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Background: In the era of "precision medicine," the availability of high-quality tumor biomarker tests is critical and tumor proliferation evaluated by Ki-67 antibody is one of the most important prognostic factors in breast cancer. But the evaluation of Ki-67 index has been shown to suffer from some interobserver variability. The goal of the study is to develop an easy, automated, and reliable Ki-67 assessment approach for invasive breast carcinoma in routine practice., Patients and Methods: A total of 151 biopsies of invasive breast carcinoma were analyzed. The Ki-67 index was evaluated by 2 pathologists with MIB-1 antibody as a global tumor index and also in a hotspot. These 2 areas were also analyzed by digital image analysis (DIA)., Results: For Ki-67 index assessment, in the global and hotspot tumor area, the concordances were very good between DIA and pathologists when DIA focused on the annotations made by pathologist (0.73 and 0.83, respectively). However, this was definitely not the case when DIA was not constrained within the pathologist's annotations and automatically established its global or hotspot area in the whole tissue sample (concordance correlation coefficients between 0.28 and 0.58)., Conclusions: The DIA technique demonstrated a meaningful concordance with the indices evaluated by pathologists when the tumor area is previously identified by a pathologist. In contrast, basing Ki-67 assessment on automatic tissue detection was not satisfactory and provided bad concordance results. A representative tumoral zone must therefore be manually selected prior to the measurement made by the DIA.

Vedolizumab was introduced in 2014 as a therapy for Inflammatory Bowel Disease (IBD). Although recommendations from the National Institute for Health and Care Excellence were based on a maintenance dose of 300 mg administered intravenously every 8 weeks, the Summary of Product Characteristics includes an option of increasing the frequency of dosing for patients who initially respond but later experience a decrease in response. In this literature review of the evidence for a shorter duration between doses we identified seven studies which report that dose interval shortening recaptures response in around 50% of cases with remission rates of 11% to 34% between 4 and 52 weeks. A sustained response was seen in the majority of patients for up to 1 year, however, patients continued to receive escalated dosing for up to 100 weeks, which does not reflect clinical practice where short-term escalation is usually prescribed. There is a lack of randomised controlled trials and a lack of trials reporting endoscopic remission, which is the goal of care in IBD. The use of therapeutic drug monitoring (TDM) to guide dose escalation is uncertain and further studies are required to help clarify the role of TDM., Competing Interests: Competing interests: None declared. Refer to the online supplementary files to view the ICMJE form(s)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Short-chain carboxylic acids (SCCAs) produced by gut microbial fermentation may reflect gastrointestinal health. Their concentrations in serum and urine are indicative of specific metabolic pathway activity; therefore, accurate quantitation of SCCAs in different biofluids is desirable. However, it is often challenging to quantitate SCCAs since matrix effects, induced by the presence of a vast variety of other compounds other than SCCAs in complex biofluids, can suppress or enhance signals. Materials used for sample preparation may introduce further analytical challenges. This study reports for the first time a LC-MS/MS-based method to quantitate ten SCCAs (lactate, acetate, 2-hydroxybutyrate, propionate, isobutyrate, butyrate, 2-methylbutyrate, isovalerate, valerate and hexanoate) and evaluates the matrix effects in five human biofluids: serum, urine, stool, and contents from the duodenum and intestinal stoma bags. The optimized method, using 3-Nitrophenylhydrazone as a derivatization agent and a Charge Surface Hybrid reverse phase column, showed clear separation for all SCCAs at a concentration range of 0.1-100 µM, in a 10.5 min run without carry-over effects. The validation of the method showed a good linearity (R2 > 0.99), repeatability (CV ≤ 15%) assessed by intra- and inter-day monitoring. The lowest limit of detection (LLOD) was 25 nM and lowest limit of quantitation (LLOQ) was 50 nM for nine SCCA except acetate at 0.5 and 1 µM, respectively. Quantitative accuracy in all biofluids for most compounds was < ±15%. In summary, this methodology has the advantages over other techniques for its simple and fast sample preparation and a high level of selectivity, repeatability and robustness for SCCA quantification. It also reduced interferences from the matrix or sample containers, making it ideal for use in high-throughput analyses of biofluid samples from large-scale studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Significant research has been conducted on the effects of soil salinity issue on agricultural productivity. However, limited consideration has been given to its critical effects on soil biogeochemistry (e.g., soil microorganisms, soil organic carbon and greenhouse gas (GHG) emissions), land desertification, and biodiversity loss. This article is based on synthesis of information in 238 articles published between 1989 and 2022 on these effects of soil salinity. Principal findings are as follows: (1) salinity affects microbial community composition and soil enzyme activities due to changes in osmotic pressure and ion effects; (2) soil salinity reduces soil organic carbon (SOC) content and alters GHG emissions, which is a serious issue under intensifying agriculture and global warming scenarios; (3) soil salinity can reduce crop yield up to 58 %; (4) soil salinity, even at low levels, can cause profound alteration in soil biodiversity; (5) due to severe soil salinity, some soils are reaching critical desertification status; (6) innovate mitigation strategies of soil salinity need to be approached in a way that should support the United Nations Sustainable Development Goals (UN-SDGs). Knowledge gaps still exist mainly in the effects of salinity especially, responses of GHG emissions and biodiversity. Previous experiences quantifying soil salinity effects remained small-scale, and inappropriate research methods were sometimes applied for investigating soil salinity effects. Therefore, further studies are urgently required to improve our understanding on the effects of salinity, address salinity effects in larger-scale, and develop innovative research methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Groundwater is a vital natural resource required to satisfy the domestic and agricultural needs. In general, human health is linked to the quality of the consumed water. For instance, long-term exposure to high nitrate levels in groundwater may cause problems. Hence, the present study was conducted to assess the nitrate contamination of groundwater as well as its related health risks for the inhabitants of the Sfax region, Sahel Tunisia. Irrigation groundwater suitability has been evaluated with sodium content (%Na), electrical conductivity (EC), magnesium hazard (MH), sodium adsorption ratio (SAR), permeability index (PI), Kelly's ratio (KR) and soluble sodium percent (SSP). The results indicate that the selected groundwater is characterized by low to moderate quality for irrigation. Furthermore, the drinking water quality index (DWQI) was assessed using potential of hydrogen (pH), total dissolved solids (TDS), magnesium (Mg 2+ ), calcium (Ca 2+ ), sodium (Na + ), chloride (Cl - ), sulfate (SO 4 2- ), potassium (K + ), bicarbonate (HCO 3 - ) and nitrate (NO 3 - ). The results indicate that 3.63% of samples have good quality of water, while 41.82% have poor to very poor water quality and the rest (54.55%) are unfit for drinking. The nitrate pollution index (NPI) model revealed that about 42% of the samples present significant to very significant type of pollution. Based on human health risk assessment, the children are at higher risks compared to the other affected groups. The obtained results could be used as a basic document for realistic management of groundwater quality and to provide an overview for decision-making authorities to take necessary actions., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy., Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy., Results: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes., Conclusion: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Most studies of the prevalence of cannabis use among patients with schizophrenia used a self-report as declared by the patient himself. We hypothesize that patients with schizophrenia did not tell the truth and might underreport their use for many reasons to be discussed later. Indeed, the under-report of cannabis use among these patients can affect the effectiveness of their treatment., Aims: To assess the degree of agreement between the prevalence values obtained from patients' reports and the results of the toxicological tests., Methods: A cross-sectional study was carried out on 403 patients with schizophrenia. A sociodemographic, psychiatric history and illicit drug use profile was performed for each patient. We assessed the patients with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression score (CDSS), Barratt Impulsiveness Score (BIS-10) and Medication Adherence Rating Scale (MARS). The consumption of cannabis used was confirmed with MINI International Neuropsychiatric Interview (MINI-DSM IV) and using toxicological analysis., Results: Among the 403 patients who consented to give their urine samples, 49.1% (198/403) tested positive for cannabis, and 41.41% (82/198) underreported their use. The sensitivity and specificity of the questionnaire were 0.58 and 0.74. Based on the comparison between sociodemographic and psychiatric history data of patients who self-report and underreport their cannabis use, no significant difference was observed except for the duration of cannabis use and the score on the medication adherence scale. Moreover, it was found that impulsivity, PANSS score, CDSS score, and the type of schizophrenia are not involved in predicting the underreporting of cannabis use., Conclusion: The rate of patients who under-report cannabis use is important. Therefore, toxicological analysis is becoming relevant for identifying drug use among schizophrenic patients and in the addictive comorbidity research field., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Groundwater (GW) studies have been conducted worldwide with regard to several pressures, including climate change, seawater intrusion, and water overexploitation. GW quality is a very important sector for several countries in the world, in particular for Tunisia. The shallow coastal aquifer of Sfax (located in Tunisia) was found to be under the combined conditions of continuous drop in GW and further deterioration of the groundwater quality (GWQ). This study was conducted to identify the processes that control GWQ mainly in relation to mineralization sources in the shallow Sfax coastal aquifer. To perform this task, 37 wells are considered. Data include 10 physico-chemical properties of groundwater analyzed in water samples: pH, EC, calcium (Ca), sodium (Na), magnesium (Mg), potassium (K), chloride (Cl), sulfate (SO 4 ), bicarbonate (HCO 3 ), and nitrate (NO 3 ), i.e., investigation was based on a database of 370 observations. Principal component analysis (PCA) and hydrochemical facies evolution (HFE) were conducted to extract the main factors affecting GW chemistry. The results obtained using the PCA model show that GWQ is mainly controlled by either natural factors (rock-water interactions) or anthropogenic ones (agricultural and domestic activities). Indeed, the GW overexploitation generated not only the GWQ degradation but also the SWI. The inverse distance weighted (IDW) method, integrated in a geographic information system (GIS), is employed to achieve spatial mapping of seawater intrusion locations. Hydrochemical facies evolution (HFE) results corroborate the seawater intrusion and its spatial distribution. Furthermore, the mixing ratio showed that Jebeniana and Chaffar-Mahares localities are characterized by high SWI hazard. This research should be done to better manage GW resources and help to develop a suitable plan for the exploitation and protection of water resources.

Aim: The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies., Method: Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post-proctectomy were considered; univariate analysis was performed., Results: Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre-operative C-reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre-operative albumin., Conclusion: More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

The respiration rate (RR) is a vital sign in physiological measurement and clinical diagnosis. RR can be measured using stretchable and wearable strain gauge sensors which detect the respiratory movements in the abdomen or thorax areas caused by volumetric changes. In different body locations, the accuracy of RR detection might differ due to different respiratory movement amplitudes. Few studies have quantitatively investigated the effect of the measurement location on the accuracy of new sensors in RR detection. Using a stretchable and wearable inkjet-printed strain gauge (IPSG) sensor, RR was measured from five body locations (umbilicus, upper abdomen, xiphoid process, upper thorax, and diagonal) on 30 healthy test subjects while sitting on an armless chair. At each location, reference RR was simultaneously detected by the e-Health sensor, and the measurement was repeated twice. Subjects were asked about the comfortableness of locations. Based on Levene's test, ANOVA was performed to investigate if there is a significant difference in RR between sensors, measurement locations, and two repeated measurements. Bland-Altman analysis was applied to the RR measurements at different locations. The effects of measurement site and measurement trials on RR difference between sensors were also investigated. There was no significant difference between IPSG and reference sensors, between any locations, and between the two measurements (all p > 0.05). As to the RR deviation between IPSG and reference sensors, there was no significant difference between any locations, or between two measurements (all p > 0.05). All the 30 subjects agreed that diagonal and upper thorax positions were the most uncomfortable and most comfortable locations for measurement, respectively. The IPSG sensor could accurately detect RR at five different locations with good repeatability. Upper thorax was the most comfortable location.

Objective: Doxorubicin (DOX) treatment has been reported to increase the risk of serious toxicity in testis, therefore the aim of the present study was to investigate the antioxidant effects of training and Crocin on doxorubicin-induced testicular toxicity in rats. Materials and methods: ⊆ max ) 5 day/w. Also, groups 2 to 7 administered 2 mg/kg/w DOX intraperitoneal. The testes were removed and glutathione peroxidase (GP X ), total antioxidant capacity (TAC) and protein carbonyl (PC) were analyzed using ELISA methods, one-way analysis of variance along with Bonferroni's post hoc test were used for analysis in SPSS (P≤0.05). Results: The results of the present study showed that doxorubicin induced oxidative stress in testicular tissue by decreasing the level of GPX and TAC and increasing PC level (P≤0.05); TAC and GPX improved in all groups except groups 2 and 5, respectively, and their increase in the group 7 was significantly higher compared to other groups (P≤0.05). Increased PC levels were significantly reduced in the groups 5, 6 and 7. Conclusion: The increase in antioxidant levels in the concurrent Crocin and training group seems to be dose-dependent, but the oxidative stress in both Crocin and training groups of 10 and 50 mg/kg/d is associated with a decrease, but its modulation in the Crocin consumption group alone depends on the dose., (Copyright © 2021 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.)

Background and Aims: The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]., Methods: Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed., Results: Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses., Conclusions: A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology., (© European Crohn’s and Colitis Organisation 2019.)

Understanding the controlling factor of groundwater quality could certainly enhance the promotion of the sustainable development of groundwater resources. In fact, during the last decades, the coastal aquifer of Mahdia-Ksour Essef that belongs to the semi-arid region of Tunisia has been marked by an increase of groundwater extraction for irrigation and water for drinking. Moreover, the water quality shows deterioration due to the septic tanks and intensive agricultural activities especially in the coastal side of the aquifer. This study aimed to (1) assess the water quality using Piper Diagram, Box Plot, ions scatter diagrams, (2) understand the processes of mineralization acquisition in the aquifer, and (3) identify the chemical processes and their spatial distribution in the study area. To solve these objectives, the multivariate statistical analysis such as multiple correspondence analysis and hydrochemical analysis was performed. Accordingly, two types of groundwater are identified through the hydrochemical analysis as Na-Cl and Ca-SO 4 . According to multiple correspondence analysis, three water groups are determined (G1, G2, and G3). Indeed, the groundwater quality is controlled by the water-rock interactions and affected by the seawater intrusion and agricultural activities. The generated results would be helpful to provide a managing model highlighting the threatened locations. It could be considered as a basis for future monitoring programs that aspire to protect water resources.

Objective: Cannabis use is considered a major clinical problem associated with a poorer outcome in patients with schizophrenia. The objective of the present study was to assess the prevalence of cannabis us among patients with schizophrenia. The assessment consists in comparing some factors related to substance use in a population of schizophrenic patients between cannabis users and non., Materials and Methods: Four hundred and three participants who were examined prospectively during their hospitalization answered the PANNS scale of schizophrenia, GAF, BIS-10, CDSS, and MARS. The consumption of cannabis was investigated using urine toxicological analysis. Sociodemographic, clinical and therapeutic data were also recorded., Results: The prevalence of cannabis use among schizophrenic inpatients was 49%. Patients with cannabis use were younger (31.7 vs 34.9 years old, p<0.001), more often male (52 vs 20% female, p<0.001), and they presented more often a history of imprisonment (68.8% vs 31.2%, p<0.001). Patients who were users of cannabis had a lower age at onset of the disease than non-users (23.6 vs 24.8 years, p=0.029), and more often with poor medication adherence (p=0.001). Logistic regression revealed that factors associated with cannabis use among schizophrenics were the age, gender, history of imprisonment and poor medication adherence., Conclusion: The study showed that a high prevalence of cannabis use among patients with schizophrenia which was associated with negative overall outcomes. Determining comorbid substance use disorders among schizophrenic patients is crucial as it may contribute to establish a better therapeutic strategy., Competing Interests: The authors have declared that there is no conflict of interest.

The respiration rate (RR) is a key vital sign that links to adverse clinical outcomes and has various important uses. However, RR signals have been neglected in many clinical practices for several reasons and it is still difficult to develop low-cost RR sensors for accurate, automated, and continuous measurement. This study aims to fabricate, develop and evaluate a novel stretchable and wearable RR sensor that is low-cost and easy to use. The sensor is fabricated using the soft lithography technique of polydimethylsiloxane substrates (PDMS) for the stretchable sensor body and inkjet printing technology for creating the conductive circuit by depositing the silver nanoparticles on top of the PDMS substrates. The inkjet-printed (IJP) PDMS-based sensor was developed to detect the inductance fluctuations caused by respiratory volumetric changes. The output signal was processed in a Wheatstone bridge circuit to derive the RR. Six different patterns for a IJP PDMS-based sensor were carefully designed and tested. Their sustainability (maximum strain during measurement) and durability (the ability to go bear axial cyclic strains) were investigated and compared on an automated mechanical stretcher. Their repeatability (output of the sensor in repeated tests under identical condition) and reproducibility (output of different sensors with the same design under identical condition) were investigated using a respiratory simulator. The selected optimal design pattern from the simulator evaluation was used in the fabrication of the IJP PDMS-based sensor where the accuracy was inspected by attaching it to 37 healthy human subjects (aged between 19 and 34 years, seven females) and compared with the reference values from e-Health nasal sensor. Only one design survived the inspection procedures where design #6 (array consists of two horseshoe lines) indicated the best sustainability and durability, and went through the repeatability and reproducibility tests. Based on the best pattern, the developed sensor accurately measured the simulated RR with an error rate of 0.46 ± 0.66 beats per minute (BPM, mean ± SD). On human subjects, the IJP PDMS-based sensor and the reference e-Health sensor showed the same RR value, without any observable differences. The performance of the sensor was accurate with no apparent error compared with the reference sensor. Considering its low cost, good mechanical property, simplicity, and accuracy, the IJP PDMS-based sensor is a promising technique for continuous and wearable RR monitoring, especially under low-resource conditions.

Background: Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal., Methods: The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure., Findings: We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p<0·0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12·4% [95% CI 6·9-19·9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0·29 [0·16-0·52] for infliximab; 0·03 [0·01-0·12] for adalimumab; p<0·0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62·8% (95% CI 59·0-66·3) for infliximab and 28·5% (24·0-32·7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0·39 [95% CI 0·32-0·46] for infliximab; 0·44 [0·31-0·64] for adalimumab; p<0·0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004)., Interpretation: Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes., Funding: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Research on tumor angiogenesis has mainly focused on the vascular endothelial growth factor (VEGF) family and on methods to block its actions. However, reports on VEGF receptor (VEGFR) expression in tumor-associated endothelial cells (ECs) are limited. Thus, we evaluated VEGF, VEGFR-1 and VEGFR-2 expression in ECs of colorectal cancer (CRC) using immunohistochemistry. VEGF, VEGFR-1 and -2 expression in ECs was quantitatively evaluated by digital image analysis in a retrospective series of 204 tumor tissue samples and related to clinical variables. The data show that the VEGF, VEGFR-1 and VEGFR-2 expression in ECs is heterogeneous. Multivariate analysis including a set of clinicopathological variables reveals that high EC VEGFR-1 expression is an independent prognostic factor for overall survival (OS). The combination of low VEGFR-1 and high VEGFR-2 expression in ECs outperforms models integrating VEGFR-1 and VEGFR-2 as separate markers. Indeed, this VEGFR-1&#95;VEGFR-2 combination is an independent negative prognostic factor for OS ( p = 0.012) and metastasis-free survival ( p = 0.007). In conclusion, this work illustrates the importance of studying the distribution of VEGF members in ECs of CRC. Interestingly, our preliminary data suggest that high VEGFR-1 and low VEGFR-2 expression in ECs appear to be involved in the progression of CRC, suggesting that targeting EC VEGFR-1 could offer novel opportunities for CRC treatment. However, a prospective validation study is needed.

Purpose of Review: The purpose of this article is to provide an update on recent developments in fecal microbiota transplantation (FMT) in the last year., Recent Findings: Although FMT is an accepted treatment for recurrent Clostridium difficile infection (CDI), recently it is also gaining acceptance for the treatment of refractory CDI. FMT is showing promise in ulcerative colitis and is experimental in many other conditions. The optimal practical aspects to enhance the success of FMT are still being established., Summary: The implication of current research is that the indications of FMT may be extended to other conditions in the future.

Objective: The aim of this study was to determine the occurrence of latent tuberculosis infections (LTBI) and active TB in a cohort of patients with inflammatory bowel disease (IBD) treated with biologics. We also examined the effects of immunosuppressive drugs on indeterminate interferon-gamma release assays (IGRA) in LTBI screening., Design: Retrospective study of patients treated with biologics between March 2007 and November 2015., Setting: St Mark's Hospital, North West London, UK., Patients: 732 patients with IBD who were screened for LTBI using either tuberculin skin test or IGRA before starting a biologic treatment., Methods: Retrospective case note review of all patients with IBD who were screened for LTBI prior to initiating biologics. Patients who developed active TB were identified from the London TB register., Results: Of 732 patients with IBD, 31 (4.2%) were diagnosed with and treated for LTBI with no significant side effects. Six of 596 patients (1.0%) who received biologic treatment developed active TB. There was a higher proportion of indeterminate IGRA in the immunosuppressive medication group compared with the non-immunosuppressive group (33% (59/181) compared with 9% (6/66), p<0.001). The combination of steroids and thiopurines had the highest proportion of indeterminate IGRA (64%, 16/25). High and low doses of steroids were equally likely to result in an indeterminate IGRA result (67% (8/12) and 57% (4/7), respectively)., Conclusions: This study highlights the challenges of LTBI screening prior to commencing biologic therapy and demonstrates the risk of TB in patients who have been screened and who are receiving prolonged and continuing doses of antitumour necrosis factor., Competing Interests: Competing interests: None declared.

Iron deficiency anaemia (IDA) is an important, common clinical condition and 8-15% of these patients will be diagnosed with a gastrointestinal cancer. IDA is defined as haemoglobin below the lower limit of normal, in the presence of characteristic iron studies. This article will discuss the causes and clinical diagnosis of iron deficiency, including interpretation of common laboratory tests that differentiate this from other causes of anaemia. We suggest an initial approach for investigating the cause of iron deficiency in these patients and also consider the subsequent treatment and indications for further investigation., (© Royal College of Physicians 2018. All rights reserved.)

The continuance of agricultural production in regions of the world with chronic water shortages depends upon understanding how soil salinity is impacted by irrigation practises such as water salinity, irrigation frequency and amount of irrigation. A two-year field study was conducted in a Saharan oasis of Tunisia (Lazala Oasis) to determine how the soil electrical conductivity was affected by irrigation of date palms with high saline water. The study area lacked a saline shallow water table. Field results indicate that, under current irrigation practises, soil electrical conductivity can build up to levels which exceed the salt tolerance of date palm trees. The effects of irrigation practises on the soil electrical conductivity were also evaluated using model simulations (HYDRUS-1D) of various irrigation regimes with different frequencies, different amounts of added water and different water salinities. The comparison between the simulated and observed results demonstrated that the model gave an acceptable estimation of water and salt dynamics in the soil profile, as indicated by the small values of root mean square error (RMSE) and the high values of the Nash-Sutcliffe model efficiency coefficient (NSE). The simulations demonstrated that, under field conditions without saline shallow groundwater, saline irrigation water can be used to maintain soil electrical conductivity and soil water content at safe levels (soil electrical conductivity <4 dS m(-1) and soil water content >0.04 cm(3) cm(-3)) if frequent irrigations with small amounts of water (90 % of the evapotranspiration requirements) were applied throughout the year.

Spontaneous bacterial peritonitis (SBP) in cirrhotic patients is a serious complication associated with a high mortality rate. A baseline audit of the acute medical take (AMT) at Northwick Park suggested a lack of awareness regarding management. A questionnaire based on contemporary SBP guidelines was circulated to all trainee doctors (FY1 to SpR). Ascitic fluid testing requests were analysed over a six-month period. The electronic requesting system was updated to include prompts and direct links to Trust SBP guidelines, and a one-hour lecture to all members of the AMT, supported by an educational booklet on SBP, was performed. Re-audit was carried out six months post-intervention, the AMT completed a second questionnaire and ascitic fluid testing requests were re-audited. In comparable pre- and post-intervention AMT cohorts, a clinical and educational intervention led to a significant improvement in understanding of when to investigate (p≤0.001), samples (p = 0.002) and containers (p≤0.001) required, urgency of obtaining results (p≤0.001), and initiation of treatment for suspected SBP (p = 0.007). Significantly more ascitic samples were sent, with specific suspicion of SBP more readily documented, crucial to expediting laboratory processing. Targeted education and production of a clinical algorithm has significantly improved the management of patients with SBP., (© Royal College of Physicians 2015. All rights reserved.)

Gastrointestinal endoscopy is a widely used diagnostic and therapeutic procedure both within the United Kingdom and worldwide. With an increasingly older population the potential for complications is increased. The Wolfson Unit for Endoscopy at St. Mark's Hospital in London is a tertiary referral centre, which conducts over 14,000 endoscopic procedures annually. However, despite this high throughput, our baseline observations were that the procedure for safety checks was highly variable. Over a seven-day period we conducted a questionnaire-based survey to all staff members involved with endoscopy within our unit. We found that there was little consensus between team members, both in terms of essential safety checks and designating responsibility for the checks. A panel of experts was convened in order to devise a safety checklist and a strategy for increasing compliance with the checklist among all staff members. Using a combination of electronic and physical reminders and incentives, we found that there was a significant increase in completed checklist (53% to 66%, p = 0.021) and decrease in the number of checklists left blank post intervention (10% to 2%, p=0.03). We believe that post implementation validation of safety checklists is an important method to ensure their proper use.

Background: Current European and American guidelines recommend the perioperative initiation of a course of β-blockers in those at risk of cardiac events undergoing high- or intermediate-risk surgery or vascular surgery. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) family of trials, the bedrock of evidence for this, are no longer secure. We therefore conducted a meta-analysis of randomised controlled trials of β-blockade on perioperative mortality, non-fatal myocardial infarction, stroke and hypotension in non-cardiac surgery using the secure data., Methods: The randomised controlled trials of initiation of β-blockers before non-cardiac surgery were examined. Primary outcome was all-cause mortality at 30 days or at discharge. The DECREASE trials were separately analysed., Results: Nine secure trials totalling 10 529 patients, 291 of whom died, met the criteria. Initiation of a course of β-blockers before surgery caused a 27% risk increase in 30-day all-cause mortality (p=0.04). The DECREASE family of studies substantially contradict the meta-analysis of the secure trials on the effect of mortality (p=0.05 for divergence). In the secure trials, β-blockade reduced non-fatal myocardial infarction (RR 0.73, p=0.001) but increased stroke (RR 1.73, p=0.05) and hypotension (RR 1.51, p<0.00001). These results were dominated by one large trial., Conclusions: Guideline bodies should retract their recommendations based on fictitious data without further delay. This should not be blocked by dispute over allocation of blame. The well-conducted trials indicate a statistically significant 27% increase in mortality from the initiation of perioperative β-blockade that guidelines currently recommend. Any remaining enthusiasts might best channel their energy into a further randomised trial which should be designed carefully and conducted honestly.

Aims: Prognostic benefit from CRT compared with controls is well established. Symptomatic response rates, however, are controversial and have never been systematically evaluated with standard subtraction of control rates to establish the incremental symptomatic response effect of CRT pacing., Methods and Results: First, we identified 150 consecutive CRT papers and assessed researchers' perceptions of the symptomatic response to CRT. The mean quoted response rate was 66%. Only 26 studies acknowledged the existence of response without the device. Secondly, we examined actual symptomatic response rates in the randomized trials (CARE-HF, COMPANION, CONTAK-CD, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, MUSTIC, and REVERSE) totalling 3904 patients. The NYHA status improved in 51% of those randomized to CRT vs. 35% of controls (incremental effect 16%). This incremental improvement was significantly greater in open studies (with no device for controls) than in blinded studies (control arm receiving a device but no CRT, such as a defibrillator or a CRT programmed off), 20% vs. 13%, P < 0.001., Conclusions: Quoting CRT responder rates in isolation without recognizing spontaneous 'response' is common but unwise. The incremental symptomatic response rate from CRT pacing is ∼16%, much lower than widely reported. This value is similar to that for drugs in heart failure and should not be considered disappointing: they both exert powerful prognostic benefits. For scientific purposes, e.g. to explore potential improvements, symptomatic benefit from CRT should be quantified, like all other effects, by comparison with a control.

Objective: Cerebral hyperperfusion syndrome is a preventable cause of stroke after carotid endarterectomy (CEA). It manifests as headache, seizures, hemiparesis or coma due to raised intracranial pressure or intracerebral haemorrhage (ICH). There is currently no consensus on whether to control blood pressure, blood pressure thresholds associated with cerebral hyperperfusion syndrome, choice of anti-hypertensive agent(s) or duration of treatment., Method: A systematic review of the PubMed database (1963-2010) was performed using appropriate search terms according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: A total of 36 studies were identified as fitting a priori inclusion criteria. Following CEA, the incidence of severe hypertension was 19%, that of cerebral hyperperfusion 1% and ICH 0.5%. The postoperative mean systolic blood pressure of patients, who went on to develop cerebral hyperperfusion syndrome, was 164 mmHg (95% confidence interval (CI) 150-178 mmHg) and the cumulative incidence of cases rose appreciably above a postoperative systolic blood pressure of 150 mmHg. The mean systolic blood pressure of cerebral hyperperfusion cases was 189 mmHg (95% CI 183-196 mmHg) at presentation. The incidence of cerebral hyperperfusion in the first week was 92% with a median time to presentation of 5 days (interquartile range (IQR) 3-6 days). 36% of patients presented with seizures 31% with hemiparesis and 33% with both. The proportion of patients with severe hypertension was significantly higher in cases than in post-CEA controls (p < 0.0001, Odds ratio 19 (95% CI 9-41)). Three large case-control studies identify postoperative hypertension as a risk factor for ICH., Conclusion: There is currently level-3 evidence for the prevention of ICH through control of postoperative blood pressure. From the available data, we suggest a definition for cerebral hyperperfusion syndrome, blood pressure thresholds, duration of monitoring and a postoperative blood pressure control strategy for validation in a prospective study. The implications of this are that one in five patients would need intravenous anti-hypertensives and home blood pressure monitoring for 1 week., (Copyright © 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder, characterised by progressive motor neuron degeneration and muscle paralysis. Heat shock proteins (HSPs) have significant cytoprotective properties in several models of neurodegeneration. To investigate the therapeutic potential of heat shock protein 27 (HSP27) in a mouse model of ALS, we conducted an extensive characterisation of transgenic mice generated from a cross between HSP27 overexpressing mice and mice expressing mutant superoxide dismutase (SOD1(G93A)). We report that SOD1(G93A)/HSP27 double transgenic mice showed delayed decline in motor strength, a significant improvement in the number of functional motor units and increased survival of spinal motor neurons compared to SOD1(G93A) single transgenics during the early phase of disease. However, there was no evidence of sustained neuroprotection affecting long-term survival. Marked down-regulation of HSP27 protein occurred during disease progression that was not associated with a reduction in HSP27 mRNA, indicating a translational dysfunction due to the presence of mutant SOD1 protein. This study provides further support for the therapeutic potential of HSPs in ALS and other motor neuron disorders.