Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Estimates of Probabilities of Successful Development of Pain Medications: An Analysis of Pharmaceutical Clinical Development Programs from 2000 to 2020.

BACKGROUND: The authors estimate the probability of successful development and duration of clinical trials for medications to treat neuropathic and nociceptive pain. The authors also consider the effect of the perceived abuse potential of the medication on these variables. METHODS: This study uses the Citeline database to compute the probabilities of success, duration, and survivorship of pain medication development programs between January 1, 2000, and June 30, 2020, conditioned on the phase, type of pain (nociceptive vs. neuropathic), and the abuse potential of the medication. RESULTS: The overall probability of successful development of all pain medications from phase 1 to approval is 10.4% (standard error, 1.5%). Medications to treat nociceptive and neuropathic pain have a probability of successful development of 13.3% (standard error, 2.3%) and 7.1% (standard error, 1.9%), respectively. The probability of successful development of medications with high abuse potential and low abuse potential are 27.8% (standard error, 4.6%) and 4.7% (standard error, 1.2%), respectively. The most common period for attrition is between phase 3 and approval. CONCLUSIONS: The authors' data suggest that the unique attributes of pain medications, such as their abuse potential and intended pathology, can influence the probability of successful development and duration of development.

Infectious Complications of Dorsal Root Ganglion Stimulation: A Systematic Review and Pooled Analysis of Incidence.

BACKGROUND AND OBJECTIVES: Dorsal root ganglion stimulation (DRGS) is a newer form of neuromodulation that targets the dorsal root ganglion. DRGS has superior efficacy in complex regional pain syndrome compared to spinal cord stimulation (SCS) and may have efficacy in other forms of chronic pain. While decades of safety data are available for SCS, there is less available safety information for DRGS. The objectives of this systematic review and pooled analysis of incidence are to determine the overall incidence of DRGS infections, incidence at each stage (trial vs implant vs revision), infection characteristics, and outcomes. MATERIALS AND METHODS: A comprehensive search of databases from January 1980 to January 2021 was conducted. RESULTS: Ten studies met inclusion criteria. Eight studies reported patients with trial data (n = 291), ten studies reported patients with implant data (n = 250), and seven studies reported data with revisions (n = 26). The pooled incidence of trial infections was 1.03% (95% CI 0.35-2.99%), implant infections was 4.80% (95% CI 2.77-8.20%), revision infections was 3.85% (95% CI 0.20-21.59%), and overall infections was 2.82% (95% CI 1.62-4.54%). There was a statistically significant difference in infection rates between the trial, implant, and revision stages, X2 (2, N = 567) = 8.9839, p = 0.01. CONCLUSIONS: This is the first systematic review and pooled analysis that followed PRISMA guidelines to report infectious complications of DRGS by stage (trial vs implant vs revision). DRGS trial appears to be low risk for infection but that risk is significantly increased with DRGS implant. Our findings highlight the need for further study of infectious complications, their risks, and optimal prophylaxis.

Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis-related fatigue.

BACKGROUND: Fatigue is the most common symptom of MS and has no effective pharmacotherapy. OBJECTIVE: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. METHODS: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models. RESULTS: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (-0.10 point; 95% confidence interval (CI): -0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (-5.2 points; 95% CI: -10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (-13.5 point; 95% CI: -25.0, -1.98; p = 0.04). CONCLUSIONS: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.

Implementation research training for learners in low- and middle-income countries: evaluating behaviour change after participating in a massive open online course.

BACKGROUND: Implementation research (IR) can play a critical role in the delivery of disease control interventions, particularly in low- and middle-income countries (LMICs). The growing demand for IR training has led to the development of a range of training programmes and university courses, the majority of which can not be accessed by learners in LMICs. This article reports on the evaluation of the massive open online course (MOOC) developed by the Special Programme for Research and Training in Tropical Diseases hosted by WHO on the topic of IR with a focus on infectious diseases of poverty. This study followed the Kirkpatrick Model to evaluate training programmes with a specific focus on post-training changes in behaviour. METHODS: MOOC participants were invited to take part in an anonymous online survey examining their knowledge of IR and how they applied it in their professional practice approximately 1-1.5 years after completing their course. The survey contained 43 open-ended, multiple choice and Likert-type questions. Descriptive statistics were calculated for the quantitative data and responses to the open-ended questions were thematically coded. RESULTS: A total of 748 MOOC participants responded to the survey. The demographic profile of the survey respondents aligned with that of the MOOC participants, with nearly 70% of respondents originating from Africa. Responses to the quantitative and open-ended survey questions revealed that respondents' knowledge of IR had improved to a large extent as a result of the MOOC, and that they used the knowledge and skills gained in their professional lives frequently and had consequently changed their professional behaviour. Respondents most often cited the problem-solving aspect of IR as a substantial area of behavioral change influenced by participating in the MOOC. CONCLUSIONS: These findings indicate that the MOOC was successful in targeting learners from LMICs, in strengthening their IR knowledge and contributing to their ability to apply it in their professional practice. The utility of MOOCs for providing IR training to learners in LMICs, where implementation challenges are encountered often, makes this platform an ideal standalone learning tool or one that could be combined with other training formats.

Morphine decreases the function of primary human natural killer cells by both TLR4 and opioid receptor signaling.

BACKGROUND: Opioids are commonly used to provide analgesia for cancer pain, and functional opioid receptors have been identified on natural killer (NK) cells, the lymphocytes responsible for surveillance and elimination of cancer cells. Opioids also bind to other lymphocyte receptors, such as Toll-like receptor (TLR)-4. Here, we characterized the effects of morphine on primary human NK cell cytotoxicity and mediator release, which occur through classical opioid receptor or TLR4 signaling. METHODS: Purified primary human NK cells were pretreated with inhibitors of opioid receptors or TLR4 before being cultured with target tumor cell line K562 in the presence or absence of morphine. Apoptosis of K562 cells in each treatment condition was measured with an Annexin V flow cytometry-based assay and compared to that of K562 cells cultured with NK cells alone. Supernatant concentrations of 13 cytokines and cytotoxic mediators were measured with a multiplex bead-based flow cytometry assay. RESULTS: Exposure of NK cells to morphine decreased their ability to induce apoptosis in K562 cells. Pretreating the NK cells with either naloxone, a mu- and kappa-opioid receptor antagonist, or TAK-242, a selective inhibitor of TLR4 signaling, prevented this effect. Paradoxically, morphine increased the concentration of interleukin-6, granzyme A, and granzyme B in cell supernatants. Pretreatment of NK cells with TAK-242 prevented the morphine-induced increase in interleukin-6, whereas pretreatment with naloxone inhibited the morphine-induced increase in granzymes A and B. CONCLUSIONS: Both classical opioid receptors and TLR4 participate in morphine-induced suppression of NK cell cytotoxic activity. These studies have important implications for maintenance of immune function during management of cancer pain.

Cerebral Autoregulation-Guided Optimal Blood Pressure in Sepsis-Associated Encephalopathy: A Case Series.

BACKGROUND: Impaired cerebral autoregulation and cerebral hypoperfusion may play a critical role in the high morbidity and mortality in patients with sepsis-associated encephalopathy (SAE). Bedside assessment of cerebral autoregulation may help individualize hemodynamic targets that optimize brain perfusion. We hypothesize that near-infrared spectroscopy (NIRS)-derived cerebral oximetry can identify blood pressure ranges that enhance autoregulation in patients with SAE and that disturbances in autoregulation are associated with severity of encephalopathy. METHODS: Adult patients with acute encephalopathy directly attributable to sepsis were followed using NIRS-based multimodal monitoring for 12 consecutive hours. We used the correlation in time between regional cerebral oxygen saturation and mean arterial pressure (MAP) to determine the cerebral oximetry index (COx) as a measure of cerebral autoregulation. Autoregulation curves were constructed for each patient with averaged COx values sorted by MAP in 3 sequential 4-hour periods; the optimal pressure (MAPOPT), defined as the MAP associated with most robust autoregulation (lowest COx), was identified in each period. Severity of encephalopathy was measured with Glasgow coma scale (GCS). RESULTS: Six patients with extracranial sepsis met the stringent criteria specified, including no pharmacological sedation or neurologic premorbidity. Optimal MAP was identified in all patients and ranged from 55 to 115 mmHg. Additionally, MAPOPT varied within individual patients over time during monitoring. Disturbed autoregulation, based on COx, was associated with worse neurologic status (GCS < 13) both with and without controlling for age and severity of sepsis (adjusted odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.77-2.52; P < .001; OR: 2.97; 95% CI: 1.63-5.43; P < .001). CONCLUSIONS: In this high-fidelity group of patients with SAE, continuous, NIRS-based monitoring can identify blood pressure ranges that improve autoregulation. This is important given the association between cerebral autoregulatory function and severity of encephalopathy. Individualizing blood pressure goals using bedside autoregulation monitoring may better preserve cerebral perfusion in SAE than current practice.

Incorporating operational research in programmes funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria in four sub-Saharan African countries.

BACKGROUND: The current study builds upon a previous situation analysis of the extent to which grants from the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) are being utilized to support operational research and implementation research (OR/IR) activities in recipient countries. The objective of this follow-up study was to identify approaches and pathways to implement an OR component into grants to the Global Fund, in four sub-Saharan African countries. Special focus was given to the Structured Operational Research and Training IniTiative (SORT IT). METHODS: The conceptual framework was based on an analysis to identify elements supporting and blocking the integration of OR, called force field analysis, and a behavioural change assessment covering aspects such as opportunity, motivation, capability and triggers to do the integration. Data were collected through online surveys and stakeholder interviews both via telephone/online conference tools and in person in four countries with a high burden of malaria and tuberculosis. These countries were Ghana, Sierra Leone, the United Republic of Tanzania and Zimbabwe. The stakeholders included programme managers, implementation partners, representatives from international organisations, academic and governmental research institutions and other individuals involved in the countries' needs assessment and National Strategic Plan development. RESULTS: We identified opportunities to integrate OR into the countries' programmes during the funding process, the country's needs assessment being the most important one, including the need of OR-related capacity. Both the force field analysis and the behavioural change assessment showed that the necessary elements to integrate OR were present in the countries. Motivation, capability and efficiency were found to be a managerial value omnipresent across stakeholders. However, those elements were influenced by the tendency to favour tangible assets over any abstract ones, such as increasing organisational capacity in OR. CONCLUSIONS: In each of the countries assessed, there is potential to integrating OR into the programmes supported by the Global Fund. However, given the relative lack of OR-related capacity and skills encountered, a capacity strengthening tool, such as SORT IT, would be of benefit helping to identify and carry forward OR activities sustainably.

Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future.

The field of spinal cord stimulation is expanding rapidly, with new waveform paradigms asserting supraspinal sites of action. The scope of treatment applications is also broadening from chronic pain to include cerebral ischemia, dystonia, tremor, multiple sclerosis, Parkinson disease, neuropsychiatric disorders, memory, addiction, cognitive function, and other neurologic diseases. The role of neurostimulation as an alternative strategy to opioids for chronic pain treatment is under robust discussion in both scientific and public forums. An understanding of the supraspinal mechanisms underlying the beneficial effects of spinal cord stimulation will aid in the appropriate application and development of optimal stimulation strategies for modulating pain signaling pathways. In this review, the authors focus on clinical and preclinical studies that indicate the role of supraspinal mechanisms in spinal cord stimulation-induced pain inhibition, and explore directions for future investigations.

Suppression of Human Natural Killer Cells by Different Classes of Opioids.

BACKGROUND: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized. METHODS: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester-labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction. RESULTS: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5] enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells. CONCLUSIONS: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not observed after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with µ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by µ- and κ-receptor agonism and that suppression is similar with many clinically used opioids.

Cannabis for the Treatment of Chronic Pain in the Era of an Opioid Epidemic: A Symposium-Based Review of Sociomedical Science.

OBJECTIVE: This manuscript reviews medical literature published pertaining to the management of chronic pain with medical marijuana therapy (MMJ), with an emphasis on the social, medical, and legal aspects of therapy. DESIGN: Narrative review of peer-reviewed literature. METHODS: The 3rd Symposium on Controlled Substances and Their Alternatives for the Treatment of Pain was held in Boston on February 27, 2016, with a focus on MMJ for the treatment of chronic pain. Invited speakers had diverse backgrounds, including pain management, addiction psychiatry, neurology, and legal authorities. The purpose of this conference and this subsequent narrative review is to provide a medical, legal, and logistical framework for physicians and other health care providers to refer to when considering the initiation of medical marijuana therapy. RESULTS: The invited speakers each covered a unique aspect of MMJ therapy for the treatment of chronic pain. These presentations highlighted the current data for and against the use of MMJ as a pain therapy. Optimal patient selection and screening, in addition to policy developments, were discussed. CONCLUSIONS: Increasing interest in MMJ for chronic pain underscores a need for primary care and pain physicians to better understand the indications and evidence for its use free from cultural bias. Given a lack of full conclusive clinical utility, continued research is needed to better understand how to best utilize MMJ therapy for the treatment of chronic pain. Policy initiatives, such as enumerated indications, should follow medical science in order to prevent another abused substance epidemic.

Strengthening health research capacity in sub-Saharan Africa: mapping the 2012-2017 landscape of externally funded international postgraduate training at institutions in the region.

BACKGROUND: The objective was to guide key stakeholders on future directions of external funding of international postgraduate training (Master's and PhD) of health research students at institutions in sub-Saharan Africa by mapping the numbers and characteristics of students, the location of institutions, and sources of external support. A cross-sectional survey of eligible external funding organizations and programmes was conducted in 2017. Information was gathered from funders' websites or through the assistance of institutional contacts. The information requested included the number of Master's and PhD grantees supported from January 2012 to June 2017, as well as each grantee's institution of study, gender, country of origin and research area. RESULTS: Of 72 organizations contacted, there were 44 responses. Of the 44, 30 funders reported programmes within the inclusion criteria, and 19 funders provided data on relevant programmes. The Wellcome Trust, the International Development Research Centre and the Norwegian Agency for Development Cooperation supported the greatest number of grantees. There was concentrated support for grantees in eastern and southern Africa, countries with developed research capacity, and highly-developed research and training centres. More support was provided for PhD than Master's degree programmes and for research areas more upstream along the research spectrum. Challenges were identified in recognizing relevant funding organizations and obtaining responses. Information was presented inconsistently across organizations, which were often unable to provide relevant and complete data within the survey timeframe. CONCLUSIONS: External funders should collect, analyse and report data at regular intervals on their support for strengthening postgraduate health research capacity in sub-Saharan Africa. Standardization of this process and development of an online database would not only help to avoid overlap between programmes and promote synergy between funders, but also inform dialogue between external funders and key stakeholders on strategic issues. These issues include how external funders can a) optimise their support for research capacity strengthening to maximise the benefits of research for health and development on an equitable basis, and b) optimise the distribution of support for researchers at different career stages and for research on different parts of the research spectrum to maximise the health benefits of research.

Neuropathic Pain Medication Use Does Not Alter Outcomes of Spinal Cord Stimulation for Lower Extremity Pain.

INTRODUCTION: Spinal cord stimulation (SCS) for the treatment of lower extremity pain is believed to the result of increased activity in the descending inhibitory and decreased activity in the ascending excitatory tracts. Evidence suggests that the analgesia afforded by SCS may be altered using certain neuropathic pain medications that also modulate neurotransmitters in these sensory tracts. We hypothesize that neuropathic pain medications may alter the response to SCS therapy. METHODS: One hundred and fifteen subjects undergoing SCS therapy for lower extremity pain were retrospectively examined. The pharmacologic profile, including stable use of neuropathic and opioid medications, were recorded. Three separate logistic regression models examined the odds ratio of primary outcomes; a successful SCS trial, a 50% decrease in pain or a 50% reduction in opioid use one year after implant. RESULTS: Neither the use of opioids or neuropathic pain medications were associated with changes in the odds of a successful SCS trial or a 50% pain reduction. A higher dose of chronic opioids use prior to a trial was associated with greater odds of having a 50% reduction in opioid use following implant. OR 1.02, 95% CI 1.01-1.02, p-value < 0.01). CONCLUSIONS: The use of neuropathic pain medications did not change the odds of either a successful SCS trial, or of experiencing a 50% reduction in pain at one year. The association between higher opioid doses and greater odds of a 50% reduction in opioid use may be the reflective of SCS's ability to reduce opioid reliance in chronic pain patients.

Opioid Reduction Following Interventional Procedures for Chronic Pain: A Synthesis of the Evidence.

The past decade has witnessed the tremendous growth of procedures to treat chronic pain, which has resulted in increased third-party scrutiny. Although most of these procedures appear to be associated with significant pain relief, at least in the short and intermediate term, their ability to improve secondary outcome measures, including function and work status is less clear-cut. One of these secondary outcome measures that has garnered substantial interest in the pain and general medical communities is whether interventions can reduce opioid intake, which is associated with significant risks that in most cases outweigh the benefits in the long term. In the article, we examine whether procedural interventions for chronic pain can reduce opioid intake. Most studies that have examined analgesic reduction as a secondary outcome measure have not separated opioid and nonopioid analgesics, and, among those studies that have, few have demonstrated between-group differences. Reasons for failure to demonstrate opioid reduction can be broadly classified into procedural, design-related, clinical, psychosocial, biological, and pharmacological categories, all of which are discussed. In the future, clinical trials in which this outcome is examined should be designed to evaluate this, at least on a preliminary basis.

Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization.

Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence-Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied.

The Combination of IV and Perineural Dexamethasone Prolongs the Analgesic Duration of Intercostal Nerve Blocks Compared with IV Dexamethasone Alone.

Objective: The use of multiple-level, single-injection intercostal nerve blocks for pain control following video-assisted thorascopic surgery (VATS) is limited by the analgesic duration of local anesthetics. This study examines whether the combination of perineural and intravenous (IV) dexamethasone will prolong the duration of intraoperatively placed intercostal nerve blocks following VATS compared with IV dexamethasone and a perineural saline placebo. Design: Prospective, double-blind, randomized placebo-controlled trial. Setting: Single level-1 academic trauma center. Subjects: Forty patients undergoing a unilateral VATS under the care of a single surgeon. Methods: Patients were randomly assigned to two groups and received an intercostal nerve block containing 1) 0.5% bupivacaine with epinephrine and 1 ml of 0.9% saline or 2) 0.5% bupivacaine with epinephrine and 1 ml of a 4 mg/ml dexamethasone solution. All patients received 8 mg of IV dexamethasone. Results: Group 2 had lower NRS-11 scores at post-operative hours 8 (5.05, SD = 2.13 vs 3.50, SD = 2.50; p = 0.04), 20 (4.30, SD = 2.96 vs 2.26, SD = 2.31; p = 0.02), and 24 (4.53, SD = 1.95 vs 2.26, SD = 2.31; p = 0.02). Equianalgesic opioid requirement was decreased in group 2 at 32 hours (5.78 mg, SD = 5.77 vs 1.67 mg, SD = 3.49; p = 0.02). Group 2 also had greater FEV1 measured at 8, 12, 24, and 44 hours; greater FVC at 24 hours; greater PEF at 28 through 48 hours; and greater FEV1/FVC at 8 and 36 hours. Conclusions: The combination of IV and perineural dexamethasone prolonged the duration of a single-injection bupivacaine intercostal nerve block as measured by NRS-11 compared with IV dexamethasone alone at 24 hours. Reduced NRS-11 at other times, reduced opioid requirements, and increased PFTs were observed in group 2.

Thermal QST Phenotypes Associated with Response to Lumbar Epidural Steroid Injections: A Pilot Study.

OBJECTIVE: Response to lumbar epidural steroid injection in lumbar radicular pain varies. The purpose of this study is to characterize the changes in quantitative sensory testing (QST) phenotypes of subjects and compare the QST characteristics in patients who do respond to treatment of radicular pain with a lumbar epidural steroid injection (ESI). DESIGN: Prospective, observational pilot study. SETTING: Outpatient pain center. METHODS: Twenty subjects with a lower extremity (LE) radicular pain who were scheduled to have an ESI were recruited. At the visit prior to and four weeks following an ESI, subjects underwent QST measurements of both the affected LE and the contralateral unaffected UE. RESULTS: Following an ESI, nine subjects reported a greater than 30% reduction in radicular pain and 11 reported a less than 30% reduction in radicular pain. Subjects who had less than 30% pain reduction response (nonresponders) to an ESI had increased pre-injection warm sensation threshold (37.30 °C, SD = 2.51 vs 40.39, SD = 3.36, P = 0.03) and heat pain threshold (47.22 °C, SD = 1.38, vs 48.83 °C, SD = 2.10, P = 0.04). Further, the nonresponders also showed increased pre-injection warm sensation threshold as measured in the difference of warm sensation detection threshold difference in the affected limb and the unaffected arm (2.68 °C, SD = 2.92 vs 5.67 °C, SD = 3.22, P = 0.045). Other QST parameters were not affected. CONCLUSIONS: The results show that the nonresponders to ESIs have increased detection threshold to heat pain and warm sensation, suggesting that a preexisting dysfunction in the C fibers in this group of subjects who can be detected by QST. Such altered QST characteristics may prognosticate the response to ESIs.

Operational and implementation research within Global Fund to Fight AIDS, Tuberculosis and Malaria grants: a situation analysis in six countries.

BACKGROUND: Operational/implementation research (OR/IR) is a key activity to improve disease control programme performance. We assessed the extent to which malaria and tuberculosis (TB) grants from the Global Fund to Fight AIDS, Tuberculosis and Malaria ("Global Fund") include support for OR/IR, and discuss the implications of the current Global Fund operating mechanisms for OR/IR support. METHODS: The situation analysis focussed on malaria and TB, while HIV was excluded. Stakeholder interviews were conducted at the Global Fund secretariat and in six purposefully selected high disease burden countries, namely the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Myanmar and Zimbabwe. Interviewed in-country stakeholders included the relevant disease control programme managers, project implementation partners, representatives from international organisations with a stake in global health, academic and governmental research institutions, and other relevant individuals such as members of the country coordination mechanism. Additionally, documentation of grants and OR/IR obtained from the Global Fund was reviewed. RESULTS: The Global Fund provides substantial resources for malaria and TB surveys, and supports OR/IR if such support is requested and the application is well justified. We observed considerable variations from one country to another and between programmes with regards to need, demand, absorption capacity and funding for OR/IR related to malaria and TB. Important determinants for the extent of such funding are the involvement of national research coordination bodies, established research agendas and priorities, human and technical research capacity, and involvement of relevant stakeholders in concept note development. Efforts to disseminate OR/IR findings were generally weak, and the Global Fund does not maintain a central OR/IR database. When faced with a need to choose between procurement of commodities for disease control and supporting research, countries tend to seek research funding from other donors. The Global Fund is expected to issue more specific guidance on the conditions under which it supports OR/IR, and to adapt administrative procedures to facilitate research. CONCLUSIONS: The importance of OR/IR for optimising disease control programmes is generally accepted but countries vary in their capacity to demand and implement studies. Countries expect guidance on OR/IR from the Global Fund. Administrative procedures specifically related to the budget planning should be modified to facilitate ad-hoc OR/IR funding. More generally, several countries expressed a need to strengthen capacity for planning, negotiating and implementing research.

Reporting guidelines for implementation and operational research.

In public health, implementation research is done to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them. Researchers identify practical problems facing public health programmes and aim to find solutions that improve health outcomes. In operational research, routinely-collected programme data are used to uncover ways of delivering more effective, efficient and equitable health care. As implementation research can address many types of questions, many research designs may be appropriate. Existing reporting guidelines partially cover the methods used in implementation and operational research, so we ran a consultation through the World Health Organization (WHO), the Alliance for Health Policy & Systems Research (AHPSR) and the Special Programme for Research and Training in Tropical Diseases (TDR) and developed guidelines to facilitate the funding, conduct, review and publishing of such studies. Our intention is to provide a practical reference for funders, researchers, policymakers, implementers, reviewers and editors working with implementation and operational research. This is an evolving field, so we plan to monitor the use of these guidelines and develop future versions as required.

Dans le domaine de la santé publique, des recherches sur la mise en œuvre sont menées pour améliorer l'accès aux interventions qui se sont révélées efficaces, mais qui n'ont pas touché toutes les personnes qui auraient pu en bénéficier. Les chercheurs identifient les difficultés pratiques qui compromettent les programmes de santé publique et s'efforcent de trouver des solutions pour améliorer les résultats sanitaires. Les données de programme systématiquement collectées dans le cadre des recherches opérationnelles, sont utilisées pour mettre en lumière des moyens de rendre les soins de santé plus efficaces, efficients et équitables. D'autre part, comme il est possible que les recherches sur la mise en œuvre portent sur de nombreux types de questions, différents plans de recherche peuvent s'avérer appropriés. Les directives existantes concernant l'établissement de rapports traitent en partie des méthodes utilisées dans le cadre des recherches sur la mise en œuvre et des recherches opérationnelles. Nous avons donc mené une consultation au sein de l'Organisation mondiale de la Santé (OMS), de l'Alliance pour la recherche sur les politiques et les systèmes de santé (AHPSR) et du Programme spécial de recherche et de formation concernant les maladies tropicales (TDR) et élaboré des directives pour faciliter le financement, la conduite, la révision et la publication de ce type de recherches. Notre objectif est de fournir une référence pratique pour les bailleurs de fonds, les chercheurs, les décideurs, les responsables de la mise en œuvre, les réviseurs et les éditeurs associés aux recherches sur la mise en œuvre et aux recherches opérationnelles. Ce domaine étant en constante évolution, nous prévoyons de suivre l'utilisation de ces directives et de rédiger, si besoin est, de futures versions.

En la salud pública, las investigaciones sobre la ejecución se llevan a cabo para mejorar el acceso a las intervenciones que se ha demostrado que funcionan pero que no han llegado a una gran parte de las personas que podrían beneficiarse de ellas. Los investigadores identifican los problemas prácticos a los que se enfrentan los programas de salud pública y tratan de encontrar soluciones que mejoren los resultados sanitarios. En las investigaciones operativas, se utilizan datos de programas recopilados rutinariamente para descubrir formas de ofrecer una atención sanitaria más efectiva, eficiente y equitativa. Puesto que una investigación sobre la ejecución puede abordar muchos tipos de cuestiones, pueden ser apropiados muchos diseños de investigación. Las directrices existentes sobre la presentación de informes cubren parcialmente los métodos utilizados en las investigaciones operativas y sobre la ejecución, por lo que se llevó a cabo una consulta a través de la Organización Mundial de la Salud (OMS), la Alianza para la Investigación en Políticas y Sistemas de Salud (Alianza IPSS) y el Programa Especial de Investigaciones y Enseñanzas sobre Enfermedades Tropicales (TDR) y se desarrollaron directrices para facilitar la financiación, realización, revisión y publicación de dichos estudios. El objetivo es proporcionar una referencia práctica para financiadores, investigadores, responsables de la formulación de políticas, implementadores, revisores y editores que trabajen con investigaciones operativas y sobre la ejecución. Se trata de un área en evolución, por lo que prevemos supervisar el uso de estas directrices y desarrollar versiones futuras si fuera necesario.

Scaling-up antiretroviral therapy in Malawi.

PROBLEM: In Malawi, health-system constraints meant that only a fraction of people infected with human immunodeficiency virus (HIV) and in immediate need of antiretroviral treatment (ART) received treatment. APPROACH: In 2004, the Malawian Ministry of Health launched plans to scale-up ART nationwide, adhering to the principle of equity to ensure fair geographical access to therapy. A public health approach was used with standardized training and treatment and regular supervision and monitoring of the programme. LOCAL SETTING: Before the scale-up, an estimated 930 000 people in Malawi were HIV-infected, with 170 000 in immediate need of ART. About 3000 patients were on ART in nine clinics. RELEVANT CHANGES: By December 2015, cumulatively 872 567 patients had been started on ART from 716 clinics, following national treatment protocols and using the standard monitoring system. LESSONS LEARNT: Strong national leadership allowed the ministry of health to implement a uniform system for scaling-up ART and provided benchmarks for implementation on the ground. New systems of training staff and accrediting health facilities enabled task-sharing and decentralization to peripheral health centres and a standardized approach to starting and monitoring ART. A system of quarterly supervision and monitoring, into which operational research was embedded, ensured stocks of drug supplies at facilities and adherence to national treatment guidelines.