Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study.

BACKGROUND: We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of response. METHODS: Personalised Anti-TNF therapy in Crohn's disease (PANTS) is a UK-wide, multicentre, prospective observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients with active luminal Crohn's disease aged 6 years and older. At the end of the first year, sites were invited to enrol participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449, and is now complete. FINDINGS: Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and 209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age 32·5 years [IQR 22·1-46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7-43·7), 34·4% (29·9-39·0), and 34·7% (29·8-39·5), and for adalimumab 35·9% (95% CI 31·2-40·5), 32·9% (26·8-39·2), and 28·9% (21·9-36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later timepoints were 6·1-10·0 mg/L for infliximab and 10·1-12·0 mg/L for adalimumab. After excluding patients who had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3 were, for infliximab 34·4% (95% CI 30·4-38·2), 54·5% (49·4-59·0), and 60·0% (54·1-65·2), and for adalimumab 32·1% (26·7-37·1), 47·2% (40·2-53·4), and 68·4% (50·9-79·7), respectively. In multivariable analysis, loss of response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45 [95% CI 0·30-0·67], adalimumab: 0·39 [0·22-0·70]). For patients treated with infliximab, loss of response was also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11-1·95]), obesity (vs not obese 1·62 [1·08-2·42]), baseline white cell count (1·06 [1·02-1·11) per 1 × 109 increase in cells per L), and thiopurine dose quartile. Among patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response (HR 1·95 [95% CI 1·17-3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1-49·4) among patients treated with infliximab and 20·3% (13·8-26·2) among those treated with adalimumab. The development of anti-drug antibodies associated with undetectable drug concentrations was significantly associated with treatment without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40 [95% CI 0·31-0·52], adalimumab 0·42 [95% CI 0·24-0·75]), and with carriage of HLA-DQA1*05 risk variant for infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13-1·88]) but not for adalimumab (HR 1·60 [0·92-2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated with increased time without the development of anti-drug antibodies associated with undetectable drug concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20-3·74]) or introduction of an immunomodulator after anti-TNF initiation (1·70 [1·11-2·59]). In years 2 and 3, 16 (4%) of 389 patients treated with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal. Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections in years 2 and 3. INTERPRETATION: Only around a third of patients with active luminal Crohn's disease treated with an anti-TNF drug were in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment, particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05 and mitigated by concomitant immunomodulator use for both drugs. FUNDING: Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion Healthcare.

Drag Reduction by Fish-Scale Inspired Transverse Asymmetric Triangular Riblets: Modelling, Preliminary Experimental Analysis and Potential for Fouling Control.

The natural surfaces of many plants and animals provide examples of textures and structures that remain clean despite the presence of environmental fouling contaminants. A biomimetic approach to deciphering the mechanisms used by nature will facilitate the development and application of fouling-resistant surfaces to a range of engineering challenges. This study investigated the mechanism underlying the drag reduction phenomenon that was shown to be responsible for fouling resistance for underwater surfaces. For this purpose, a novel fish-scale-inspired microstructure was shown to exhibit a drag reduction effect similar to that of its natural replica. The primary mechanism through which this occurs is a delayed transition to turbulence. To investigate this mechanism, a Large Eddy simulation was performed at several Reynolds numbers (Re). This analysis demonstrated a peak drag reduction performance of 6.7% at Re = 1750. The numerical data were then experimentally validated through pressure drop measurements performed by means of a custom-built micro-channel. In this case, a peak drag reduction of 4.8% was obtained at Re = 1000. These results suggest a relative agreement between the experimental and numerical data. Taken together, this study advocates that, for the analyzed conditions, drag reduction occurs at low Reynolds numbers. Nonetheless, once flow conditions become more turbulent, the decline in drag reduction performance becomes apparent.

Pretreatment Vitamin D Concentrations Do Not Predict Therapeutic Outcome to Anti-TNF Therapies in Biologic-Naïve Patients With Active Luminal Crohn's Disease.

Background and Aims: Vitamin D has a regulatory role in innate and adaptive immune processes. Previous studies have reported that low pretreatment vitamin D concentrations are associated with primary non-response (PNR) and non-remission to anti-TNF therapy. This study aimed to assess whether pretreatment 25-hydroxyvitamin D concentrations predicted PNR and non-remission to infliximab and adalimumab in patients with active luminal Crohn's disease. Methods: 25-Hydroxyvitamin D concentrations were measured in stored baseline samples from 659 infliximab- and 448 adalimumab-treated patients in the Personalised Anti-TNF Therapy in Crohn's disease (PANTS) study. Cut-offs for vitamin D were deficiency <25 nmol/L, insufficiency 25-50 nmol/L, and adequacy/sufficiency >50 nmol/L. Results: About 17.1% (189/1107; 95% CI, 15.0-19.4) and 47.7% (528/1107; 95% CI, 44.8-50.6) of patients had vitamin D deficiency and insufficiency, respectively. 22.2% (246/1107) of patients were receiving vitamin D supplementation. Multivariable analysis confirmed that sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations, and non-treatment with vitamin D supplementation were independently associated with lower vitamin D concentrations. Pretreatment vitamin D status did not predict response or remission to anti-TNF therapy at week 14 (infliximab Ppnr = .89, adalimumab Ppnr = .18) or non-remission at week 54 (infliximab P = .13, adalimumab P = .58). Vitamin D deficiency was, however, associated with a longer time to immunogenicity in patients treated with infliximab, but not adalimumab. Conclusions: Vitamin D deficiency is common in patients with active Crohn's disease. Unlike previous studies, pretreatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or nonremission at week 54.

Preliminary Assessment of Asymmetric Triangular Riblet Microstructures for Drag Deduction and Fouling Resistance: Numerical Modeling, Fabrication, and Performance Evaluation.

Several species of plants and animals demonstrate an ability to resist the accumulation of contaminants natural to their environments. To explain this phenomenon, mechanisms that facilitate fouling resistance have to be deciphered. Along these lines, this study is focused on the correlation between drag reduction and fouling resistance for underwater surfaces. This was accomplished by means of a novel microtopography inspired by fish-scales and conceived as a series of asymmetric triangular microgrooves oriented in the spanwise direction. A parametric study involving Large Eddy simulations was carried out to determine the most effective dimensions of the riblets and the results obtained have indicated a 9.1% drag reduction with respect to a flat reference surface. Following this, functional samples were fabricated in acrylic by means of a multi-axis micromachining center and diamond tooling. Surface quality and form accuracy of the fabricated samples were assessed with an optical microscope and optical profilometer. Finally, the fouling resistance of the samples was assessed by subjecting them to a flow of contaminated water. The results demonstrate that a relationship exists between the relative size of the particle and the fouling resistance of the microstructured surface.

Prospective Study Investigating the Prevalence and Evolution of Malnourishment in the Acute Orthopaedic Trauma Patient.

Background: Orthopaedic trauma surgeons believe that nutritional status is important. The primary aim of this study was to prospectively investigate the prevalence and progression of malnourishment in orthopaedic trauma patients and determine when and what labs should be ordered. The secondary aim was to determine if malnourished patients had increased complications. Methods: Prospective cohort study of orthopaedic trauma patients at a Level I trauma center. Assessment of nutritional status over the hospital course was performed using the Rainey MacDonald nutritional index (RMNI) and nutritional laboratory markers on admission, day 3, day 7, and 6 weeks post-op. Results: 98 patients were enrolled and included. On admission, 60%, 41%, and 38% of patients were malnourished based on albumin, prealbumin, and RMNI values, respectively, with 31% in severe acute-phase response (APR) as determined by CRP. By day 3, a significant increase in the percent of malnourished patients was noted based on the laboratory markers, 85%, 90%, and 80%, respectively, with 70% in severe APR. On day 7, values stabilized at 74%, 89%, 69%, with 56% in severe APR. At six weeks, malnourishment persisted in 13%, 19%, and 12% of patients, with 4% in severe APR. Older patients demonstrated a greater depression of nutritional markers throughout the hospital stay. Conclusion: The prevalence of malnourishment, based on serum nutritional markers, in the presence of acute orthopaedic injury is substantial, and it continues to rise during the acute hospital stay. Recommend obtaining prealbumin or albumin levels on hospital day 3 to assess nutritional status.

Adalimumab and Infliximab Impair SARS-CoV-2 Antibody Responses: Results from a Therapeutic Drug Monitoring Study in 11 422 Biologic-Treated Patients.

BACKGROUND AND AIMS: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown. METHODS: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021. RESULTS: Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94-9.96] vs 5.02 [2.18-18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39-68.10, p < 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels [<0.8 mg/L] were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were treated with anti-TNF. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% [12/152] of patients after a median time of 183.5 days [129.8-235.3], without differences between drugs. CONCLUSION: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.

Sexual Response Differs during Partnered Sex and Masturbation in Men With and Without Sexual Dysfunction: Implications for Treatment.

BACKGROUND: It is unclear whether men who experience sexual difficulty during partnered sex experience similar difficulty during masturbation. AIM: To determine whether sexual functionality and dysfunctionality were similar or different during masturbation vs partnered sex. METHODS: We compared sexual responsivity during masturbation vs partnered sex in a multinational sample of 4,209 men with and without a sexual dysfunction to determine whether dysfunctionality was greater, less, or about the same during these 2 types of sexual activity. OUTCOMES: Consistently lower impairment of sexual function was found during masturbation compared with partnered sex for all 3 sexual problems assessed: erectile dysfunction, premature ejaculation, and delayed ejaculation. CLINICAL TRANSLATION: These findings reiterate the potential value of assessing sexual responsivity during masturbation as well as melding masturbation strategies with couples therapy in order to attenuate impaired response during partnered sex. STRENGTH & LIMITATIONS: Although this study provides the first empirical evidence based on a large multinational sample indicating that sexual functionality is consistently higher during masturbation than partnered sex, it does not provide an empirically-derived explanation for this difference. CONCLUSION: Understanding a man's response potential during masturbation may be important to improving sexual response during partnered sex, with the need for more targeted research that more directly evaluates the use of such strategies in the treatment of men's sexual problems. Rowland DL, Hamilton BD, Bacys KR et al. Sexual Response Differs during Partnered Sex and Masturbation in Men With and Without Sexual Dysfunction: Implications for Treatment. J Sex Med 2021;18:1835-1842.

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine. DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4ß7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine. RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine. CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

The Role of Orgasmic Difficulty in Attributing Cause for Positive and Negative Sexual Outcomes in Women: The Importance of Cross-Cultural Analyses.

Studies investigating women's attributions for positive and negative sexual experiences have been slow to adopt a cross-cultural perspective, resulting in a perspective defined by Western experiences. This cross-cultural analysis examined such attribution processes in 88 Pakistani and 187 USA women, and identified differences related to orgasmic difficulty and country-of-origin. Pakistani and USA women differed on both self-blame and relationship blame related to negative sexual outcomes, an effect intensified in Pakistani women who reported orgasmic difficulty during partnered sex. Differences are interpreted within a cultural context and underscore the importance of addressing women's sexual experiences in a more global context.

Clinical Features and Genetic Risk of Demyelination Following Anti-TNF Treatment.

BACKGROUND: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. METHODS: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. RESULTS: Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7-63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median time of 6.8 months [0.1-28.7]. After 33.0 months of follow-up, partial recovery was observed in 29 [55%] patients, relapsing and remitting episodes in nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10-4, standard deviation [SD] 0.0039) and controls [mean -1.1 × 10-3, SD 0.0042] [p = 0.23]. CONCLUSIONS: Patients who experienced demyelination events following anti-TNF exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.

Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD. METHODS: We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist-hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption. RESULTS: Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference. CONCLUSIONS: These results provide strong evidence that a higher waist-hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.

Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.

BACKGROUND AND AIMS: The causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank. METHODS: In total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores. RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis. CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study.

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.

Risk Factors for Conversion to Total Hip Arthroplasty After Acetabular Fractures Involving the Posterior Wall.

OBJECTIVES: Identify risk factors for early conversion to total hip arthroplasty (THA) in an effort to aid in counseling patients and selecting the optimal treatment for patients who sustain a fracture involving the posterior wall of the acetabulum. DESIGN: Retrospective cohort analysis. SETTING: Level I trauma center. PATIENTS: Patients with acetabular fractures involving the posterior wall managed with open reduction internal fixation at least 4 years out from surgery. INTERVENTION: Preoperative and postoperative computed tomography scans were reviewed for injury characteristics and reduction quality. Participants were contacted by telephone to document reoperations and functional outcomes including the SF-8 and modified Merle d'Aubigne Hip Scale. MAIN OUTCOME MEASURE: Conversion to THA. RESULTS: The overall rate of conversion to THA was 5% at 2 years, 14% at 5 years, and 17% at 9 years. Presence of 5 specific radiographic features was associated with a 50% rate of conversion to THA in contrast to 11% if 4 or less features were present. Among cases with less than 1 mm of diastasis/step-off on postoperative computed tomography scan, there were no THA conversions, 10% conversion for 1-4 mm, and 54% if 4 mm or more of malreduction. There was no difference in SF-8 or modified Merle d'Aubigne scores comparing patients who underwent THA and those who did not. CONCLUSIONS: Acetabular fractures with posterior wall involvement are associated with a significantly higher rate of conversion to THA if reduction is not near-anatomic. A combination of clinical/radiographic findings is associated with poorer reductions and higher rate of conversion to THA. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Humeral shaft fractures: results of operative and non-operative treatment.

PURPOSE: There has been little direct comparison between non-operative and operative management of humeral shaft fractures. The present study aimed to compare union rates and complication rates between these two modalities of treatment. METHODS: A retrospective cohort study was performed at a regional level 1 trauma centre. A total of 296 patients with humeral shaft fractures met inclusion criteria; 69 patients were treated with a functional brace and 227 with surgical intervention. The primary end point was radiographic union. Nonunion was defined as failure of radiological union at six months, requiring surgical intervention. Time to union, nerve palsy rate, and rate of infection were also examined. RESULTS: The nonunion rate was significantly higher in the non-operative group (23.2 % vs 10.2 %) despite higher rates of open fractures and high energy mechanisms of injury in the operative group. No significant difference in time to union was found. Nerve palsy was more common in the operative group (20 % vs 39 %); however, only two cases (1 %) of radial nerve palsy in the operative group were iatrogenic and both were transient. Infection rates were higher for the operative group (3.5 % vs 0 %). CONCLUSIONS: Conservative treatment of humeral shaft fractures has a higher rate of nonunion, while operative treatment is associated with a low incidence of iatrogenic nerve palsy but higher rates of infection.

Near shore groundwater acidification during and after a hydrological drought in the Lower Lakes, South Australia.

An extreme hydrological drought in the Lower Lakes of the Murray-Darling Basin (Ramsar listed site) resulted in exposure of large areas of lake bed (25% of pre-drought lake area), containing the reduced iron (Fe) sulfide mineral pyrite. The pyrite oxidised and the resulting acidification (pH<4) posed risks of acid and metals entering shallow groundwater and potentially discharging to the remaining lake water body. Piezometer transects were installed at four locations and monitoring of the groundwater levels and quality was undertaken for six years from 2009 (drought) to 2014 (4years post-reinundation). Acidic (pH3-5) groundwater was recorded at three of the four piezometer locations and included sites close to the lake water. The acidic groundwater (0.5-2m below lake bed) at these sites is likely to have originated from the transport of acid from the upper oxidised sediment layer formed during the drought. High soluble metal (Fe, Al, Mn) levels were also recorded at acidic locations. Acidic shallow groundwater has persisted at many sites for over 4years following reinundation post-drought, and is likely due to slow diffusion and limited sulfate reduction. Increases in dissolved Fe and Mn with decreases in redox potential suggest that reductive dissolution of Fe and Mn hydrous oxides and Fe oxy-hydroxysulfate minerals (e.g. jarosite) occurred post-drought. Groundwater hydraulic head gradients were low, indicating there was limited potential for groundwater to discharge to the lake. The hydraulic gradients at all locations were dynamic with complex relationships along the near-shore environment. The results highlight the long lasting and severe effects on groundwater that can occur following hydrological drought in aquatic environments with sulfidic sediments.

Determining Stability in Posterior Wall Acetabular Fractures.

OBJECTIVES: To determine if the radiographic parameters of femoral head coverage by the intact posterior wall, acetabular version, and location of the fracture or a history of dislocation were determinates of hip stability in patients with posterior wall acetabular fractures. DESIGN: Retrospective review. SETTING: Level I trauma hospital. PATIENTS: One hundred eighty-five consecutive patients with isolated unilateral posterior wall (OTA 62-A1) acetabular fractures. INTERVENTION: Patients underwent dynamic stress fluoroscopic examination under general anesthesia to determine hip stability. MAIN OUTCOME MEASUREMENTS: A number of radiographic measurements were performed, and an examination under anesthesia served as a standard to compare stable versus unstable hips. RESULTS: Examination under anesthesia (EUA) determined 116 hips to be stable and 22 hips as unstable. Moed and Keith method of wall size measurements and cranial exit point of fracture was statistically different between stable and unstable hips. Twenty-three percent of the unstable hips had wall sizes less than 20%. Average cranial exit point of fracture from dome was 5.0 mm in the unstable group and 9.5 mm in the stable group, and fractures that extend into the dome demonstrate a statistically significant increase in hip instability. CONCLUSIONS: Determination of hip stability can be challenging in patients with posterior wall acetabular fractures. Our data suggest that the location of the exit point of the fracture in relation to the dome of the acetabulum is a radiographic marker that can be used to aid physician in determining stability, and wall sizes less than 20% is not a reliable indicator of stability. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Neurologic Injury in Operatively Treated Acetabular Fractures.

OBJECTIVES: The purpose of this study is to evaluate a series of operatively treated acetabular fractures with neurologic injury and to track sensory and motor recovery. METHODS: Operatively treated acetabular fractures with neurologic injury from 8 trauma centers were reviewed. Patients were followed for at least 6 months or to neurologic recovery. Functional outcome was documented at 3 months, 6 months, and final follow-up. Outcomes included motor and sensory recovery, brace use, development of chronic regional pain syndrome, and return to work. RESULTS: One hundred thirty-seven patients (101 males and 36 females), average age 42 (17-87) years, met the criteria. Mechanism of injury included MVC (67%), fall (11%), and other (22%). The most common fracture types were transverse + posterior wall (33%), posterior wall (23%), and both-column (23%). Deficits were identified as preoperative in 57%, iatrogenic in 19% (immediately after surgery), and those that developed postoperatively in 24%. A total of 187 nerve deficits associated with the following root levels were identified: 7 in L2-3, 18 in L4, 114 in L5, and 48 in S1. Full recovery occurred in 54 (29%), partial recovery in 69 (37%), and 64 (34%) had no recovery. Forty-three percent of S1 deficits and 29% of L5 deficits had no recovery. Fifty-five percent of iatrogenic injuries did not recover. Forty-eight patients wore a brace at the final follow-up, all for an L5 root level deficit. Although 60% (42/70) returned to work, chronic regional pain syndrome was seen to develop in 19% (18/94). CONCLUSIONS: Peripheral neurologic injury in operatively treated acetabular fractures occurs most commonly in the sciatic nerve distribution, with L5 root level deficits having only a 26% chance of full recovery. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The capacity of biochar made from common reeds to neutralise pH and remove dissolved metals in acid drainage.

We tested the capacity of biochar (made at 450 °C from a common reed species) to neutralise pH and remove metals in two acid drainage waters (pH 2.6 and 4.6) using column leaching and batch mixing experiments. In the column experiments, the acid drainage water was neutralised upon passage through the biochar with substantial increases (4-5 pH units) in the leachate pH. In the batch experiments, the leachate pH remained above 6.5 when the drainage:biochar ratio was less than approximately 700:1 (L acid drainage:kg biochar) and 20:1 for the pH 4.6 and pH 2.6 drainage waters, respectively. Dissolved metal concentrations were reduced by 89-98 % (Fe ≈ Al > Ni ≈ Zn > Mn) in the leachate from the biochar. A key mechanism of pH neutralisation appears to be solid carbonate dissolution as calcite (CaCO3) was identified (via X-ray diffraction) in the biochar prior to contact with acid drainage, and dissolved alkalinity and Ca was observed in the leachate. Proton and metal removal by cation exchange, direct binding to oxygen-containing functional groups, and metal oxide precipitation also appears important. Further evaluation of the treatment capacity of other biochars and field trials are warranted.