Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages.

Molecular predictors for decitabine efficacy in meningiomas - a pilot study.

PURPOSE: Effective chemotherapeutical agents for the treatment of meningiomas are still lacking. Previous in-vitro analyses revealed efficacy of decitabine (DCT), a DNA methyltransferase (DNMT) inhibitor established in the treatment of leukemia, in a yet undefined subgroup of meningiomas. METHODS: Effects of DCT on proliferation and viability was analyzed in primary meningioma cells by immunofluorescence and MTT assays, and cases were classified as drug responders and non-responders. Molecular preconditions for efficacy were analyzed using immunofluorescence for Ki67, DNMT1, and five oncogenes (TRIM58, FAM84B, ELOVL2, MAL2, LMO3) previously found to be differentially methylated after DCT exposition, as well as by genome-wide DNA methylation analyses. RESULTS: Efficacy of DCT (10µM) was found in eight (62%) of 13 meningioma cell lines 48 h after drug exposition (p < .05). DCT significantly reduced DNMT1 expression in all but two cell lines, and median ΔDNMT1 reduction 48 h after drug exposition was lower in DCT-resistant (-11.1%) than in DCT-sensitive (-50.5%, p = .030) cells. Rates of cell lines responsive to DCT exposition distinctly decreased to 25% after 72 h. No significant correlation of the patients´ age, sex, histological subtype, location of the paternal tumor, expression of Ki67, DNMT1 or the analyzed oncogenes with treatment response was found (p > .05, each). DCT efficacy was further independent of the methylation class and global DNA methylation of the paternal tumor. CONCLUSION: Early effects of DCT in meningiomas are strongly related with DNMT1 expression, while clinical, histological, and molecular predictors for efficacy are sparse. Kinetics of drug efficacy might indicate necessity of repeated exposition and encourage further analyses.

Iatrogenic lumbosacral infiltration with petroleum (hydrodesulfurized heavy) with secondary intrathecal distribution-a case report.

Petroleum is commonly used as a solvent, and primary intrathecal administration or secondary diffusion and subsequent clinical management has not been reported. We report the case of a male patient with intrathecal petroleum diffusion following accidental lumbar infiltration. After the onset of secondary myeloencephalopathy with coma and tetraparesis, continuous cranio-lumbar irrigation using an external ventricular and a lumbar drain was established. Cranial imaging revealed distinct supra- and infratentorial alterations. The patient improved slowly and was referred to rehabilitation. Intrathecal petroleum leads to myeloencephalopathy and continuous cranio-lumbar irrigation might be a safe treatment option.

New MraYAA Inhibitors with an Aminoribosyl Uridine Structure and an Oxadiazole.

New inhibitors of the bacterial transferase MraY from Aquifex aeolicus (MraYAA), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) of the enzyme active site, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin. A panel of ten compounds was synthetized notably thanks to a robust microwave-activated one-step sequence for the synthesis of the oxadiazole ring that involved the O-acylation of an amidoxime and subsequent cyclization. The synthetized compounds, with various hydrophobic substituents on the oxadiazole ring, were tested against the MraYAA transferase activity. Although with poor antibacterial activity, nine out of the ten compounds revealed the inhibition of the MraYAA activity in the range of 0.8 µM to 27.5 µM.

The Emesis Trial: Depressive Glioma Patients Are More Affected by Chemotherapy-Induced Nausea and Vomiting.

PURPOSE: Glioma patients face a limited life expectancy and at the same time, they suffer from afflicting symptoms and undesired effects of tumor treatment. Apart from bone marrow suppression, standard chemotherapy with temozolomide causes nausea, emesis and loss of appetite. In this pilot study, we investigated how chemotherapy-induced nausea and vomiting (CINV) affects the patients' levels of depression and their quality of life. METHODS: In this prospective observational multicentre study (n = 87), nausea, emesis and loss of appetite were evaluated with an expanded MASCC questionnaire, covering 10 days during the first and the second cycle of chemotherapy. Quality of life was assessed with the EORTC QLQ-C30 and BN 20 questionnaire and levels of depression with the PHQ-9 inventory before and after the first and second cycle of chemotherapy. RESULTS: CINV affected a minor part of patients. If present, it reached its maximum at day 3 and decreased to baseline level not before day 8. Levels of depression increased significantly after the first cycle of chemotherapy, but decreased during the further course of treatment. Patients with higher levels of depression were more severely affected by CINV and showed a lower quality of life through all time-points. CONCLUSION: We conclude that symptoms of depression should be perceived in advance and treated in order to avoid more severe side effects of tumor treatment. Additionally, in affected patients, delayed nausea was most prominent, pointing toward an activation of the NK1 receptor. We conclude that long acting antiemetics are necessary totreat temozolomide-induced nausea.

A Sub-Micromolar MraYAA Inhibitor with an Aminoribosyl Uridine Structure and a (S,S)-Tartaric Diamide: Synthesis, Biological Evaluation and Molecular Modeling.

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraYAA transferase activity, and the most active compound with an original (S,S)-tartaric diamide linker inhibits MraY activity with an IC50 equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.

The applicability of established clinical and histopathological risk factors for tumor recurrence during long-term postoperative care in meningioma patients.

Risk factors to predict late-onset tumor recurrence in meningioma patients are urgently needed to schedule control intervals during long-term follow-up. We therefore analyzed the value of established risk factors for postoperative meningioma recurrence for the prediction of long-term prognosis. Correlations of clinical and histopathological variables with tumor relapse after 3, 5, and 10 years following microsurgery were analyzed in uni- and multivariate analyses, and compared to findings in the entire cohort. In the entire cohort (N = 1218), skull base location (HR: 1.51, 95%CI 1.05-2.16; p = .026), Simpson ≥ IV resections (HR: 2.41, 95%CI 1.52-3.84; p < .001), high-grade histology (HR: 3.70, 95%CI 2.50-5.47; p < .001), and male gender (HR: 1.46, 95%CI 1.01-2.11; p = .042) were independent risk factors for recurrence. Skull base location (HR: 1.92, 95%CI 1.17-3.17; p = .010 and HR: 2.02, 95%CI 1.04-3.95; p = .038) and high-grade histology (HR: 1.87, 95%CI 1.04-3.38; p = .038 and HR: 2.29, 95%CI 1.07-4.01; p = .034) but not subtotal resection (HR: 1.53, 95%CI .68-3.45; p = .303 and HR: 1.75, 95%CI .52-5.96; p = .369) remained correlated with recurrence after a recurrence-free follow-up of ≥ 3 and ≥ 5 years, respectively. Postoperative tumor volume was related with recurrence in general (p < .001) but not beyond a follow-up of ≥ 3 years (p > .05). In 147 patients with a follow-up of ≥ 10 years, ten recurrences occurred and were not correlated with any of the analyzed variables. Skull base tumor location and high-grade histology but not the extent of resection should be considered when scheduling the long-term follow-up after meningioma surgery. Recurrences ≥ 10 years after surgery are rare, and predictors are lacking.

Lesión traumática expuesta, compleja y grave de tibia, tratada con fijador externo Álvarez Cambras / Exposed, complex and severe traumatic injury of the tibia treated with Alvarez Cambra external fixation

RESUMEN Con el paulatino incremento de accidentes automovilísticos, de trabajo, y la violencia urbana, las fracturas expuestas y complejas constituyen traumatismos de creciente incidencia y de difícil solución, con largos períodos de convalecencia que ponen en peligro la vida o la conservación del miembro lesionado. Un gran número de ellas dejan secuelas invalidantes. Existen varios tratamientos, entre ellos la fijación externa, utilizando el sistema creado por el profesor Rodrigo Álvarez Cambras, con varias ventajas que proporcionan una mejor evolución. Se realizó este trabajo con el objetivo de mostrar la evolución y los resultados de un paciente ingresado y operado con el diagnóstico de lesión expuesta, compleja y grave de la extremidad inferior, específicamente de tibia. Este presentó varias complicaciones, por lo que se le colocó un aparato de osteosíntesis de fijación externa Álvarez Cambras en el Hospital Provincial Clínico Quirúrgico Docente José Ramón López Tabrane, de Matanzas (AU).

ABSTRACT With the gradual increase of automobile and work accidents as well as urban violence, exposed and complex fractures are traumas of increasing incidence and difficult solution, with long periods of convalescence that endanger the life or the conservation of the injured member. A large number of them leave invalidating sequels. There are several treatments, including external fixation using the system created by Professor Rodrigo Alvarez Cambra, with several advantages that provide a better evolution. The current work was carried out with the objective of showing the evolution and results of a patient who entered the Teaching Provincial Clinical-surgical Hospital Jose Ramon Lopez Tabrane, of Matanzas, and underwent a surgery with the diagnosis of exposed, complex and serious lesion in the lower limb, specifically of tibia. The patient had several complications and so he was put an Alvarez Cambra external fixation osteosynthesis devise (AU).

Synthesis, biological evaluation and molecular modeling of urea-containing MraY inhibitors.

The straightforward synthesis of aminoribosyl uridines substituted by a 5'-methylene-urea is described. Their convergent synthesis involves the urea formation from various activated amides and an azidoribosyl uridine substituted at the 5' position by an aminomethyl group. This common intermediate resulted from the diastereoselective glycosylation of a phthalimido uridine derivative with a ribosyl fluoride as a ribosyl donor. The inhibition of the MraY transferase activity by the synthetized 11 urea-containing inhibitors was evaluated and 10 compounds revealed MraY inhibition with IC50 ranging from 1.9 µM to 16.7 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative bacteria. Four compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 µg mL-1, including methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Interestingly, one compound also revealed antibacterial activity against Pseudomonas aeruginosa with MIC equal to 64 µg mL-1. Docking experiments predicted two modes of positioning of the active compounds urea chain in different hydrophobic areas (HS2 and HS4) within the MraY active site from Aquifex aeolicus. However, molecular dynamics simulations showed that the urea chain adopts a binding mode similar to that observed in structural model and targets the hydrophobic area HS2.

Imaging temozolomide-induced changes in the myeloid glioma microenvironment.

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [18F]FET (amino acid metabolism) and [18F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRInu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [18F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [18F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [18F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [18F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.

Virulence genes of Escherichia coli in diarrheic and healthy calves.

Escherichia coli ETEC, EPEC, NTEC and STEC/EHEC pathotypes are often isolated from bovine feces. The objective of this study was to detect 21 E. coli virulence genes in feces from 252 dairy calves in Uruguay (149 with neonatal diarrhea - NCD - and 103 asymptomatic). Genes iucD, f17A, afa8E, papC, clpG and f17G(II) were the most prevalent (81.3%; 48.4%; 37.3%; 35.7%; 34.1%; 31.3%, respectively). Genes eae, stx1and stx2 were poorly represented; 13/252 animals harbored one or a combination of these genes. The prevalence of the cnf gene was 4.4%, while that of cdt-IV and cdt-III genes was 24.2% and 12.7% respectively. This study reports updated data about the virulence profiles of E. coli in dairy calves in Uruguay. A large number of adhesins and toxin genes were detected. Our results demonstrate that E. coli from bovine feces has diarrheagenic and extraintestinal profiles although other NCD risks factors may contribute to the disease outcome.

Modeling the effects of perisaccadic attention on gaze statistics during scene viewing.

How we perceive a visual scene depends critically on the selection of gaze positions. For this selection process, visual attention is known to play a key role in two ways. First, image-features attract visual attention, a fact that is captured well by time-independent fixation models. Second, millisecond-level attentional dynamics around the time of saccade drives our gaze from one position to the next. These two related research areas on attention are typically perceived as separate, both theoretically and experimentally. Here we link the two research areas by demonstrating that perisaccadic attentional dynamics improve predictions on scan path statistics. In a mathematical model, we integrated perisaccadic covert attention with dynamic scan path generation. Our model reproduces saccade amplitude distributions, angular statistics, intersaccadic turning angles, and their impact on fixation durations as well as inter-individual differences using Bayesian inference. Therefore, our result lend support to the relevance of perisaccadic attention to gaze statistics.

Trifluoromethylated proline analogues as efficient tools to enhance the hydrophobicity and to promote passive diffusion transport of the l-prolyl-l-leucyl glycinamide (PLG) tripeptide.

The synthesis of four CF3-proline analogues of the PLG peptide is reported. Our results show that the incorporation of trifluoromethylated amino acids (Tfm-AAs) at the N-terminal position of a peptide significantly increases its hydrophobicity. In addition, depending on the relative configuration and the position of the CF3 group, Tfm-AAs can also promote passive diffusion transport.

Zoonotic Potential and Antibiotic Resistance of Escherichia coli in Neonatal Calves in Uruguay.

Escherichia coli is one of the main etiological agents of neonatal calf diarrhea (NCD). The objective of this study was to assess the presence of virulence genes, genetic diversity, and antibiotic resistance mechanisms in E. coli associated with NCD in Uruguay. PCR was used to assess the presence of intimin, Shiga-like toxin, and stable and labile enterotoxin genes. Resistance to fluoroquinolones and oxyimino-cephalosporins was estimated on Müller-Hinton agar plates. Further antibiotic disc-diffusion tests were performed to assess bacterial multi-resistance. The presence of PMQR, ESBL, MCR-1, and integron genes was evaluated. Isolates were typed using ERIC-PCR, and 20 were selected for MLST, adhesion to Hep-2 cells, in vitro biofilm formation, and eukaryotic cytotoxicity. The prevalence of ETEC genes was lower than 3% in each case (estA and elt). Six isolates were EPEC (eae+) and 2 were EHEC/STEC (eae+/stx1+). The results of a diversity analysis showed high genetic heterogenicity among isolates. Additionally, different sequence types, including ST10, ST21, and ST69, were assigned to selected isolates. Thirty-six percent (96/264) of the isolates were fluoroquinolone-resistant, with 61/96 (63.5%) being multidrug-resistant. Additionally, 6 were oxyimino-cephalosporin-resistant. The qnrB, qnrS1, and blaCTX-M-14 genes were detected, whereas no isolates carried the mcr-1 gene. Isolates had the ability to adhere to Hep-2 cells and form biofilms. Only 1 isolate expressed toxins in vitro. E. coli from NCD cases in Uruguay are very diverse, potentially virulent, and may interact with eukaryotic cells. Zoonotic potential, together with resistance traits and the presence of horizontal transfer mechanisms, may play a significant role in infections caused by these microorganisms.

WITHDRAWN: Heralds of parallel MS: Data-independent acquisition surpassing sequential identification of data dependent acquisition in proteomics.

This article has been withdrawn by the authors. This article did not comply with the editorial guidelines of MCP. Specifically, single peptide based protein identifications of 9-19% were included in the analysis and discussed in the results and conclusions. We wish to withdraw this article and resubmit a clarified, corrected manuscript for review.

Enhancing the Supervision of Community Health Workers With WhatsApp Mobile Messaging: Qualitative Findings From 2 Low-Resource Settings in Kenya.

An estimated half of all mobile phone users in Kenya use WhatsApp, an instant messaging platform that provides users an affordable way to send and receive text messages, photos, and other media at the one-to-one, one-to-many, many-to-one, or many-to-many levels. A mobile learning intervention aimed at strengthening supervisory support for community health workers (CHWs) in Kibera and Makueni, Kenya, created a WhatsApp group for CHWs and their supervisors to support supervision, professional development, and team building. We analyzed 6 months of WhatsApp chat logs (from August 19, 2014, to March 1, 2015) and conducted interviews with CHWs and their supervisors to understand how they used this instant messaging tool. During the study period, 1,830 posts were made by 41participants. Photos were a key component of the communication among CHWs and their supervisors: 430 (23.4%) of all posts contained photos or other media. Of the remaining 1,400 text-based posts, 87.6% (n = 1,227) related to at least 1 of 3 defined supervision objectives: (1) quality assurance, (2) communication and information, or (3) supportive environment. This supervision took place in the context of posts about the roll out of the new mobile learning intervention and the delivery of routine health care services, as well as team-building efforts and community development. Our preliminary investigation demonstrates that with minimal training, CHWs and their supervisors tailored the multi-way communication features of this mobile instant messaging technology to enact virtual one-to-one, group, and peer-to-peer forms of supervision and support, and they switched channels of communication depending on the supervisory objectives. We encourage additional research on how health workers incorporate mobile technologies into their practices to develop and implement effective supervisory systems that will safeguard patient privacy, strengthen the formal health system, and create innovative forms of community-based, digitally supported professional development for CHWs.

Prevalence of Escherichia coli adhesion-related genes in neonatal calf diarrhea in Uruguay.

INTRODUCTION: Neonatal calf diarrhea (NCD), one of the most important diseases of neonatal dairy and beef calves in Uruguay, has become relevant in association with intensive systems. This disease generates substantial economic losses every year worldwide as a result of increased morbidity and mortality. Escherichia coli, one of the pathogens associated with NCD, can express several fimbrial and afimbrial adhesins. The objective of this study was to assess the presence of clpG, f5, f17A, f17G(II), and f17G(I) genes that encode three important adhesins expressed in diarrheagenic E. coli: F5, F17 and CS31A, isolated from feces of calves in Uruguay. METHODOLOGY: Feces of 86 (70 diarrheic and 16 healthy) calves, from 15 animal facilities in Uruguay, were collected between 2012 and 2013. Biochemical and molecular identification were performed to finally obtain 298 E. coli isolates. Partial amplification of adhesion-related genes was performed by polymerase chain reaction. RESULTS: The most prevalent gene was f17A (31.2%), followed by f17G(II), clpG, f17G(I) and f5 (25.8%, 17.5%, 3.7% and 0.7%, respectively). All genes were present in diarrheic and healthy animals except f5 and f17G(I); these genes were present only in affected calves, although in low numbers. CONCLUSIONS: This is the first report of the presence of F5, F17, and CS31A genes in E. coli strains from NCD cases in Uruguay. Prevalence values of the genes, except f5, were in accordance with regional findings. It is expected that further characterization of locally transmitted strains will contribute to control a problem of regional and international magnitude.

Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference.

This article summarizes discussions at the March 2014 conference organized by the University of Florida (UF) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), entitled "Orlando Inhalation Conference: Approaches in International Regulation." The special focus of the conference was on global scientific and regulatory issues associated with the testing and demonstration of equivalence for the registration of orally inhaled drug products (OIDPs) in the United States, Europe, Brazil, China, and India. The scope included all types of OIDPs throughout their lifecycle, e.g., innovator/brand-name products, generics, modifications due to lifecycle management, device changes, etc. Details were presented for the U.S. "weight of evidence approach" for registration of generic products (which includes demonstration of in vitro and in vivo equivalence, as well as quantitative and qualitative sameness, and device similarity). The European "stepwise" approach was elucidated, and the thinking of regulatory agencies in the major emerging markets was clarified. The conference also highlighted a number of areas that would benefit from further research and discussion, especially around patient/device interface and human factor studies, statistical methods and criteria for demonstrating equivalence, the relative roles of in vivo and in vitro tests, and appropriate designs and metrics for in vivo studies of inhaled drugs.

What do community health workers have to say about their work, and how can this inform improved programme design? A case study with CHWs within Kenya.

BACKGROUND: Community health workers (CHWs) are used increasingly in the world to address shortages of health workers and the lack of a pervasive national health system. However, while their role is often described at a policy level, it is not clear how these ideals are instantiated in practice, how best to support this work, or how the work is interpreted by local actors. CHWs are often spoken about or spoken for, but there is little evidence of CHWs' own characterisation of their practice, which raises questions for global health advocates regarding power and participation in CHW programmes. This paper addresses this issue. DESIGN: A case study approach was undertaken in a series of four steps. Firstly, groups of CHWs from two communities met and reported what their daily work consisted of. Secondly, individual CHWs were interviewed so that they could provide fuller, more detailed accounts of their work and experiences; in addition, community health extension workers and community health committee members were interviewed, to provide alternative perspectives. Thirdly, notes and observations were taken in community meetings and monthly meetings. The data were then analysed thematically, creating an account of how CHWs describe their own work, and the tensions and challenges that they face. RESULTS: The thematic analysis of the interview data explored the structure of CHW's work, in terms of the frequency and range of visits, activities undertaken during visits (monitoring, referral, etc.) and the wider context of their work (links to the community and health service, limited training, coordination and mutual support through action and discussion days, etc.), and provided an opportunity for CHWs to explain their motivations, concerns and how they understood their role. The importance of these findings as a contribution to the field is evidenced by the depth and detail of their descriptive power. One important aspect of this is that CHWs' accounts of both successes and challenges involved material elements: leaky tins and dishracks evidenced successful health interventions, whilst bicycles, empty first aid kits and recruiting stretcher bearers evidenced the difficulties of resourcing and geography they are required to overcome. CONCLUSION: The way that these CHWs described their work was as healthcare generalists, working to serve their community and to integrate it with the official health system. Their work involves referrals, monitoring, reporting and educational interactions. Whilst they face problems with resources and training, their accounts show that they respond to this in creative ways, working within established systems of community power and formal authority to achieve their goals, rather than falling into a 'deficit' position that requires remedial external intervention. Their work is widely appreciated, although some households do resist their interventions, and figures of authority sometimes question their manner and expertise. The material challenges that they face have both practical and community aspects, since coping with scarcity brings community members together. The implication of this is that programmes co-designed with CHWs will be easier to implement because of their relevance to their practices and experiences, whereas those that assume a deficit model or seek to use CHWs as an instrument to implement external priorities are likely to disrupt their work.