Predictors of Clinical Outcomes in Acute Appendicitis: A Retrospective Study.

INTRODUCTION: Acute appendicitis is one of the most common causes of intra-abdominal emergency surgery worldwide. This study was conducted to contribute to global databases by presenting data from our institution, which consist of multi-racial population. We aimed to evaluate the presentation, diagnosis, and management of acute appendicitis and post-operative outcome in our institution and evaluate the risks factors associated with severe complications and prolonged length of stay (LOS). MATERIALS AND METHODS: We performed a retrospective analysis using multivariate regression analysis of all patients who underwent appendectomy (2009-2014) in our institution. The primary outcomes included demographics, presentation, and perioperative management, and the secondary outcomes included risk factors associated with prolonged LOS. RESULTS: Of the 1185 patients, the mean age was 36.4 years, and 940 (79.3%) were male. Majority (98.1%) of patients were ASA (American Society of Anaesthesiologists) 1 or 2. Most of them (83.9%) were from the four racial subgroups (Chinese, Malay, Bangladeshi, and Indian). There was no racial variation in the diagnosis and presentation of disease. The mean duration of symptoms was 1.8 days. The history was commonly a localised or migratory abdominal pain associated with anorexia, nausea, vomiting, and fever. The commonest physical findings were right-sided abdominal tenderness associated with rebound and guarding. About 42.9% of the patients underwent pre-operative CT scan to establish the diagnosis of appendicitis prior to surgery, whilst 57.1% underwent surgery on clinical diagnosis and blood investigation (NWR and CRP). An open appendectomy was performed in 13.2% of the patients. The conversion rate of laparoscopic appendectomy was 4.9% (n = 50). The mean length of hospital stay was 3.6 days. On multivariate Cox regression, patients of Burmese and Thai descent were independently associated with a prolonged LOS. The postoperative morbidity was 5.5%. The 30-day readmission rate was 2.4%. There was no mortality in our study. DISCUSSION: Our study showed that pre-operative diagnosis of acute appendicitis can be made accurately by classical clinical presentation or by imaging. Independent risk factors associated with increased LOS included increased age, male gender, prolonged duration of symptoms pre-admission, fever, generalised tenderness, and prolonged operative time. The effect of race on LOS has been observed in the literature for other surgical procedures. The prolonged LOS found in Burmese and Thai patients contribute to the possibility of intrinsic racial differences in the post-surgery recovery. However, the numbers are small and therefore prone to type I error. Compared to the open approach, the use of laparoscopic appendectomy was associated with shorter LOS. This has similar outcomes to those reported in the literature. CONCLUSION: The identification of risks factors could help surgical team to predict the clinical outcomes and develop risk reduction strategy in post-operative care of these patients.

A case of Multisystem Inflammatory Syndrome in adults in Malaysia.

Multisystem Inflammatory Syndrome in Adults (MIS-A) is a rare but potentially life-threatening complication following SARS-CoV-2 infection. We present a Malaysian case of MISA in a 45 year old gentleman who developed cardiogenic shock following a mild SARS-CoV-2 infection.

High prevalence of central hypothyroidism among patients with transfusion dependent thalassemia in Hospital Pulau Pinang: A cross sectional study.

INTRODUCTION: Thalassemia is the most common heritable haematological disorder in Malaysia. Hypothyroidism is one of the complications of the transfusion dependent thalassemia (TDT) patients as a result of iron overload. MATERIALS AND METHODS: All registered TDT patients attending Haematology day care, Hospital Pulau Pinang from January 2019 to January 2020 were included in the study. Hypothyroidism was defined according to TSH and FT4, or based on the history of treatment for diagnosed hypothyroidism. RESULTS: There were 51 TDT patients, with 24 (47%) males and 27 (53%) females. Most of the patients were Malays (27, 53%) followed with Chinese (23, 45%) and Indonesian (1, 2%). Beta thalassemia major and HbE beta thalassaemia accounted for 35 (68.8%) and 14 (27.5%) TDT patients respectively, while two (3.9%) were HbH Constant Spring. Eleven (21.6%) had hypothyroidism; of which seven (63.6%) had central hypothyroidism, three (27.3%) had subclinical hypothyroidism, the remaining one (9.1%) had primary hypothyroidism. Three (27.3%) had concomitant hypogonadism, one (9.1%) had hypocortisolism and another (9.1%) had both diabetes mellitus and hypogonadism. There was no statistical relationship between the prevalence of hypothyroidism and age, serum ferritin, splenectomy history and iron chelation therapy. CONCLUSION: High prevalence of central hypothyroidism is reported. Measurement of both TSH and FT4 is recommended as initial screening for thyroid dysfunction among patient with TDT.

Ulcerative colitis with concomitant primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is the most common liver disease and known hepatobiliary complication of ulcerative colitis (UC). Concomitant PSC in UC is associated with increased risk of rapid progression of primary sclerosing cholangitis, and malignancy including colon carcinoma as well as hepatobiliary carcinoma. We report a case of a 26-year-old woman who was diagnosed as ulcerative colitis during her second pregnancy. Her liver function test showed a significant elevation of alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) with other parameters being within normal range. A clinical suspicion of primary sclerosing cholangitis was then made. Magnetic resonance cholangiopancreticography (MRCP) revealed beaded appearance of the right and left intrahepatic ducts with focal narrowing seen at the ducts, suggestive of primary sclerosing cholangitis. She was subsequently started on oral Ursodeoxycholic acid (UDCA) with improvement in her liver function test within 3 weeks of initiation of treatment.

Clinical and economic burden of wound care in the tropics: a 5-year institutional population health review.

The aim of this study is to evaluate the clinical and economic burden of wound care in the Tropics via a 5-year institutional population health review. Within our data analysis, wounds are broadly classified into neuro-ischaemic ulcers (NIUs), venous leg ulcers (VLUs), pressure injuries (PIs), and surgical site infections (SSIs). Between 2013 and 2017, there were a total of 56 583 wound-related inpatient admissions for 41 461 patients, with a 95.1% increase in wound episodes per 1000 inpatient admissions over this period (142 and 277 wound episodes per 1000 inpatient admissions in 2013 and 2017, respectively). In 2017, the average length of stay for each wound episode was 17.7 days, which was 2.4 times that of an average acute admission at our institution. The average gross charge per wound episode was USD $12 967. Among the 12 218 patients with 16 674 wound episodes in 2017, 71.5% were more than 65 years of age with an average Charlson Comorbidity Index (CCI) of 7.2. Half (51.9%) were moderately or severely frail, while 41.3% had two or more wound-related admission episodes. In 2017, within our healthcare cluster, the gross healthcare costs for all inpatient wound episodes stand at USD $216 million within hospital care and USD $596 000 within primary care. Most NIU patients (97.2%) had diabetes and they had the most comorbidities (average CCI 8.4) and were the frailest group of patients (44.9% severely frail). The majority of the VLU disease burden was at the specialist outpatient setting, with the average 1-year VLU recurrence rate at 52.5% and median time between healing and recurrence at 9.5 months. PI patients were the oldest (86.5% more than 65 years-old), constituted the largest cohort of patients with 3874 patients at an incidence of 64.6 per 1000 admissions in 2017, and have a 1-year all-cause mortality rate of 14.3%. For SSI patients, there was a 125% increase of 14.2 SSI wound episodes per 1000 inpatient admissions in 2013 to 32.0 in 2017, and a 413% increase in wound-related 30-day re-admissions, from 40 in 2013 (4.1% of all surgeries) to 205 (8.3% of all surgeries) in 2017. The estimated gross healthcare cost per patient ranges from USD $15789-17 761 across the wound categories. Similar to global data, there is a significant and rising trend in the clinical and economic burden of wound care in Tropics.

Reduction in surgical stoma rates in Crohn's disease: a population-based time trend analysis.

AIM: Trends in surgical rates for Crohn's disease (CD) in the biological era are controversial. We aim to assess modern trends in the formation rates of surgical stomas. METHOD: Population-based surveillance in the Calgary Health Zone (CHZ), Canada, was conducted between 1 April 2002 and 31 March 2011, using the Discharge Abstract Database to identify adult patients with CD admitted to hospital and treated with surgical stoma formation (n = 545). Annual stoma incidence was calculated by dividing the number of incident stomas by the prevalence of CD in the CHZ. Time trend analysis of the stoma-formation rate was performed, expressed as annual percentage change (APC) with 95% CI. Stoma-formation rates were stratified according to procedure (emergency vs elective) and duration of stoma [temporary (reversed within 2 years of formation) vs permanent]. RESULTS: The overall rate of stoma formation between 2002 and 2011 showed a downwards trend, of a mean of 5.2% (95% CI: -8.5 to -1.8) per year, from a rate of 2.30 stomas/100 person-years (PY) in 2002 to 1.51 stomas/100 PY in 2011. The rate of emergency stoma formation decreased significantly from 2002 to 2011 (mean APC = -9.4%; 95% CI: -15.6 to -2.8), while the rate of elective ostomies essentially showed no change (mean APC = -0.9%; 95% CI: -5.3 to 3.8). The rate of temporary stoma formation decreased significantly, by 4.6% (95% CI: -7.3 to -1.8) per year, while permanent stoma formation was stable (APC = 1.0%; 95% CI: -4.0 to +6.3). CONCLUSION: A reduction in the overall rate of stoma formation in CD has been driven by fewer emergency stomas, although rates of permanent stoma have remained stable.

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases.

BACKGROUND: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. AIM: To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. METHODS: A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. RESULTS: 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 µg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints-such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. CONCLUSION: Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn's disease: real world experience from a multicentre cohort.

BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukins-12 and -23, with efficacy in Crohn's disease (CD) demonstrated in clinical trials. AIM: To assess the real-world clinical, endoscopic and radiographic response and remission outcomes achieved with ustekinumab in medically-refractory CD. METHODS: A retrospective multicentre cohort study was performed on CD patients receiving ustekinumab between 2011 and 2016. The primary outcome was achievement of clinical and objective steroid-free response and remission at 3, 6 and 12 months. Clinical response and remission were defined by reduction in Harvey Bradshaw Index (HBI) of ≥3 points and an HBI ≤4 points respectively. Objective response was defined by improvement in endoscopic or radiographic CD, as assessed by ileocolonoscopy, contrast-enhanced ultrasound or CT/MR enterography. Objective remission was defined by endoscopic mucosal healing or complete resolution of inflammatory parameters on radiographic assessment. RESULTS: A total of 167 CD patients were treated with ustekinumab. 95.2% (159/167) previously failed anti-TNF therapy. Median follow-up was 45.6 weeks (IQR: 24.4-88.9). At 3 months, clinical response was achieved in 38.9% (65/167) and remission in 15.0% (25/167) of patients. At 6 months, clinical response was achieved in 60.3% (91/151) and remission in 25.2% (38/151) of patients. At 12 months, clinical response was achieved in 59.5% (66/111) and remission in 27.9% (31/111) of patients. Endoscopic or radiographic response was demonstrated in 54.5% (67/123) at 6 months and 55.8% (48/86) of patients at 12 months. CONCLUSIONS: Ustekinumab is an effective therapeutic option for inducing and maintaining clinical, endoscopic and radiographic response in patients with Crohn's disease failing anti-TNF therapy.

The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease.

BACKGROUND: Transplacental transfer of infliximab and adalimumab results in detectable drug levels in the cord blood and infant. AIM: To determine if pregnancy influenced the pharmacokinetics of anti-TNF agents in women with inflammatory bowel disease. METHODS: Twenty-five women from the University of Calgary inflammatory bowel disease(IBD) pregnancy clinic on maintenance infliximab or adalimumab were recruited prospectively with serum bio-banking performed each trimester. Infliximab trough and adalimumab steady-state levels were the outcomes of interest and were analysed using the ANSER infliximab and adalimumab assays. Multivariate linear mixed-effects models were constructed to assess infliximab and adalimumab drug levels during pregnancy adjusting for the clinical covariates of albumin, BMI and CRP. RESULTS: Fifteen women (eight Crohn's disease, seven ulcerative colitis) received infliximab and 10 women with 11 pregnancies were treated with adalimumab. Median age was 29.6 years (IQR: 27.6-31.2 years). Median disease duration was 9.2 years (IQR: 3.16-15.0 years). Median trough infliximab concentrations were 8.50 µg/mL (IQR: 7.23-10.07 µg/mL), 10.31 µg/mL (IQR: 7.66-15.63 µg/mL) and 21.02 µg/mL (IQR: 16.01-26.70 µg/mL) at trimesters 1, 2 and 3 respectively. Significant changes in albumin and BMI (P < 0.05) but not CRP (P > 0.05) were documented throughout pregnancy. After adjusting for albumin, BMI and CRP, infliximab trough levels increased during pregnancy, by 4.2 µg/mL per trimester (P = 0.02), while adalimumab drug levels remained stable (P > 0.05). CONCLUSIONS: Infliximab levels rise during pregnancy, whereas adalimumab levels remain stable after accounting for changes in albumin, BMI and CRP. Therapeutic drug monitoring in the second trimester may be useful in guiding dosing in the third trimester.

Review article: dermatological complications of immunosuppressive and anti-TNF therapy in inflammatory bowel disease.

BACKGROUND: With the expanding list of medications available to treat patients with inflammatory bowel disease (IBD), it is important to recognise adverse events, including those involving the skin. Dermatological adverse events may be confused with extra-intestinal manifestations of IBD. AIM: To review drug-related dermatological manifestations associated with immunosuppressive and anti-tumour necrosis factor (anti-TNF) therapy. METHODS: The literature was searched on PubMed for dermatological adverse events in IBD. RESULTS: Present thiopurine exposure was associated with a 5.9-fold [95% confidence interval (CI), 2.1-16.4] increased risk of developing non-melanoma skin cancer (NMSC). The peak incidence is highest in Caucasians over the age of 65 years with crude incidence rates of 4.0 and 5.7/1000 patient-years for present and previous use. In anti-TNF-exposed subjects, drug-induced lupus was reported in 1% of the cases and a psoriatic rash in up to 3% of the cases. Anti-TNF monotherapy increases the risk of NMSC ~2-fold to a rate of 0.5 cases per 1000 person-years. Cutaneous lymphomas have been rarely reported in subjects on thiopurine or anti-TNF drug monotherapy. Combination therapy seems to have an additive effect on the risk of developing NMSC and lymphoma. CONCLUSIONS: Physicians need to be aware of the wide spectrum of dermatological complications of immunosuppressive and anti-TNF therapy in IBD, especially psoriasis and non-melanoma skin cancer. Vigilance and regular screening for non-melanoma skin cancer is recommended. Case discussions between gastroenterologists and dermatologists should be undertaken to best manage dermatological adverse events.

MEK modulates force-fluctuation-induced relengthening of canine tracheal smooth muscle.

Tidal breathing, and especially deep breathing, is known to antagonise bronchoconstriction caused by airway smooth muscle (ASM) contraction; however, this bronchoprotective effect of breathing is impaired in asthma. Force fluctuations applied to contracted ASM in vitro cause it to relengthen, force-fluctuation-induced relengthening (FFIR). Given that breathing generates similar force fluctuations in ASM, FFIR represents a likely mechanism by which breathing antagonises bronchoconstriction. Thus it is of considerable interest to understand what modulates FFIR, and how ASM might be manipulated to exploit this phenomenon. It was demonstrated previously that p38 mitogen-activated protein kinase (MAPK) signalling regulates FFIR in ASM strips. Here, it was hypothesised that the MAPK kinase (MEK) signalling pathway also modulates FFIR. In order to test this hypothesis, changes in FFIR were measured in ASM treated with the MEK inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene). Increasing concentrations of U0126 caused greater FFIR. U0126 reduced extracellular signal-regulated kinase 1/2 phosphorylation without affecting isotonic shortening or 20-kDa myosin light chain and p38 MAPK phosphorylation. However, increasing concentrations of U0126 progressively blunted phosphorylation of high-molecular-weight caldesmon (h-caldesmon), a downstream target of MEK. Thus changes in FFIR exhibited significant negative correlation with h-caldesmon phosphorylation. The present data demonstrate that FFIR is regulated through MEK signalling, and suggest that the role of MEK is mediated, in part, through caldesmon.

Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis.

BACKGROUND AND AIMS: Antibodies to infliximab reduce serum infliximab with loss of clinical benefit, but undetectable trough serum concentrations of infliximab may occur without antibody formation. The relationship between trough serum infliximab and clinical outcomes was evaluated in acute ulcerative colitis. METHODS: In a cohort of 115 patients with ulcerative colitis treated with three-dose induction followed by scheduled maintenance infliximab, rates of clinical remission, colectomy, antibodies to infliximab and trough serum infliximab were determined. RESULTS: Rates of remission were 32% at week 10 and 37% at week 54. Colectomy occurred in 40% of patients, at a median of 5.3 (IQR 1.9-12.1) months. Detectable trough serum infliximab was present in 39% of patients and, among patients with undetectable infliximab, 41% were antibody positive and 20% were antibody negative. For antibody-positive and antibody-negative patients, rates of remission (18% vs 14%), endoscopic improvement (25% vs 35%) and colectomy (52% vs 59%) were not different. A detectable serum infliximab was associated with higher rates of remission (69% vs 15%; p<0.001) and endoscopic improvement (76% vs 28%, p<0.001). An undetectable serum infliximab predicted an increased risk for colectomy (55% vs 7%, OR 9.3; 95% CI 2.9 to 29.9; p<0.001). Concurrent immunosuppression was not associated with clinical outcomes. CONCLUSIONS: For patients with ulcerative colitis treated with infliximab, a detectable trough serum infliximab predicts clinical remission, endoscopic improvement and a lower risk for colectomy. An undetectable trough serum infliximab, irrespective of antibody status, is associated with less favourable outcomes.

Human airway smooth muscle is structurally and mechanically similar to that of other species.

Airway smooth muscle (ASM) plays a vital role in the exaggerated airway narrowing seen in asthma. However, whether asthmatic ASM is mechanically different from nonasthmatic ASM is unclear. Much of our current understanding about ASM mechanics comes from measurements made in other species. Limited data on human ASM mechanics prevents proper comparisons between healthy and asthmatic tissues, as well as human and animal tissues. In the current study, we sought to define the mechanical properties of healthy human ASM using tissue from intact lungs and compare these properties to measurements in other species. The mechanical properties measured included: maximal stress generation, force-length properties, the ability of the muscle to undergo length adaptation, the ability of the muscle to recover from an oscillatory strain, shortening velocity and maximal shortening. The ultrastructure of the cells was also examined. Healthy human ASM was found to be mechanically and ultrastructurally similar to that of other species. It is capable of undergoing length adaptation and responds to mechanical perturbation like ASM from other species. Force generation, shortening capacity and velocity were all similar to other mammalian ASM. These results suggest that human ASM shares similar contractile mechanisms with other animal species and provides an important dataset for comparisons with animal models of disease and asthmatic ASM.