Surgical management of the diabetic foot: The current evidence.

The prevalence of diabetes mellitus and its associated complications, particularly diabetic foot pathologies, poses significant healthcare challenges and economic burdens globally. This review synthesises current evidence on the surgical management of the diabetic foot, focusing on the interplay between neuropathy, ischemia, and infection that commonly culminates in ulcers, infections, and, in severe cases, amputations. The escalating incidence of diabetes mellitus underscores the urgency for effective management strategies, as diabetic foot complications are a leading cause of hospital admissions among diabetic patients, significantly impacting morbidity and mortality rates. This review explores the pathophysiological mechanisms underlying diabetic foot complications and further examines diabetic foot ulcers, infections, and skeletal pathologies such as Charcot arthropathy, emphasising the critical role of early diagnosis, comprehensive management strategies, and interdisciplinary care in mitigating adverse outcomes. In addressing surgical interventions, this review evaluates conservative surgeries, amputations, and reconstructive procedures, highlighting the importance of tailored approaches based on individual patient profiles and the specific characteristics of foot pathologies. The integration of advanced diagnostic tools, novel surgical techniques, and postoperative care, including offloading and infection control, are discussed in the context of optimising healing and preserving limb function.

Validation of the ACE [Albumin, CRP, and Endoscopy] Index in Acute Colitis: Analysis of the CONSTRUCT dataset.

BACKGROUND AND AIMS: In 2020 we reported the ACE Index in acute colitis which used biochemical and endoscopic parameters to predict steroid non-response on admission in patients with acute ulcerative colitis [UC]. We aimed to validate the ACE Index in an independent cohort. METHODS: The validation cohort comprised patients screened as eligible for inclusion in the CONSTRUCT study, a prospective, randomized, placebo-controlled trial which compared the effectiveness of treatment with infliximab vs ciclosporin in patients admitted with acute UC. The CONSTRUCT cohort database was reviewed at The Edinburgh IBD Unit and the same biochemical and endoscopic variables and cut-off values as those in the derivation cohort were applied to the validation cohort. RESULTS: In total, 800 patients were identified; 62.5% [55/88] of patients with a maximum ACE Index of 3 did not respond to intravenous [IV] steroids (positive predictive value [PPV] 62.5%, negative predictive value [NPV] 79.8%). Furthermore, 79.8% [158/198] of patients with an ACE Index of 0 responded to IV steroids [PPV 79.8%, NPV 62.5%]. Receiver operator characteristic [ROC] curve analysis produced an area under the curve [AUC] of 0.663 [p < 0.001]. CONCLUSIONS: We have now reported and externally validated the ACE Index in acute colitis in a combined cohort of over 1000 patients from across the UK. The ACE Index may be used in conjunction with clinical judgement to help identify patients admitted with active UC who are at high risk of not responding to IV steroids. Further studies are required to improve objectivity and accuracy of assessment.

Real-World Cohort Study on the Effectiveness and Safety of Filgotinib Use in Ulcerative Colitis.

BACKGROUND: Filgotinib is a small molecule with preferential inhibition of Janus kinase type 1, approved for the treatment of ulcerative colitis in Scotland in May 2022. We present the first real world experience on its use in clinical practice. METHODS: In this retrospective, observational, cohort study we assessed patients with active ulcerative colitis who received filgotinib in NHS Lothian, Scotland. Baseline demographic, phenotype and follow-up data were collected via review of electronic medical records. RESULTS: We included 91 patients with median treatment duration of 39 weeks (IQR 23-49). Among the cohort, 67% (61/91) were biologic and small molecule naïve, whilst 20.9% (19/91) had failed one and 12.1% (11/91) ≥2 classes of advanced therapy. Of the biologic and small molecule naïve patients, 18% (11/61) were also thiopurine naïve. Clinical remission (partial Mayo score <2) was achieved in 71.9% (41/57) and 76.4% (42/55) of patients at weeks 12 and 24 respectively. Biochemical remission (CRP≤5mg/L) was achieved in 87.3% (62/71) at week 12 and 88.9% (40/45) at week 24. Faecal biomarker (calprotectin <250µg/g) remission was achieved in 82.8% (48/58) at week 12 and 79.5% (35/44) at week 24.At the end of follow-up, median 42 weeks (IQR 27-50), 82.4% (75/91) of patients remained on filgotinib. Severe adverse events leading to drug discontinuation occurred in 2.2% (2/91) and there were 8.8% (8/91) moderate adverse events that required temporary discontinuation. CONCLUSION: These are the first reported data on the real-world efficacy and safety of filgotinib in ulcerative colitis. Our findings demonstrate that filgotinib is an effective and low risk treatment option for these patients.

CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury.

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206-CD163- macrophages typically associate with gland epithelium, whereas CD11c-CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy.

Longitudinal Fecal Calprotectin Profiles Characterize Disease Course Heterogeneity in Crohn's Disease.

BACKGROUND AND AIMS: The progressive nature of Crohn's disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterize the heterogeneity of disease trajectories in Crohn's disease by utilizing objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn's disease patients with similar longitudinal fecal calprotectin profiles. METHODS: We performed a retrospective cohort study at the Edinburgh IBD Unit, a tertiary referral center, and used latent class mixed models to cluster Crohn's disease subjects using fecal calprotectin observed within 5 years of diagnosis. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-square test, Fisher's exact test, and analysis of variance were used to test for associations with variables commonly assessed at diagnosis. RESULTS: Our study cohort comprised 356 patients with newly diagnosed Crohn's disease and 2856 fecal calprotectin measurements taken within 5 years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high fecal calprotectin and 3 clusters characterized by different downward longitudinal trends. Cluster membership was significantly associated with smoking (P = .015), upper gastrointestinal involvement (P < .001), and early biologic therapy (P < .001). CONCLUSIONS: Our analysis demonstrates a novel approach to characterizing the heterogeneity of Crohn's disease by using fecal calprotectin. The group profiles do not simply reflect different treatment regimens and do not mirror classical disease progression endpoints.

Macrophages in intestinal homeostasis and inflammatory bowel disease.

Macrophages are essential for the maintenance of intestinal homeostasis, yet appear to be drivers of inflammation in the context of inflammatory bowel disease (IBD). How these peacekeepers become powerful aggressors in IBD is still unclear, but technological advances have revolutionized our understanding of many facets of their biology. In this Review, we discuss the progress made in understanding the heterogeneity of intestinal macrophages, the functions they perform in gut health and how the environment and origin can control the differentiation and longevity of these cells. We describe how these processes might change in the context of chronic inflammation and how aberrant macrophage behaviour contributes to IBD pathology, and discuss how therapeutic approaches might target dysregulated macrophages to dampen inflammation and promote mucosal healing. Finally, we set out key areas in the field of intestinal macrophage biology for which further investigation is warranted.

Multiple infliximab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort.

BACKGROUND: Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). OBJECTIVE: The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. METHODS: We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C-reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival. RESULTS: 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed-up: 7.5 months [6.8-8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow-up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24. CONCLUSION: Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn's disease.

BACKGROUND: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. METHODS: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020). RESULTS: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. CONCLUSION: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.

Incidence of collagenous colitis in NHS Lothian: a population-based study.

Objective: Increases in incidence of collagenous colitis (CC) have been documented across Europe; however, previous data from NHS Lothian (1998-2003) demonstrated this to be a low-prevalence area. We aimed to assess incidence of CC in NHS Lothian over time by comparing a more recent cohort (2013-2018) with our existing cohort. Methods: All histologically confirmed diagnoses of CC between 2013 and 2018 were obtained from the NHS Lothian colorectal pathology department (Western General Hospital, Edinburgh). Case record review was performed to obtain relevant demographic and clinical data. Data were also collected regarding the availability of colonoscopy in NHS Lothian. Results: 224 cases of CC were diagnosed between 2013 and 2018, compared with 25 between 1998 and 2003. Mean annual incidence rose from 0.5/100 000 population to 4.3/100 000 population. Incidence in females ≥60 years old rose from 2.3/100 000 population to 22.4/100 000 population (p<0.001). The total number of colonoscopies performed increased by 179.1% from 15 262 (1998-2003) to 42 600 (2013-2018), with the number of CC cases per 1000 colonoscopies performed rising from 1.7 to 5.3 (p<0.001). Conclusion: We describe the increasing incidence of CC in Southeast Scotland, with temporal trends comparable to other European countries. The increase is particularly marked in older females and parallels increasing numbers of colonoscopies being performed.

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

Patterns of emergency admission for IBD patients over the last 10 years in Lothian, Scotland: a retrospective prevalent cohort analysis.

OBJECTIVE: It is unclear how the compounding prevalence of inflammatory bowel disease (IBD) has translated into the causes and rates of hospitalisation, particularly in an era of increased biologic prescribing. We aimed to analyse these trends in a population-based IBD cohort over the last 10 years. DESIGN: The Lothian IBD registry is a complete, validated, prevalent database of IBD patients in NHS Lothian, Scotland. ICD-10 coding of hospital discharge letters from all IBD patient admissions to secondary care between 1 January 2010 and 31 December 2019 was interrogated for admission cause, with linkage to local/national data sets on death and prescribed drugs. RESULTS: Fifty-seven per cent (4673/8211) of all IBD patients were admitted to secondary care for >24 h between 1 January 2010 and 31 December 2019. In patients <40 years, IBD was the commonest reason for admission (38% of admissions), whereas infection was the most common cause in those >60 years (19% of admissions). Three per cent (243/8211) of IBD patients accounted for 50% of the total IBD bed-days over the study period. Age-standardised IBD admission rates fell from 39.4 to 25.5 admissions per 100,000 population between 2010 and 2019, an average annual percentage reduction of 3% (95% CI -4.5% to -2.1%, p < 0.0001). Non-IBD admission rates were unchanged overall (145-137 per 100,000 population) and specifically for serious (hospitalisation) and severe (ITU admission or death) infection over the same period. CONCLUSION: Despite compounding prevalence and increased biologic use, IBD admission rates are falling. The cause of admission varies with age, with infection the predominant cause in older patients.

Polychlorinated biphenyl (PCB) concentrations and profiles in marine mammals from the North Atlantic Ocean.

Polychlorinated biphenyls (PCBs) can provide crucial information into the bioaccumulation and biomagnification of POPs in marine mammals. Muscle tissue samples were obtained for detailed PCB congener specific analysis of all 209 PCBs in 11 species of marine mammals stranded across the coast of the UK between 2010 and 2013. At least 145 PCB congeners were found in each individual. The highest concentrations of PCBs were recorded in a killer whale (318 mg/kg lipid) and the highest toxic equivalent in a Risso's dolphin (1687 pg/g TEQ2005 wet). Concentrations of PCBs in the majority of samples exceeded toxic thresholds (9 mg/kg lipid) for marine mammals, highlighting the health risk they face from PCB exposure. Many PCB profiles did not fit typical 'Aroclor' signatures, but instead indicated patterns of congeners that are resistant to biotransformation and elimination. However, this study identified a novel PCB signature in a sei whale that has not yet been previously observed in marine mammals. The whale had a PCB profile that included lighter and inadvertent PCB congeners such as PCB 11, suggesting that the main source of exposure was through atmospheric deposition, rather than terrestrial discharges. Seven subsamples were chosen for chiral analysis of PCB 95, 136 and 149. The enantiomer fractions (EFs) of C-PCBs 95 and 149 were non racemic suggesting there may be enantiomer selective metabolism in marine mammals. Although there has been a shift in the literature towards emerging pollutants, this study acts as a stark reminder that PCBs continue to pose a significant risk to wildlife.

The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair.

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against airborne pathogens. Tissue-specific differentiation and survival of alveolar macrophages rely on niche-derived factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor­ß (TGF-ß). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remain poorly understood. Here, we identify that the transcription factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-ß and GM-CSF in a PPAR-γ­dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for the regulation of lipids in the airways but crucial for the effective handling of the respiratory pathogen Streptococcus pneumoniae. Last, we show that EGR2 is required for repopulation of the alveolar niche after sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair after injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease.

Effectiveness and Safety of Adalimumab Biosimilar SB5 in Inflammatory Bowel Disease: Outcomes in Originator to SB5 Switch, Double Biosimilar Switch and Bio-Naïve SB5 Observational Cohorts.

BACKGROUND AND AIMS: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. METHODS: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. RESULTS: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6-15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2-12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. CONCLUSION: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up.

Analysis of colectomy rates for ulcerative colitis in pre- and postbiological eras in Lothian, Scotland.

AIM: Biological treatment is effective in maintaining remission in ulcerative colitis (UC), although the effect on colectomy rates remains unclear. In the UK the use of antitumour necrosis factor and anti-α4ß7 treatments for maintenance therapy in UC was restricted until 2015. The aim of this study was to describe the impact that this change in the prescribing of biologicals had on colectomy rates for UC. METHOD: All patients (adult and paediatric) with a diagnosis of UC who received maintenance biological treatment and/or underwent a colectomy in Lothian, Scotland between 2005 and 2018 were identified. Linear and segmental regression analyses were used to identify the annual percentage change (APC) and temporal trends (statistical joinpoints) in biological prescription and colectomy rates. RESULTS: Rates of initiation of maintenance biological therapy increased from 0.05 per 100 UC patients in 2005 to 1.26 in 2018 (p < 0.001). Colectomy rates per 100 UC patients fell from 1.47 colectomies in 2005 to 0.44 in 2018 (p < 0.001). The APC for colectomy decreased by 4.1% per year between 2005 and 2014 and by 18.9% between 2014 and 2018. Temporal trend analysis (2005-2018) identified a significant joinpoint in colectomy rates in 2014 (p = 0.019). CONCLUSION: The use of maintenance biological therapy increased sharply following the change in guidance. This has been paralleled by a significant reduction in the rates of colectomy over the same time period.

Real-world experience with tofacitinib in ulcerative colitis: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. METHODS: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8-14 weeks) and maintenance (16-26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. RESULTS: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41-60%) and 37% (26-45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31-50%) and 29% (23-36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). CONCLUSION: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

Infant dietary exposure to dioxin-like polychlorinated biphenyls (dlPCBs), polybrominated and mixed halogenated dibenzo-p-dioxins and furans (PBDD/Fs and PXDD/Fs) in milk samples of lactating mothers in Accra, Ghana.

In this study, polybrominated and mixed halogenated dibenzo-p-dioxins and furans (PBDD/Fs and PXDD/Fs), and dioxin-like polychlorinated biphenyls (dlPCBs) were quantified in 24 human milk samples of first-time lactating mothers from Greater Accra region in Ghana. The aims of the study were to determine the concentrations and toxic equivalent concentrations of PBDD/F, PXDD/F and dlPCBs in human milk, and to estimate an infant's daily intake. The samples were analysed for 12 dioxin-like PCBs, 7 congeners of 2,3,7,8-polybrominated dibenzo-p-dioxins and furans (PBDD/Fs), and 7 congeners of 2,3,7,8-mixed halogenated dioxins and furans (PXDD/Fs, where X = Br/Cl). The mean concentrations in human milk ranged from 0.15 to 212.9 pg/g lipid for dlPCB congeners (mean TEQ: 1.67 pg WHO2005-TEQ/g lipid). Lesser concentrations for 2,3,7,8-PXDD/Fs (and PBDD/Fs congeners) ranged between <0.01-1.67 pg/g lipid, with a total mean tentative TEQ of 0.56 pg WHO2005-TEQ/g lipid. For an infant of average weight 7 kg, consuming an estimated volume of 600 mL human milk, the estimated average daily intake of dlPCBs in 21 human milk samples was 4.95 pg TEQ/kg bw/day; contributions from dlPCBs, PXDD/Fs and PBDD/Fs resulted in an average estimated daily intake of 6.56 pg TEQ/kg bw/day. The results obtained in this study, although lower than infant dietary intake estimates in human milk from industrialized countries, exceeded the recommended safety standards of 1 pg TEQ/kg bw/day and 1-4 pg TEQ/kg bw/day from the Agency for Toxic Substances and Disease Registry (ATSDR) and the World Health Organization (WHO), respectively.

The ACE (Albumin, CRP and Endoscopy) Index in Acute Colitis: A Simple Clinical Index on Admission that Predicts Outcome in Patients With Acute Ulcerative Colitis.

BACKGROUND: Intravenous (IV) steroids remain the first-line treatment for patients with acute ulcerative colitis (UC). However, 30% of patients do not respond to steroids, requiring second-line therapy and/or surgery. There are no existing indices that allow physicians to predict steroid nonresponse at admission. We aimed to determine if admission biochemical and endoscopic values could predict response to IV steroids. METHODS: All admissions for acute UC (ICD-10 K51) between November 1, 2011, and October 31, 2016 were identified. Case note review confirmed diagnosis; clinical, endoscopic, and laboratory data were collected. Steroid response was defined as discharge home with no further therapy for active UC. Nonresponse was defined as requirement for second-line therapy or surgery. Univariate and binary logistic regression analyses were employed to identify factors associated with steroid nonresponse. RESULTS: Two hundred and thirty-five acute UC admissions were identified, comprising both acute severe and acute nonsevere UC; 155 of the 235 patients (66.0%) responded to steroids. Admission C-reactive protein (CRP) (P = 0.009, odds ratio [OR] 1.006), albumin (P < 0.001, OR 0.894) and endoscopic severity (P < 0.001, OR 3.166) differed significantly between responders and nonresponders. A simple UC severity score (area under the curve [AUC] 0.754, P < 0.001) was derived from these variables; 78.1% (25 of 32) of patients with concurrent CRP ≥50 mg/L, albumin ≤30 g/L, and increased endoscopic severity (severe on physician's global assessment) (maximum score = 3) did not respond to IV steroids (positive predictive value [PPV] 78.1%, negative predictive value [NPV] 87.1%). CONCLUSIONS: More than three quarters of patients scoring 3 (albumin ≤30 g/L, CRP ≥50 mg/L, and increased endoscopic severity) did not respond to IV steroids. This combination of parameters (ACE) identifies on admission a high-risk population who may benefit from earlier second-line medical treatment or surgical intervention.

Normalization of Fecal Calprotectin Within 12 Months of Diagnosis Is Associated With Reduced Risk of Disease Progression in Patients With Crohn's Disease.

BACKGROUND & AIMS: The level of fecal calprotectin (FC) correlates with endoscopic evidence of inflammation in Crohn's disease (CD). A treat-to-target algorithm for patients with CD, that incorporates FC, outperforms a treatment strategy based on symptoms alone in the induction of mucosal healing at 12 months. We investigated whether normalization of FC within 12 months of diagnosis of CD is associated with a reduction in disease progression. METHODS: We performed a retrospective cohort study at a tertiary IBD centre in the United Kingdom. We identified all incident cases of CD diagnosed from 2005 through 2017. Patients with a FC measurement ≥250 µg/g at diagnosis who also had at least 1 follow-up FC measurement within the first 12 months of diagnosis and >12 months of follow up were included. The last FC measurement within 12 months of diagnosis was used to determine normalization (cut-off <250 µg/g). The primary endpoint was time to first disease progression (composite of progression in Montreal disease behavior B1 to B2/3, B2 to B3, or new perianal disease; CD-related surgery; or CD-related hospitalization). Cox proportional hazards regression analysis was used to determine independent factors associated with time to first disease progression. RESULTS: A total of 375 patients out of 1389 incident cases were included, with a median follow up of 5.3 years (interquartile range, 3.1-7.4 years). Normalization of FC within 12 months of diagnosis was confirmed in 43.5% of patients. Patients with normalized levels of FC had a significantly lower risk of composite disease progression (hazard ratio [HR], 0.36; 95% CI, 0.24-0.53; P < .001). They also had a lower risk of reaching any of the separate progression endpoints (progression in Montreal behavior or new perianal disease HR, 0.22; 95% CI, 0.11-0.45; P < .001; hospitalization HR, 0.33; 95% CI, 0.21-0.53; P <.001; surgery HR, 0.39; 95% CI, 0.19-0.78; P = .008) CONCLUSIONS: Normalization of FC within 12 months of diagnosis is associated with a reduced risk of progression of CD.

Paediatric Patients (Less Than Age of 17 Years) Account for Less Than 1.5% of All Prevalent Inflammatory Bowel Disease Cases.

The prevalence of inflammatory bowel disease (IBD) continues to rise globally; however, the true proportion of paediatric IBD patients remains unknown. We conducted an all-age, multiparameter, population-based search using capture-recapture methodology to identify all IBD cases to August 31, 2018 within Lothian, a defined health board and the largest of the 3 within South-East Scotland. Individual case note validation was performed for all 24,601 possible IBD cases according to internationally recognised diagnostic and age criteria. Of 7035 confirmed point-prevalent patients, 560 were classified as A1 age phenotype at diagnosis, constituting just 8% of all cases. Ninety-nine patients were less than 17 years of age on August 31, 2018, constituting only 1.4% of all point-prevalent cases. These results demonstrate the true contemporary proportion of prevalent paediatric IBD patients is strikingly low, reflecting compounding prevalence in adult practice and the near-normal life expectancy of this chronic, incurable condition.