MEDI1814 selectively reduces free Aß42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

INTRODUCTION: Small molecules and antibodies are being developed to lower amyloid beta (Aß) peptides. METHODS: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aß42, the pathogenic self-aggregating species of Aß. RESULTS: MEDI1814 reduces free Aß42 without impacting Aß40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aß42, increases in total (bound and free) Aß42, but no change in total Aß40 in CSF across doses. DISCUSSION: MEDI1814 offers a differentiated approach to impacting Aß in AD via selective reduction of free Aß42.

Frailty and Long-Term Mortality Following Emergency Laparotomy: A Comparison Between the 11-Item and 5-Item Modified Frailty Indices.

INTRODUCTION: Emergency laparotomy (EL) is a high-risk operation which is increasingly performed on an aging patient population. Objective frailty assessment using a validated index has the potential to improve preoperative risk stratification. This study aimed to assess the correlation between frailty and long-term mortality and morbidity outcomes for older EL patients. Secondary aims were to compare the 11-item and shortened five-item modified frailty indices (mFIs) in terms of value and predictive validity. METHODS: A prospective multicenter observational study of patients aged ≥55 y undergoing EL was conducted across five hospitals in New Zealand between 2017 and 2022. Frailty was measured using the 11-item and abbreviated five-item mFIs. Multivariable logistic regression was used to determine whether frailty was independently associated with one-year postoperative mortality and other morbidity outcomes. Correlation between the two frailty indices were assessed with the Spearman's correlation coefficient (P). RESULTS: Frailty assessments were performed in 861 participants, with the prevalence being 18.7% and 29.8% using the 11-item and five-item mFIs, respectively. Both frailty indices demonstrated similar associations with one-year mortality (two-fold increased risk), major complications, admission to intensive care unit, rehabilitation, and 30-d readmission. The 11-item mFI demonstrated a greater association with early mortality (four-fold increased risk), reoperations, and increased length of stay compared with the five-item frailty index. Spearman P was 0.6 (P < 0.001). CONCLUSIONS: Frailty, as identified by the 11-item and five-item mFIs, was associated with one-year mortality and other important morbidity outcomes for older EL patients. These forms of frailty assessment provide important information that may aid in risk assessment and patient-centered decision-making.

Outcomes of asymptomatic common bile duct stones detected at intraoperative cholangiography.

AIMS: The aim of this study was to investigate the outcome of common bile duct stones (CBDS) in asymptomatic patients at laparoscopic cholecystectomy (LC) and intra-operative cholangiogram (IOC). METHODS: All patients undergoing LC and IOC at Te Whatu Ora - Health New Zealand Waikato between January 2017 and January 2022 were retrospectively reviewed. Electronic records were screened for asymptomatic CBDS. Exclusion criteria were hyperbilirubinaemia, gallstone pancreatitis, cholangitis and imaging-detected CBDS. IOC reports were reviewed to determine presence of CBDS. A second blinded review was undertaken by a radiologist. Outcomes were use of endoscopic retrograde pancreatography (ERCP), complications and readmission with retained CBDS. RESULTS: Included were 1,297 patients undergoing LC and IOC. Of these, 150 (24.1%) patients had a positive IOC, of which 58 (38.7%) were asymptomatic. Attempted flushing of CBDS was employed in 49 cases, 10 successfully. Common duct exploration was successful in a further six out of seven cases. Of the remaining 42 patients, 18 were offered ERCP. Seven had no stone at endoscopy. Sixteen had imaging, revealing clear ducts in 14. The remaining two then had ERCP confirming choledocholithiasis. Eight patients were managed expectantly, of whom none required readmission with retained stones. CONCLUSION: Rates of retained asymptomatic stones after positive IOC were low. Acknowledging risks associated with intervention and low rates of readmission with retained CBDS, an expectant approach could be more readily considered.

Association between frailty, long-term mortality and functional outcomes for older adults undergoing emergency laparotomy.

BACKGROUND: An increasing number of older patients are undergoing emergency laparotomy (EL). Frailty is thought to contribute to adverse outcomes in this group. The best method to assess frailty and impacts on long-term mortality and other important functional outcomes for older EL patients have not been fully explored. METHODS: A prospective multicenter study of older EL patients was conducted across four hospital sites in New Zealand from August 2017 to September 2022. The Clinical Frailty Scale (CFS) was used to measure frailty-defined as a CFS of ≥5. Primary outcomes were 30-day and one-year mortality. Secondary outcomes were postoperative morbidity, admission for rehabilitation, and increased care level on discharge. A multivariate logistic regression analysis was conducted, adjusting for age, sex, and ethnicity. RESULTS: A total of 629 participants were included. Frailty prevalence was 14.6%. Frail participants demonstrated higher 30-day and 1-year mortality-20.7% and 39.1%. Following adjustment, frailty was directly associated with a significantly increased risk of short- and long-term mortality (30-day aRR 2.6, 95% CI 1.5, 4.3, p = <0.001, 1-year aRR 2.0, 95% CI 1.5, 2.8, p < 0.001). Frailty was correlated with a 2-fold increased risk of admission for rehabilitation and propensity of being discharged to an increased level of care, complications, and readmission within 30 days. CONCLUSION: Frailty was associated with increased risk of postoperative mortality up to 1-year and other functional outcomes for older patients undergoing EL. Identification of frailty in older EL patients aids in patient-centered decision-making, which may lead to improvement in outcomes.

Rare finding of a symptomatic epidermoid cyst of the diaphragm - a case report.

Cystic lesions of the diaphragm are rare and accordingly present a diagnostic challenge. Specific radiological features with which to clinch a diagnosis may be elusive. Herein we present the case of a patient who presented with symptoms attributable to a cyst in the left upper abdomen, irritating the diaphragm. Surgery was considered appropriate for diagnostic and symptomatic purposes. Final histology demonstrated an epidermoid cyst. Resolution of symptoms was reported after surgery. Diaphragmatic epidermoid cysts appear to be a rare entity with only three prior cases reported in the literature. Given the rarity of this lesion and the lack of unique features by which they can be characterized, accurately diagnosing epidermoid cysts of the diaphragm is likely to remain difficult without surgery, although they are presumed to have a benign behaviour.

Novel application of Roux-en-Y for diversion of a cutaneous fistula from an irresectable mesenteric root mature teratoma: a case report.

Reconfiguration of the alimentary tract with the Roux-en-Y has been utilized in a wide variety of contexts since its first description by Swiss physician César Roux. We present a novel and unique application of the Roux-en-Y whereby a chronically discharging cutaneous fistula originating at a retroperitoneal mature teratoma within the root of the mesentery was diverted enterically via a cystojejunostomy and the fistula tract excised, providing a resolution of symptoms. The location of the tumour in the root of the mesentery and the involvement of major mesenteric vessels made a radical resection of the tumour technically impossible but due to the distressing symptoms caused by the fistula made diversion of the fistula an excellent treatment option.

Weekend effect in emergency laparotomy: a propensity score-matched analysis.

BACKGROUND: The 'weekend effect' is the term given to the observed discrepancy regarding patient care and outcomes on weekends compared to weekdays. This study aimed to determine whether the weekend effect exists within Aotearoa New Zealand (AoNZ) for patients undergoing emergency laparotomy (EL), given recent advances in management of EL patients. METHODS: A cohort study was conducted across five hospitals, comparing the outcomes of weekend and weekday acute EL. A propensity-score matched analysis was used to remove potential confounding patient characteristics. RESULTS: Of the 487 patients included, 132 received EL over the weekend. There was no statistically significant difference between patients undergoing EL over the weekend compared to weekdays. Mortality rates were comparable between the weekday and weekend cohorts (P = 0.464). CONCLUSIONS: These results suggest that modern perioperative care practice in New Zealand obviates the 'weekend' effect.

Sensitization of colonic nociceptors by IL-13 is dependent on JAK and p38 MAPK activity.

The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis. Furthermore, receptors for IL-13 are expressed by neurons innervating the colon, though it is not known whether IL-13 plays any role in visceral nociception per se. To resolve this, we used Ca2+ imaging of cultured sensory neurons and ex vivo electrophysiological recording from the lumbar splanchnic nerve innervating the distal colon. Ca2+ imaging revealed the stimulation of small-diameter, capsaicin-sensitive sensory neurons by IL-13, indicating that IL-13 likely stimulates nociceptors. IL-13-evoked Ca2+ signals were attenuated by inhibition of Janus (JAK) and p38 kinases. In the lumbar splanchnic nerve, IL-13 did not elevate baseline firing, nor sensitize the response to capsaicin application, but did enhance the response to distention of the colon. In line with Ca2+ imaging experiments, IL-13-mediated sensitization of the afferent response to colon distention was blocked by inhibition of either JAK or p38 kinase signaling. Together, these data highlight a potential role for IL-13 in visceral nociception and implicate JAK and p38 kinases in pronociceptive signaling downstream of IL-13.

Conversion of locally advanced to resectable pancreatic body cancer aided by phosphorus-32 brachytherapy (OncoSil).

Nil.

Sensitization of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity.

Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut-related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro-inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNFα-triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesized that TNFR1-evoked p38 MAPK activity may also be responsible for TNFα sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNFα-mediated increases in intracellular [Ca2+ ] and sensitization of capsaicin responses. The sensitizing effects of TNFα were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre-treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα-induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease. KEY POINTS: The pro-inflammatory cytokine TNFα is elevated in gastrointestinal disease and sensitizes colonic afferents via modulation of TRPA1 and NaV 1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα-mediated colonic afferent sensitization. Specifically, we show that: TNFα sensitizes sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα-mediated sensitization of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitization of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively these data support the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in gastrointestinal disease.

Beware the pancreatic incidentaloma in colorectal tumours: pancreatic adenocarcinoma with metastases to the colon and rectum.

Colorectal cancer (CRC) is the third most diagnosed malignancy in the Western world. Routine staging of CRC often identifies incidental lesions on cross-sectional imaging. Appropriate treatment is dependent on a correct histological diagnosis. Pancreatic Ductal Adenocarcinoma (PDAC) is a rarer and often devastating diagnosis for which the treatment pathway differs significantly to CRC. We report two rare cases: the first recorded case of PDAC with synchronous rectal metastasis and a case of an acute presentation with large bowel obstruction from synchronous colonic metastasis. Both cases presented a significant diagnostic challenge. The management of both cases would have been altered had the histological diagnosis been known prior to surgery. Clinicians treating CRC should be wary of incidental lesions on staging investigations as they rarely represent an occult extra-intestinal primary malignancy. Immunohistochemistry plays an important role in ascertaining the origin of gastrointestinal malignancy.

Surgical management of duodenal web in an adult presenting with melaena; Case report and literature review.

INTRODUCTION: Duodenal web is a rare pathology presenting infrequently in adults. Diagnosis is challenging and definitive management is commonly delayed. We present a case of a patient with a late diagnosis of duodenal web, who underwent laparotomy, intraoperative gastroscopy and surgical removal of the web performed by two general surgeons. CASE PRESENTATION: A 32-year-old woman with a previous diagnosis of irritable bowel syndrome presented with a three day history of abdominal pain, nausea and anorexia, and a one day history of melaena and haematemesis. Investigations including a magnetic resonance enterography, barium swallow study and gastroscopy revealed the diagnosis. The patient underwent laparotomy and excision of duodenal web. Intraoperative gastroscopy assisted with identification of the web's anatomical location. A longitudinal duodenotomy was performed and this was closed in a transverse fashion using the Heineke-Mikulicz technique. DISCUSSION: This case reports successful application of intraoperative gastroscopy during laparotomy and duodenotomy. Longitudinal duodenotomy with excision of the web and transverse closure of the duodenum appears to be the best approach. There are no previous publications detailing gastroscopy at the time of laparotomy with duodenal web. This technique may be utilised in appropriate situations to improve operative accuracy. CONCLUSION: Duodenal web is a rare entity in adults, and delayed diagnosis may lead to significant patient morbidity. Incorporating intraoperative endoscopy ensures accurate anatomical visualisation. This technique avoids duodenectomy, organ damage, bypass, or an unnecessarily large incision.

Noninvasive Mechanical Joint Loading as an Alternative Model for Osteoarthritic Pain.

OBJECTIVE: Mechanisms responsible for osteoarthritic (OA) pain remain poorly understood, and current analgesic therapies are often insufficient. This study was undertaken to characterize and pharmacologically test the pain phenotype of a noninvasive mechanical joint loading model of OA, thus providing an alternative murine model for OA pain. METHODS: The right knees of 12-week-old male C57BL/6 mice were loaded at 9N or 11N (40 cycles, 3 times per week for 2 weeks). Behavioral measurements of limb disuse and mechanical and thermal hypersensitivity were acquired before mechanical joint loading and monitored for 6 weeks postloading. The severity of articular cartilage lesions was determined postmortem with the Osteoarthritis Research Society International scoring system. To assess efficacy of various treatments for pain, 9N-loaded mice were treated for 4 weeks with diclofenac (10 mg/kg), gabapentin (100 mg/kg), or anti-nerve growth factor (anti-NGF) (3 mg/kg). RESULTS: Mechanical hypersensitivity and weight bearing worsened significantly in 9N-loaded mice (n = 8) and 11N-loaded mice (n = 8) 2 weeks postloading, compared to baseline values and nonloaded controls. Maximum OA scores of ipsilateral knees confirmed increased cartilage lesions in 9N-loaded mice (mean ± SEM 2.8 ± 0.2; P < 0.001) and 11N-loaded mice (5.3 ± 0.3; P < 0.001), compared to nonloaded controls (1.0 ± 0.0). Gabapentin and diclofenac restored pain behaviors to baseline values after 2 weeks of daily treatment, and gabapentin was more effective than diclofenac. A single injection of anti-NGF alleviated nociception 2 days after treatment and remained effective for 2 weeks, with a second dose inducing stronger and more prolonged analgesia. CONCLUSION: Our findings show that mechanical joint loading induces OA lesions in mice and a robust pain phenotype that can be reversed using analgesics known to alleviate OA pain in patients. This establishes the use of mechanical joint loading as an alternative model for the study of OA pain.

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.

Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins.

Communicating the location of potential skin neoplasms for excision between the referring and the operating doctor--an audit of skin lesion referrals in Whanganui, New Zealand.

AIM: The importance of correctly defining the location of potential skin cancer when surgical treatment may be required is self-evident. Clear communication is essential if the professional diagnosing potential skin cancer is not the same professional providing treatment. We aimed to assess the nature of the localising information provided in referrals to the local anaesthetic skin lesion theatre in our institution. METHODS: Information localising target lesions for new patients seen in our local anaesthetic skin excision theatre was recorded during a 2-month period April to May 2012 inclusive RESULTS: 100 patients were seen in our skin excision theatre during the study period; 16 patients were not able to identify the target skin lesion at the time they entered the operating theatre. The target lesion could not be determined from the referral text in 30/100 cases. Diagrams were provided in 19/100 cases. Photographs were provided in 3/100 cases. CONCLUSIONS: Pictorial and photographic means of communicating the location of suspicious lesions are under-utilised in our service. Relying on the patient or the referral text to correctly identify the lesion leaves considerable room for error. We suggest that photographic information for skin lesion referrals is adopted as a minimum standard.