Nationwide Real-World Exclusive Enteral Nutrition Practice Over Time: Persistence of Use as Induction for Pediatric Crohn's Disease and Emerging Combination Strategy With Biologics.

BACKGROUND: Exclusive enteral nutrition (EEN) is the recommended first-line induction treatment in pediatric patients with active luminal Crohn's disease (CD). We aimed to provide a nationwide overview of evolving EEN practices during an era of increasing biologic use. METHODS: We analyzed a prospectively identified nationwide cohort of newly diagnosed pediatric patients with CD in Scotland between January 1, 2015, and June 30, 2022. Patients who received EEN for any indication were divided into 6-monthly epochs and examined over time. Differences during the COVID-19 pandemic (March 16, 2020, to July 19, 2021) were examined. Data were retrospectively collected from electronic medical records: demographics, anthropometrics, concomitant treatments, aspects of EEN administration, and remission/response rates. Descriptive statistics and linear regression were used for analyses. RESULTS: A total of 649 patients with CD were identified (63% male; median age 12.6 [interquartile range, 10.8-14.8] years); 497 (77%) of 649 received EEN as postdiagnosis induction therapy with a median course length of 7.7 (interquartile range, 5.9-8.0) weeks. Including repeat courses, 547 EEN courses were examined. An increasing incidence of CD was observed over time with no significant changes in EEN usage, remission or response rates, nasogastric tube usage, or course completion (all P > .05). Increasing use of EEN combined with biologics (combination induction) as first-line induction was observed over time (P < .001). Considering COVID-19, lower rates of EEN usage were observed (P = .008) with no differences in remission, oral administration, and course completion rates (all P > .05). CONCLUSIONS: Over the past 7.5 years, except during the COVID-19 pandemic, EEN usage rates have not changed despite an increase in biologic use, although combination induction is an emerging trend.

Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes.

Background: Schistosoma mansoni, a parasitic worm species responsible for the neglected tropical disease schistosomiasis, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic and epigenetic processes. As inhibition of S. mansoni epigenetic machinery components impairs key transitions throughout the parasite's digenetic lifecycle, a greater understanding of how epi-drugs affect molecular processes in schistosomes could lead to the development of new anthelmintics. Methods:   In vitro whole organism assays were used to assess the anti-schistosomal activity of 39 Homo sapiens Lysine Specific Demethylase 1 (HsLSD1) inhibitors on different parasite life cycle stages. Moreover, tissue-specific stains and genomic analysis shed light on the effect of these small molecules on the parasite biology. Results: Amongst this collection of small molecules, compound 33 was the most potent in reducing ex vivo viabilities of schistosomula, juveniles, miracidia and adults. At its sub-lethal concentration to adults (3.13 µM), compound 33 also significantly impacted oviposition, ovarian as well as vitellarian architecture and gonadal/neoblast stem cell proliferation. ATAC-seq analysis of adults demonstrated that compound 33 significantly affected chromatin structure (intragenic regions > intergenic regions), especially in genes differentially expressed in cell populations (e.g., germinal stem cells, hes2 + stem cell progeny, S1 cells and late female germinal cells) associated with these ex vivo phenotypes. KEGG analyses further highlighted that chromatin structure of genes associated with sugar metabolism as well as TGF-beta and Wnt signalling were also significantly perturbed by compound 33 treatment. Conclusions: This work confirms the importance of histone methylation in S. mansoni lifecycle transitions, suggesting that evaluation of LSD1 - targeting epi-drugs may facilitate the search for next-generation anti-schistosomal drugs. The ability of compound 33 to modulate chromatin structure as well as inhibit parasite survival, oviposition and stem cell proliferation warrants further investigations of this compound and its epigenetic target SmLSD1.

Protective human IgE responses are promoted by comparable life-cycle dependent Tegument Allergen-Like expression in Schistosoma haematobium and Schistosoma mansoni infection.

Schistosoma haematobium is the most prevalent of the human-infecting schistosome species, causing significant morbidity in endemically exposed populations. Despite this, it has been relatively understudied compared to its fellow species, S. mansoni. Here we provide the first comprehensive characterization of the S. haematobium Tegument Allergen-Like protein family, a key protein family directly linked to protective immunity in S. mansoni infection. Comparable with observations for S. mansoni, parasite phylogenetic analysis and relative gene expression combined with host serological analysis support a cross-reactive relationship between S. haematobium TAL proteins, exposed to the host immune system as adult worms die, and closely related proteins, exposed during penetration by the infecting cercarial and early schistosomulae stages. Specifically, our results strengthen the evidence for host immunity driven by cross-reactivity between family members TAL3 and TAL5, establishing it for the first time for S. haematobium infection. Furthermore, we build upon this relationship to include the involvement of an additional member of the TAL protein family, TAL11 for both schistosome species. Finally, we show a close association between experience of infection and intensity of transmission and the development of protective IgE responses to these antigens, thus improving our knowledge of the mechanisms by which protective host immune responses develop. This knowledge will be critical in understanding how control efforts such as mass drug administration campaigns influence the development of host immunity and subsequent patterns of infection and disease within endemic populations.

Special considerations for studies of extracellular vesicles from parasitic helminths: A community-led roadmap to increase rigour and reproducibility.

Over the last decade, research interest in defining how extracellular vesicles (EVs) shape cross-species communication has grown rapidly. Parasitic helminths, worm species found in the phyla Nematoda and Platyhelminthes, are well-recognised manipulators of host immune function and physiology. Emerging evidence supports a role for helminth-derived EVs in these processes and highlights EVs as an important participant in cross-phylum communication. While the mammalian EV field is guided by a community-agreed framework for studying EVs derived from model organisms or cell systems [e.g., Minimal Information for Studies of Extracellular Vesicles (MISEV)], the helminth community requires a supplementary set of principles due to the additional challenges that accompany working with such divergent organisms. These challenges include, but are not limited to, generating sufficient quantities of EVs for descriptive or functional studies, defining pan-helminth EV markers, genetically modifying these organisms, and identifying rigorous methodologies for in vitro and in vivo studies. Here, we outline best practices for those investigating the biology of helminth-derived EVs to complement the MISEV guidelines. We summarise community-agreed standards for studying EVs derived from this broad set of non-model organisms, raise awareness of issues associated with helminth EVs and provide future perspectives for how progress in the field will be achieved.

The inexorable increase of biologic exposure in paediatric inflammatory bowel disease: a Scottish, population-based, longitudinal study.

BACKGROUND: The use of biologics in paediatric-onset inflammatory bowel disease (PIBD) is rapidly changing. AIMS: To identify the incidence and prevalence of biologic use within Scottish PIBD services, and to describe patient demographics and outcomes for those patients who required escalation of therapy beyond anti-tumour necrosis factor alpha (anti-TNFα) agents METHODS: We captured a nationwide cohort of prospectively identified patients less than 18 years of age with PIBD (A1 phenotype; diagnosed <17 years of age) within paediatric services over a 4.5-year period (1 January 2015-30 June 2019). All patients who received infliximab, adalimumab, vedolizumab or ustekinumab during the study period and/or received their first dose of these biologics were audited retrospectively. RESULTS: Scotland-wide PIBD-prevalence cases increased from 554 to 644 over the study period. A total of 495 incident new-start biological therapies were commenced on 403 PIBD patients: 295 infliximab (60%), 161 adalimumab (32%), 24 vedolizumab (5%) and 15 ustekunumab (3%). The proportion of new-start biologics changed with infliximab initiation rates decreasing (87%-54%) while adalimumab (13%-31%), vedolizumab (0%-9%) and ustekinumab (0%-6%) all increased. The incidence rate (first dose of new biologic not including biosimilar switch) increased from 6.9% to 8.1% over the study period and point prevalence rates (any biologic use) increased from 20.2% to 43.5% - an average annual percentage increase of 20%. Biosimilar penetration of new-start anti-TNFα agents increased from 3% to 91%. Demographics and outcomes of those patients receiving vedolizumab and ustekinumab were similar. CONCLUSIONS: Complete accrual of Scottish nationwide biologic usage within paediatric services demonstrates a rapidly changing, inexorably increasing PIBD biologics landscape.

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production.

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni's α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290's female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

Key concepts for informed health choices: Where's the evidence?

Background: The Informed Health Choices (IHC) Key Concepts is a framework that provides a basis for developing educational resources and evaluating people's ability to think critically about health actions. We developed the original Key Concepts framework by reviewing texts and checklists for the public, journalists, and health professionals and collecting structured feedback from an international advisory group. We revised the original 2015 framework yearly from 2016 to 2018 based on feedback and experience using the framework. The objectives of this paper are to describe the development of the framework since 2018 and summarise their basis. Methods: For the 2019 version, we responded to feedback on the 2018 version. For the current 2022 version, in addition to responding to feedback on the 2019 version, we reviewed the evidence base for each of the concepts. Whenever possible, we referenced systematic reviews that provide a basis for a concept. We screened all Cochrane methodology reviews and searched Epistemonikos, PubMed, and Google Scholar for methodology reviews and meta-epidemiological studies. Results: The original framework included 32 concepts in six groups. The 2019 version and the current 2022 version include 49 concepts in the same three main groups that we have used since 2016. There are now 10 subgroups or higher-level concepts. For each concept, there is an explanation including one or more examples, the basis for the concept, and implications. Over 600 references are cited that support the concepts, and over half of the references are systematic reviews. Conclusions: There is a large body of evidence that supports the IHC key concepts and we have received few suggestions for changes since 2019.

In silico characterisation of the complete Ly6 protein family in Fasciola gigantica supported through transcriptomics of the newly-excysted juveniles.

Fasciola gigantica is one of the aetiological trematodes associated with fascioliasis, which heavily impacts food-production systems and human and animal welfare on a global scale. In the absence of a vaccine, fascioliasis control and treatment is restricted to pasture management, such as clean grazing, and a limited array of chemotherapies, to which signs of resistance are beginning to appear. Research into novel control strategies is therefore urgently required and the advent of 'omics technologies presents considerable opportunity for novel drug and vaccine target discovery. Here, interrogation of the first available F. gigantica newly excysted juvenile (NEJ) transcriptome revealed several protein families of current interest to parasitic flatworm vaccine research, including orthologues of mammalian complement regulator CD59 of the Ly6 family. Ly6 proteins have previously been identified on the tegument of Schistosoma mansoni and induced protective immunity in vaccination trials. Incorporating the recently available F. gigantica genome, the current work revealed 20 novel Ly6 family members in F. gigantica and, in parallel, significantly extended the F. hepatica complement from 3 to 18 members. Phylogenetic analysis revealed several distinct clades within the family, some of which are unique to Fasciola spp. trematodes. Analysis of available proteomic databases also revealed three of the newly discovered FhLy6s were present in extracellular vesicles, which have previously been prioritised in studying the host-parasite interface. The presentation of this new transcriptomic resource, in addition to the Ly6 family proteins here identified, represents a wealth of opportunity for future vaccine research.

The Epidemiology of Pediatric Autoimmune Hepatitis in Scotland: A National Cohort Study.

Autoimmune hepatitis (AIH) is a rare, but potentially severe, cause of liver disease in children. We aimed to summarize how children with AIH in Scotland presented, were investigated and managed in addition to producing novel epidemiological data and outcomes. Methods: All prevalent pediatric patients with AIH cared for in pediatric services between January 2013 and September 2018 were included. Individual patient data were obtained from electronic patient records in the 3-main academic pediatric centers in Scotland covering the entire population. Results: Thirty-eight patients were included (25 female) with median follow-up of 33 months (range, 2-145 mo) and 136 total patient years. The incidence between 2014 and 2017 was 0.49/100 000/y (95% confidence interval, 0.29-0.78) and point prevalence between 2013 and 2018 was 1.75/100 000 (95% confidence interval, 1.42-2.13). Thirty-five (92%) patients were autoantibody positive, most commonly anti-nuclear antibody (63%) and anti-smooth muscle antibody (42%). Thirty-seven (97%) patients had induction therapy with oral corticosteroids, 30 (79%) required maintenance treatment with azathioprine, and 23 (61%) received ursodeoxycholic acid. There were 1.4 disease flares per 10 patient years and 3 patients required liver transplantation with an overall 5-year survival rate without the need for transplantation of 95%. Conclusions: We calculated a novel incidence and prevalence rate for pediatric AIH in Scotland. Nearly all were invariably treated initially with corticosteroids with most placed-on azathioprine as maintenance therapy. Outcomes were generally favorable with low rates of disease flares and the need for transplantation being rare.

Giving and taking: ethical treatment assignment in controlled trials.

The current version of the Declaration of Helsinki states that 'the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention(s) … '. This wording implies that it is acceptable for patients to be assigned to receive an unproven new intervention and to be denied a best current proven intervention. We assert that patients being invited to participate in controlled trials cannot, ethically, be expected to forego proven beneficial forms of care. Patients being treated in controlled trials should not knowingly be disadvantaged compared with similar patients being treated in usual clinical care, where they have access to beneficial care. In this article, we have tried to separate for discussion 'the withholding of effective care from trial participants', 'informed consent to treatment', 'blinding' and 'use of placebos'.

Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1) is an immunogenic antigen found in EVs released from pre-acetabular glands of invading cercariae.

Extracellular Vesicles (EVs) are an integral component of cellular/organismal communication and have been found in the excreted/secreted (ES) products of both protozoan and metazoan parasites. Within the blood fluke schistosomes, EVs have been isolated from egg, schistosomula, and adult lifecycle stages. However, the role(s) that EVs have in shaping aspects of parasite biology and/or manipulating host interactions is poorly defined. Herein, we characterise the most abundant EV-enriched protein in Schistosoma mansoni tissue-migrating schistosomula (Schistosoma mansoni Larval Extracellular Vesicle protein 1 (SmLEV1)). Comparative sequence analysis demonstrates that lev1 orthologs are found in all published Schistosoma genomes, yet homologs are not found outside of the Schistosomatidae. Lifecycle expression analyses collectively reveal that smlev1 transcription peaks in cercariae, is male biased in adults, and is processed by alternative splicing in intra-mammalian lifecycle stages. Immunohistochemistry of cercariae using a polyclonal anti-recombinant SmLEV1 antiserum localises this protein to the pre-acetabular gland, with some disperse localisation to the surface of the parasite. S. mansoni-infected Ugandan fishermen exhibit a strong IgG1 response against SmLEV1 (dropping significantly after praziquantel treatment), with 11% of the cohort exhibiting an IgE response and minimal levels of detectable antigen-specific IgG4. Furthermore, mice vaccinated with rSmLEV1 show a slightly reduced parasite burden upon challenge infection and significantly reduced granuloma volumes, compared with control animals. Collectively, these results describe SmLEV1 as a Schistosomatidae-specific, EV-enriched immunogen. Further investigations are now necessary to uncover the full extent of SmLEV1's role in shaping schistosome EV function and definitive host relationships.

Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation.

Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold. Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC50 = 4.59 µM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC50 = 0.44 µM, 0.20 µM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum. Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.

Characterization of class II fumarase from Schistosoma mansoni provides the molecular basis for selective inhibition.

Schistosomiasis is a neglected tropical disease that affects more than 250 million people worldwide. The only drug available for its treatment undergoes first-pass hepatic metabolism and is not capable of preventing reinfection, which makes the search of new therapies urgently needed. Due to the essential role of fumarases in metabolism, these enzymes represent potential targets for developing novel schistosomiasis treatments. Here, we evaluate the expression profiles for class I and class II fumarases from Schistosoma mansoni (SmFHI and SmFHII, respectively), and report the complete characterization of SmFHII. The first SmFHII structure in complex with L-malate was determined at 1.85 Å resolution. The significant thermoshift observed for SmFHII in the presence of identified ligands makes the differential scanning fluorimetry an adequate technique for ligand screening. A complete kinetic characterization of SmFHII was performed, and comparison with the human fumarase (HsFH) revealed differences regarding the turnover number (kcat). Structural characterization allowed us to identify differences between SmFHII and HsFH that could be explored to design new selective inhibitors. This work represents the very first step towards validate the fumarases as drug targets to treat schistosomiasis. Our results provide the structural basis to rational search for selective ligands.

'The ethics approval took 20 months on a trial which was meant to help terminally ill cancer patients. In the end we had to send the funding back': a survey of views on human research ethics reviews.

BACKGROUND: We conducted a survey to identify what types of health/medical research could be exempt from research ethics reviews in Australia. METHODS: We surveyed Australian health/medical researchers and Human Research Ethics Committee (HREC) members. The survey asked whether respondents had previously changed or abandoned a project anticipating difficulties obtaining ethics approval, and presented eight research scenarios, asking whether these scenarios should or should not be exempt from ethics review, and to provide (optional) comments. Qualitative data were analysed thematically; quantitative data in R. RESULTS: We received 514 responses. Forty-three per cent of respondents to whom the question applied, reported changing projects in anticipation of obstacles from the ethics review process; 25% reported abandoning projects for this reason. Research scenarios asking professional staff to provide views in their area of expertise were most commonly exempted from ethics review (to prioritise systematic review topics 84%, on software strengths/weaknesses 85%); scenarios involving surplus samples (82%) and N-of-1 (single case) studies (76%) were most commonly required to undergo ethics review. HREC members were 26% more likely than researchers to require ethics review. Need for independent oversight, and low risk, were most frequently cited in support of decisions to require or exempt from ethics review, respectively. CONCLUSIONS: Considerable differences exist between researchers and HREC members, about when to exempt from review the research that ultimately serves the interests of patients and the public. It is widely accepted that evaluative research should be used to reduce clinical uncertainties-the same principle should apply to ethics reviews.

Claims of 'no difference' or 'no effect' in Cochrane and other systematic reviews.

Estimates of treatment effects/differences derived from controlled comparisons are subject to uncertainty, both because of the quality of the data and the play of chance. Despite this, authors sometimes use statistical significance testing to make definitive statements that 'no difference exists between' treatments. A survey to assess abstracts of Cochrane reviews published in 2001/2002 identified unqualified claims of 'no difference' or 'no effect' in 259 (21.3%) out of 1212 review abstracts surveyed. We have repeated the survey to assess the frequency of such claims among the abstracts of Cochrane and other systematic reviews published in 2017. We surveyed the 643 Cochrane review abstracts published in 2017 and a random sample of 643 abstracts of other systematic reviews published in the same year. We excluded review abstracts that referred only to a protocol, lacked a conclusion or did not contain any relevant information. We took steps to reduce biases during our survey. 'No difference/no effect' was claimed in the abstracts of 36 (7.8%) of 460 Cochrane reviews and in the abstracts of 13 (6.0%) of 218 other systematic reviews. Incorrect claims of no difference/no effect of treatments were substantially less common in Cochrane reviews published in in 2017 than they were in abstracts of reviews published in 2001/2002. We hope that this reflects greater efforts to reduce biases and inconsistent judgements in the later survey as well as more careful wording of review abstracts. There are numerous other ways of wording treatment claims incorrectly. These must be addressed because they can have adverse effects on healthcare and health research.

Schistosoma mansoni venom allergen-like protein 6 (SmVAL6) maintains tegumental barrier function.

The Schistosoma mansoni venom allergen-like protein (SmVAL) superfamily is a collection of at least 29 molecules that have been classified into two distinctive groups (Group 1 and Group 2 SmVALs). The fundamental basis for SmVAL segregation relates to signal peptide and conserved cysteine retention (present in all Group 1 SmVALs, but absent in all Group 2 SmVALs). These structural differences have led to the hypothesis that most Group 1 SmVALs, found as components of schistosome excretory/secretory (E/S) products, predominantly interact with their environment (intermediate or definitive hosts) whereas the Group 2 SmVALs are retained within the schistosome to fulfil parasite-related functions. While experimental evidence to support Group 1 SmVAL/host interactions is growing, similar support for identification of parasite-related Group 2 SmVAL functions is currently lacking. By applying a combination of approaches to the study of SmVAL6, we provide the first known evidence for an essential function of a Group 2 SmVAL in schistosome biology. After whole mount in situ hybridisation (WISH) localised Smval6 to the anterior region of the oesophageal gland (AOG) and cells scattered through the mesenchyme in adult schistosomes, short interfering RNA (siRNA)-mediated silencing of Smval6 was employed to assess loss of function phenotypes. Here, siSmval6-mediated knockdown of transcript and protein levels led to an increase in tegumental permeability as assessed by the quantification of TAMRA-labelled dextran throughout sub-tegumental cells/tissues. Yeast two hybrid screening using SmVAL6 as a bait revealed Sm14 (a fatty acid binding protein) and a dynein light chain (DLC) as directly interacting partners. Interrogation of single-cell RNA-seq (scRNA-seq) data supported these protein interactions by demonstrating the spatial co-expression of Smval6/dlc/Sm14 in a small proportion of adult cell types (e.g. neurons, tegumental cells and neoblasts). In silico modelling of SmVAL6 with Sm14 and DLC provided evidence that opposing faces of SmVAL6 were likely responsible for these protein/protein interactions. Our results suggest that SmVAL6 participates in oesophageal biology, formation of higher order protein complexes and maintenance of tegumental barrier function. Further studies of other Group 2 SmVALs may reveal additional functions of this enigmatic superfamily.

Mammographic Screening in the Occupied Palestinian Territory: A Critical Analysis of Its Promotion, Claimed Benefits, and Safety in Palestinian Health Research.

PURPOSE: To critically review the evidence and opinions expressed about mammographic screening (MS) in research reports on breast cancer in the occupied Palestinian territory (oPt) and to assess whether benefits and harms in MS are presented in a balanced way. METHODS: Searches of PubMed, Cochrane, MEDLINE, EMBASE, CINAHL, and gray literature identified 14 eligible research reports relating to the oPt. We reviewed these documents and then used a thematic analysis to describe and analyze the evidence and the opinions about MS expressed in them. RESULTS: All 14 research reports mentioned that MS would improve survival rates in the oPt. Only three gave information on major harmful effects, and only two emphasized that MS must be accompanied by effective treatment to have any beneficial effects on population mortality. There was no consistency in the recommended frequency of MS. CONCLUSION: Most information presented by Palestinian health researchers was selective and failed to address the important established harms of MS. Thus, calls to support MS in the oPt are not based on a measured discussion of the risks and benefits for women or grounded in the systemic readiness of health care necessary for its effectiveness. As long as diagnostic and treatment facilities remain deficient, screening cannot lead to reduced mortality from breast cancer.