 published English national standards for screening and outcomes from 2006 to 2009. RESULTS: During the study period 53 332 participants attended for colonoscopy. The colonoscopy completion rate was 95.6% overall. The mean cancer detection rate was 7.1%, the polyp detection rate was 45.7% and the adenoma detection rate was 35.5%. The overall complication rate was 0.47%. CONCLUSION: Colonoscopy quality in the SBoSP has exceeded the standard set for screening colonoscopy in England, despite not adopting a multi-faceted programme for screening colonoscopy. However, the overall adenoma detection rate in Scotland was 9.1% lower than that in England which has implications for colonoscopy quality and may have an impact on cancer prevention rates, a key aim of the SBoSP.

An evidence-based treatment algorithm for colorectal polyp cancers: results from the Scottish Screen-detected Polyp Cancer Study (SSPoCS).

OBJECTIVES: Colorectal polyp cancers present clinicians with a treatment dilemma. Decisions regarding whether to offer segmental resection or endoscopic surveillance are often taken without reference to good quality evidence. The aim of this study was to develop a treatment algorithm for patients with screen-detected polyp cancers. DESIGN: This national cohort study included all patients with a polyp cancer identified through the Scottish Bowel Screening Programme between 2000 and 2012. Multivariate regression analysis was used to assess the impact of clinical, endoscopic and pathological variables on the rate of adverse events (residual tumour in patients undergoing segmental resection or cancer-related death or disease recurrence in any patient). These data were used to develop a clinically relevant treatment algorithm. RESULTS: 485 patients with polyp cancers were included. 186/485 (38%) underwent segmental resection and residual tumour was identified in 41/186 (22%). The only factor associated with an increased risk of residual tumour in the bowel wall was incomplete excision of the original polyp (OR 5.61, p=0.001), while only lymphovascular invasion was associated with an increased risk of lymph node metastases (OR 5.95, p=0.002). When patients undergoing segmental resection or endoscopic surveillance were considered together, the risk of adverse events was significantly higher in patients with incomplete excision (OR 10.23, p<0.001) or lymphovascular invasion (OR 2.65, p=0.023). CONCLUSION: A policy of surveillance is adequate for the majority of patients with screen-detected colorectal polyp cancers. Consideration of segmental resection should be reserved for those with incomplete excision or evidence of lymphovascular invasion.

Cross-sectional description of nursing and midwifery pre-service education accreditation in east, central, and southern Africa in 2013.

BACKGROUND: In 2013, the World Health Organization issued guidelines, Transforming and Scaling Up Health Professional Education and Training, to improve the quality and relevance of health professional pre-service education. Central to these guidelines was establishing and strengthening education accreditation systems. To establish what current accreditation systems were for nursing and midwifery education and highlight areas for strengthening these systems, a study was undertaken to document the pre-service accreditation policies, approaches, and practices in 16 African countries relative to the 2013 WHO guidelines. METHODS: This study utilized a cross-sectional group survey with a standardized questionnaire administered to a convenience sample of approximately 70 nursing and midwifery leaders from 16 countries in east, central, and southern Africa. Each national delegation completed one survey together, representing the responses for their country. RESULTS: Almost all countries in this study (15; 94%) mandated pre-service nursing education accreditation However, there was wide variation in who was responsible for accrediting programs. The percent of active programs accredited decreased by program level from 80% for doctorate programs to 62% for masters nursing to 50% for degree nursing to 35% for diploma nursing programs. The majority of countries indicated that accreditation processes were transparent (i.e., included stakeholder engagement (81%), self-assessment (100%), evaluation feedback (94%), and public disclosure (63%)) and that the processes were evaluated on a routine basis (69%). Over half of the countries (nine; 56%) reported limited financial resources as a barrier to increasing accreditation activities, and seven countries (44%) noted limited materials and technical expertise. CONCLUSION: In line with the 2013 WHO guidelines, there was a strong legal mandate for nursing education accreditation as compared to the global average of 50%. Accreditation levels were low in the programs that produce the majority of the nurses in this region and were higher in public programs than non-public programs. WHO guidelines for transparency and routine review were met more so than standards-based and independent accreditation processes. The new global strategy, Workforce 2030, has renewed the focus on accreditation and provides an opportunity to strengthen pre-service accreditation and ensure the production of a qualified and relevant nursing workforce.

Preventing Soft-Tissue Triangle Collapse in Modern Rhinoplasty.

The unique anatomy of the soft-tissue triangle makes it prone to notching in primary, secondary, and reconstructive rhinoplasty. Understanding the anatomy of the region is critical to appropriate treatment. This article is meant to further clarify the anatomy of the soft-tissue triangle and to present the senior author's (R.J.R.) approach to proactive correction and prevention of soft-tissue triangle notching through five key steps: (1) precise dissection and incision placement, (2) providing internal support with cartilage grafting if needed, (3) closure of dead space, (4) avoiding undue tension during closure, and (5) providing external support postoperatively.

Universal BRCA1/BRCA2 Testing for Ovarian Cancer Patients is Welcomed, but with Care: How Women and Staff Contextualize Experiences of Expanded Access.

Decreasing costs of genetic testing and advances in treatment for women with cancer with germline BRCA1/BRCA2 mutations have heralded more inclusive genetic testing programs. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) Study, investigates the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (universal genetic testing or UGT). Study participants and staff were interviewed to: (i) assess the impact of UGT (ii) integrate patients' and staff perspectives in the development of new UGT programs. Semi-structured interviews were conducted with twelve GTEOC Study participants and five members of staff involved in recruiting them. The transcripts were transcribed verbatim and analyzed using Interpretative Phenomenological Analysis. There are two super-ordinate themes: motivations and influences around offers of genetic testing and impacts of genetic testing in ovarian cancer patients. A major finding is that genetic testing is contextualized within the broader experiences of the women; the impact of UGT was minimized in comparison with the ovarian cancer diagnosis. Women who consent to UGT are motivated by altruism and by their relatives' influence, whilst those who decline are often considered overwhelmed or fearful. Those without a genetic mutation are usually reassured by this result, whilst those with a genetic mutation must negotiate new uncertainties and responsibilities towards their families. Our findings suggest that UGT in this context is generally acceptable to women. However, the period shortly after diagnosis is a sensitive time and some women are emotionally overburdened. UGT is considered a 'family affair' and staff must acknowledge this.

Facial Danger Zones: Techniques to Maximize Safety during Soft-Tissue Filler Injections.

Given the short recovery and immediate results, facial fillers have become a popular alternative to surgical rejuvenation of the face. Reported complications arising from facial filler injections include erythema, tissue loss, blindness, stroke, and even death. In this article, the authors describe their anatomically based techniques to minimize risk and maximize safety when injecting in the facial danger zones, including the glabella/brow, temporal region, perioral region, nasolabial fold, nose, and infraorbital region. Complications generally arise secondary to vasculature injury and/or cannulation with filler. The authors have outlined their preferred injection techniques in the facial danger zones with respect to the pertinent anatomy in an attempt to minimize risk and maximize results. Most importantly, the practitioner should be able to recognize complications and address them immediately.

Improved HIV and TB Knowledge and Competence Among Mid-level Providers in a Cluster-Randomized Trial of One-on-One Mentorship for Task Shifting.

INTRODUCTION: Health worker shortages pose a challenge to the scale up of HIV care and treatment in Uganda. Training mid-level providers (MLPs) in the provision of HIV and tuberculosis (TB) treatment can expand existing health workforce capacity and access to HIV services. METHODS: We conducted a cluster-randomized trial of on-site clinical mentorship for HIV and TB care at 10 health facilities in rural Uganda. Twenty MLPs at 5 randomly assigned to an intervention facilities received 8 hours a week of one-on-one mentorship, every 6 weeks over a 9-month period; and another 20 at 5 control facilities received no clinical mentorship. Enrolled MLPs' clinical knowledge and competence in management of HIV and TB was assessed using case scenarios and clinical observation at baseline and immediately after the 9-month intervention. The performance of the study health facilities on 8 TB and HIV care indicators was tracked over the 9-month period using facility patient records. RESULTS: Thirty-nine out 40 enrolled MLPs had case scenario and clinical observation scores for both the baseline and end of intervention assessments. Mentorship was associated with a mean score increase of 16.7% (95% confidence interval: 9.8 to 23.6, P < 0.001) for the case scenario assessments and 25.9% (95% confidence interval: 14.4 to 37.5, P < 0.001) for the clinical observations. On-site clinical mentorship was significantly associated with an overall improvement for 5 of the 8 health facility TB and HIV indicators tracked. CONCLUSIONS: One-on-one on-site mentorship improves individual knowledge and competence, has a downstream effect on facility performance, and is a simple approach to training MLPs for task shifting.

Anatomy of the Facial Danger Zones: Maximizing Safety during Soft-Tissue Filler Injections.

With limited downtime and immediate results, facial filler injections are becoming an ever more popular alternative to surgical rejuvenation of the face. The results, and the complications, can be impressive. To maximize safety during injections, the authors have outlined general injection principles followed by pertinent anatomy within six different facial danger zones. Bearing in mind the depth and the location of the vasculature within each zone, practitioners can tailor their injection techniques to prevent vessel injury and avoid cannulation.

How Can the Health System Retain Women in HIV Treatment for a Lifetime? A Discrete Choice Experiment in Ethiopia and Mozambique.

INTRODUCTION: Option B+, an approach that involves provision of antiretroviral therapy (ART) to all HIV-infected pregnant women for life, is the preferred strategy for prevention of mother to child transmission of HIV. Lifelong retention in care is essential to its success. We conducted a discrete choice experiment in Ethiopia and Mozambique to identify health system characteristics preferred by HIV-infected women to promote continuity of care. METHODS: Women living with HIV and receiving care at hospitals in Oromia Region, Ethiopia and Zambézia Province, Mozambique were shown nine choice cards and asked to select one of two hypothetical health facilities, each with six varying characteristics related to the delivery of HIV services for long term treatment. Mixed logit models were used to estimate the influence of six health service attributes on choice of clinics. RESULTS: 2,033 women participated in the study (response rate 97.8% in Ethiopia and 94.7% in Mozambique). Among the various attributes of structure and content of lifelong ART services, the most important attributes identified in both countries were respectful provider attitude and ability to obtain non-HIV health services during HIV-related visits. Availability of counseling support services was also a driver of choice. Facility type, i.e., hospital versus health center, was substantially less important. CONCLUSIONS: Efforts to enhance retention in HIV care and treatment for pregnant women should focus on promoting respectful care by providers and integrating access to non-HIV health services in the same visit, as well as continuing to strengthen counseling.

MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms.

BACKGROUND: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. METHODS: We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. RESULTS: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. CONCLUSIONS: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.

Malignancy within a Tail Gut Cyst: A Case of Retrorectal Carcinoid Tumour.

Purpose. Tailgut cysts with malignant transformation are rare entities. We discuss the diagnostic strategy and treatment of a malignancy within a tailgut cyst. Methods. In this study we report on the case of a 61-year-old man with a malignant neuroendocrine tumour arising within a tailgut cyst and an overview of the literature emphasising the histopathological characteristics and differential diagnosis. Results. Our patient presented with lower back pain, rectal pain, and increased urgency of defecation. MRI scan and CT-guided biopsy on histological analysis revealed a diagnosis of carcinoid tumour of the presacral space. The patient subsequently underwent an abdominoperineal excision of the rectum. Conclusions. This case highlights the importance of tailgut cysts as a differential diagnosis of presacral masses. It is a rare congenital lesion developing from remnants of the embryonic postanal gut and is predominantly benign in nature. Approximately half of cases remain asymptomatic; therefore, diagnosis is often delayed. Magnetic resonance imaging is the investigation of choice and an awareness of the possibility of malignant potential is critical to avoiding missed diagnosis and subsequent morbidity. Complete surgical excision allows accurate diagnosis, confirmation of oncological clearance, and prevention of mortality.

Four-step medial thighplasty: refined and reproducible.

BACKGROUND: The medial thigh remains a troublesome region for body contouring in both the aging patient and in the massive weight loss patient. Liposuction-assisted medial thighplasty is the next step in the series of medial thigh contouring refinements to improve complications and outcomes. METHODS: Forty-five patients are presented who underwent medial thigh contouring with liposuction-assisted medial thighplasty. After anatomical analysis of the medial thigh, noting skin and fat redundancy, patients were selected for either an upper/inner medial thighplasty or an extended medial thighplasty. Operative markings, liposuction, and the excisional technique are presented with intraoperative video footage. RESULTS: Twenty-nine patients (64 percent) presented with aging thigh lipodystrophy, whereas 16 patients (36 percent) were massive weight loss lipodystrophy patients. The patients' ages ranged from 30 to 67 years, with 0.5 month to 9.5 years of follow-up. Liposuction evacuation volumes ranged from 175 to 1950 ml per thigh. Ten patients had minor wound breakdown, which healed with conservative wound care. CONCLUSIONS: Liposuction-assisted medial thighplasty is a safe, efficient, and reproducible procedure that should follow a four-step algorithm: (1) L-shaped anterior markings, (2) superwet infiltration, (3) circumferential combined superficial ultrasound-assisted/suction-assisted liposuction, and (4) predesigned and patterned skin excision and layered closure. It simplifies the markings and resection, and the procedure preserves the lymphatics and nerves, minimizes blood loss, and maintains the saphenous vein system to prevent skin loss and wound breakdown. It produces reliable and predictable results, with optimal outcomes. This technique offers another refinement in the evolution of medial thigh contouring.

Development of a framework to measure health profession regulation strengthening.

This paper describes the development of a framework to evaluate the progress and impact of a multi-year US government initiative to strengthen nursing and midwifery professional regulation in sub-Saharan Africa. The framework was designed as a capability maturity model, which is a stepwise series of performance levels that describe the sophistication of processes necessary to achieve an organization's objectives. A model from the field of software design was adapted to comprise the key functions of a nursing and midwifery regulatory body and describe five stages of advancing each function. The framework was used to measure the progress of five countries that received direct assistance to strengthen regulations and to benchmark the status of regulations in the 17 countries participating in the initiative. The framework captured meaningful advancements in regulatory strengthening in the five supported countries and the level of regulatory capacity in participating countries. The project uses the framework to assess yearly progress of supported countries, track the overall impact of the project on national and regional nursing regulation, and to identify national and regional priorities for regulatory strengthening. It is the first of its kind to document and measure progress toward sustainably strengthening nursing and midwifery regulation in Africa.

A survey of nurse-initiated and -managed antiretroviral therapy (NIMART) in practice, education, policy, and regulation in east, central, and southern Africa.

In sub-Saharan Africa, nurses and midwives perform many HIV service delivery tasks, such as diagnosis of HIV and prescription of antiretroviral therapy (ART), which used to be the responsibility of physicians. While this task shifting is critical to scaling-up HIV services in Africa, the extent of HIV task shifting is not well understood. A survey of senior nursing leadership teams from 15 African countries was carried out to describe the extent of nurse-initiated and -managed antiretroviral therapy (NIMART) in practice, education, policy, and regulation. The survey took place at the African Health Professions Regulatory Collaborative meeting in Pretoria, South Africa, in June 2012. The findings indicated that NIMART is widely practiced and authorized in policy, but is not reinforced by regulation nor incorporated into preservice education. Further investment in policy, regulation, and pre-service education is needed to ensure sustainable, high quality ART service expansion through the region.