Daratumumab, cyclophosphamide, bortezomib and dexamethasone for non-transplant eligible myeloma (AMaRC 03-16).

In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard of care regimens. In a randomized trial, we tested whether similar improvements would be seen when daratumumab was added to the bortezomib, cyclophosphamide and dexamethasone (VCD) regimen. Non-transplant eligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). 121 patients were randomized, 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the two arms. The median PFS was 16.8m (95%CI 15.3 - 21.7m) and 25.8m (95%CI 19.9 - 33.5) in the VCD and VCDD arms, respectively (HR 0.67, log-rank test p=0.066). In a pre-planned analysis, the estimated PFS at fixed time-points post-randomization demonstrated significantly improved PFS for the daratumumab containing arm from 18 months onwards. The proportions of patients who were progression free at the following time points were: 18 months, 48% vs 68% (p=0.0002); 24 months, 36% vs 52% (p=0.0001); and 30 months, 27% vs 41% (p<0.0001) in the VCD and VCDD arms, respectively. The best overall response and VGPR rate were significantly better in the daratumumab arm (65% vs 86%, p=0.007 and 28% vs 52%, p=0.009) for the VCD and VCDD arms, respectively. Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of non-transplant eligible patients with myeloma. Australian and New Zealand Clinical Trials Registry (ACTRN12617000202369). https://www.anzctr.org.au/.

An intronic RNA element modulates Factor VIII exon-16 splicing.

Pathogenic variants in the human Factor VIII (F8) gene cause Hemophilia A (HA). Here, we investigated the impact of 97 HA-causing single-nucleotide variants on the splicing of 11 exons from F8. For the majority of F8 exons, splicing was insensitive to the presence of HA-causing variants. However, splicing of several exons, including exon-16, was impacted by variants predicted to alter exonic splicing regulatory sequences. Using exon-16 as a model, we investigated the structure-function relationship of HA-causing variants on splicing. Intriguingly, RNA chemical probing analyses revealed a three-way junction structure at the 3'-end of intron-15 (TWJ-3-15) capable of sequestering the polypyrimidine tract. We discovered antisense oligonucleotides (ASOs) targeting TWJ-3-15 partially rescue splicing-deficient exon-16 variants by increasing accessibility of the polypyrimidine tract. The apical stem loop region of TWJ-3-15 also contains two hnRNPA1-dependent intronic splicing silencers (ISSs). ASOs blocking these ISSs also partially rescued splicing. When used in combination, ASOs targeting both the ISSs and the region sequestering the polypyrimidine tract, fully rescue pre-mRNA splicing of multiple HA-linked variants of exon-16. Together, our data reveal a putative RNA structure that sensitizes F8 exon-16 to aberrant splicing.

Rescue of blood coagulation Factor VIII exon-16 mis-splicing by antisense oligonucleotides.

The human Factor VIII ( F8 ) protein is essential for the blood coagulation cascade and specific F8 mutations cause the rare bleeding disorder Hemophilia A (HA). Here, we investigated the impact of HA-causing single-nucleotide mutations on F8 pre-mRNA splicing. We found that 14/97 (∼14.4%) coding sequence mutations tested in our study induced exon skipping. Splicing patterns of 4/11 (∼36.4%) F8 exons tested were especially sensitive to the presence of common disease-causing mutations. RNA-chemical probing analyses revealed a three-way junction structure at the 3' end of intron 15 (TWJ-3-15). TWJ-3-15 sequesters the polypyrimidine tract, a key determinant of 3' splice site strength. Using exon-16 of the F8 gene as a model, we designed specific antisense oligonucleotides (ASOs) that target TWJ-3-15 and identified three that promote the splicing of F8 exon-16. Interaction of TWJ-3-15 with ASOs increases accessibility of the polypyrimidine tract and inhibits the binding of hnRNPA1-dependent splicing silencing factors. Moreover, ASOs targeting TWJ-3-15 rescue diverse splicing-sensitive HA-causing mutations, most of which are distal to the 3' splice site being impacted. The TWJ-3-15 structure and its effect on mRNA splicing provide a model for HA etiology in patients harboring specific F8 mutations and provide a framework for precision RNA-based HA therapies.

Comparative assessment of the effects of DREADDs and endogenously expressed GPCRs in hippocampal astrocytes on synaptic activity and memory.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have proven themselves as one of the key in vivo techniques of modern neuroscience, allowing for unprecedented access to cellular manipulations in living animals. With respect to astrocyte research, DREADDs have become a popular method to examine the functional aspects of astrocyte activity, particularly G-protein coupled receptor (GPCR)-mediated intracellular calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) dynamics. With this method it has become possible to directly link the physiological aspects of astrocytic function to cognitive processes such as memory. As a result, a multitude of studies have explored the impact of DREADD activation in astrocytes on synaptic activity and memory. However, the emergence of varying results prompts us to reconsider the degree to which DREADDs expressed in astrocytes accurately mimic endogenous GPCR activity. Here we compare the major downstream signaling mechanisms, synaptic, and behavioral effects of stimulating Gq-, Gs-, and Gi-DREADDs in hippocampal astrocytes of adult mice to those of endogenously expressed GPCRs.

Teleophthalmology Using Remote Retinal Imaging During the COVID-19 Pandemic.

Introduction: Lower insurance reimbursements have limited the financial sustainability of remote eye screening programs. Greater utilization and insurance coverage for teleophthalmology screening during the coronavirus disease 2019 (COVID-19) pandemic in 2020 may enhance awareness and expand remote retinal imaging services. This retrospective cross-sectional study evaluates utilization and insurance coverage for remote retinal imaging in the United States in 2020. Methods: We analyzed teleretinal imaging utilization and insurance payments from January 1 to December 31, 2020, using the Optum Labs Data Warehouse, a comprehensive national database of deidentified administrative claims for commercial and Medicare Advantage enrollees in the United States. We evaluated frequency of claims and insurance payment for services using the Current Procedural Terminology codes 92227 and 92228 for remote eye imaging by any provider, and 92250 for fundus photography by non-eye care providers. Results: The use of remote retinal imaging in the United States declined rapidly during the initial COVID-19 lockdown from 3,627 claims in February 2020 to 1,414 claims in April 2020, but returned to 3,133 claims by December 2020, similar to mean prepandemic levels in 2019 (2,841 ± 174.8 claims). The proportion of insurance payments for remote imaging increased temporarily from 47.4% in February to 56.7% in April, and then returned to 45.9% in December of 2020. Discussion: Utilization of remote retinal imaging declined steeply, while the insurance coverage increased during the initial COVID-19 lockdown in 2020, but returned to prepandemic levels by end of the year. Changes in utilization and relaxed restrictions on insurance reimbursements for teleophthalmology during the COVID-19 pandemic were not sustained.

Long-Term Retinal Vascular Changes in Age-Related Macular Degeneration Measured Using Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: To determine if age-related macular degeneration (AMD) status affects longitudinal retinal vessel changes. PATIENTS AND METHODS: Retrospective, cohort study of 125 eyes (75 patients) with AMD, following retinal vessel density (VD) and foveal avascular zone (FAZ) measurements using optical coherence tomography angiography (OCT-A) over 24 months. RESULTS: FAZ area (P < .001) and perimeter (P < .001) increased over 2 years, with no difference between nonexudative and exudative AMD (P = .134-.976). Eyes with geographic atrophy (GA) showed greater progressive VD loss (P = .023-.038), and greater increase in FAZ area (P = .044) and perimeter (P = .040) compared to eyes without GA. Neither baseline nor 2-year change in vascular parameters were associated with choroidal neovascularization (CNV) or GA incidence in nonexudative AMD, or anti-VEGF injection frequency in exudative AMD (P = .070-.952). CONCLUSION: AMD eyes with GA undergo more rapid loss of retinal vessel density and FAZ enlargement over 2 years, suggesting a relationship between the retinal vasculature and AMD pathophysiology. [Ophthalmic Surg Lasers Imaging Retina 2022;53:529-536.].

Pediatric paranasal sinuses-Development, growth, pathology, & functional endoscopic sinus surgery.

The paranasal sinuses (maxillary, frontal, ethmoid, and sphenoid sinuses) are complex anatomical structures. The development and growth of these have been investigated utilizing a number of different methods ranging from cadaveric analysis to modern cross sectional imaging with 3D modeling. An understanding of normal pediatric paranasal sinus embryology and development enables us to better determine when pathology may be affecting the normal developmental process. Cystic fibrosis, chronic sinusitis, deviated nasal septum and cleft lip and palate are some of the conditions which have been shown to effect paranasal sinus development to varying degrees. Functional endoscopic sinus surgery (FESS) is becoming increasingly common and an understanding of sinus anatomy together with when periods of rapid growth occur during childhood is important clinically. Although concerns have been raised regarding the impact of FESS on facial growth, there is limited evidence of this in regards to either changes in anthropomorphic measurements or clinical assessments of symmetry post operatively.

SARS-CoV-2 vaccine responses following CD20-depletion treatment in patients with haematological and rheumatological disease: a West Midlands Research Consortium study.

B-cell-depleting agents are among the most commonly used drugs to treat haemato-oncological and autoimmune diseases. They rapidly induce a state of peripheral B-cell aplasia with the potential to interfere with nascent vaccine responses, particularly to novel antigens. We have examined the relationship between B-cell reconstitution and SARS-CoV-2 vaccine responses in two cohorts of patients previously exposed to B-cell-depleting agents: a cohort of patients treated for haematological B-cell malignancy and another treated for rheumatological disease. B-cell depletion severely impairs vaccine responsiveness in the first 6 months after administration: SARS-CoV-2 antibody seroprevalence was 42.2% and 33.3% in the haemato-oncological patients and rheumatology patients, respectively and 22.7% in patients vaccinated while actively receiving anti-lymphoma chemotherapy. After the first 6 months, vaccine responsiveness significantly improved during early B-cell reconstitution; however, the kinetics of reconstitution was significantly faster in haemato-oncology patients. The AstraZeneca ChAdOx1 nCoV-19 vaccine and the Pfizer BioNTech 162b vaccine induced equivalent vaccine responses; however, shorter intervals between vaccine doses (<1 m) improved the magnitude of the antibody response in haeamto-oncology patients. In a subgroup of haemato-oncology patients, with historic exposure to B-cell-depleting agents (>36 m previously), vaccine non-responsiveness was independent of peripheral B-cell reconstitution. The findings have important implications for primary vaccination and booster vaccination strategies in individuals clinically vulnerable to SARS-CoV-2.

Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia.

BACKGROUND: Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses. METHOD: We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms. RESULTS: Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination. CONCLUSIONS: These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort.

Assessment of pharyngeal motor function using a novel velopharyngeal squeeze maneuver and a novel endoscopic pharyngeal contraction grade scale in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: To investigate a novel velopharyngeal squeeze maneuver (VPSM) and novel endoscopic pharyngeal contraction grade (EPCG) scale for the evaluation of pharyngeal motor function. METHODS: During endoscopic examination of 77 post-irradiated nasopharyngeal carcinoma patients and control subjects, VPSM was rated and lateral pharyngeal wall movement graded with EPCG scale during swallowing. Pharyngeal constriction ratio (PCR) measured by videofluoroscopy was used for correlation. RESULTS: VPSM and EPCG scale showed almost perfect intra-rater and inter-rater reliability (Kappa: >0.90). VPSM was present in 61% of patients suggesting good pharyngeal motor function. VPSM was predictive of EPCG scale (Wald statistic = 29.99, p < 0.001). EPCG scale also correlated strongly with PCR (r: 0.812) and was predictive for aspiration (odds ratio: 22.14 [95% CI 5.01-97.89, p < 0.001]). CONCLUSIONS: VPSM and EPCG scale are two novel tools to assess pharyngeal motor function, and both correlate well with pharyngeal contractility and aspiration.

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment.

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate.

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472, p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies.

Cost Analysis of Teleophthalmology Screening for Diabetic Retinopathy Using Teleophthalmology Billing Codes.

BACKGROUND AND OBJECTIVE: To evaluate the financial sustainability of teleophthalmology screening for diabetic retinopathy (DR) using telehealth billing codes. PATIENTS AND METHODS: The authors performed an Institutional Review Board-approved retrospective review of medical records, billing data, and quality metrics at the University of California Davis Health System from patients screened for DR through an internal medicine-based telemedicine program using CPT codes 92227 or 92228. RESULTS: A total of 290 patients received teleophthalmology screening over a 12-month period, resulting in an increase in the DR screening rate from 49% to 63% (P < .0001). The average payment per patient was $19.86, with an estimated cost of $41.02 per patient. The projected per-patient incentive bonus was $43.06 with a downstream referral revenue of $39.38 per patient. One hundred seventy-eight clinic visits were eliminated, providing an estimated cost savings of $42.53 per patient. CONCLUSION: Sustainable teleophthalmology screening may be achieved by billing telehealth codes but only with health care incentive bonuses, patient referrals, and by accounting for the projected cost-savings of eliminating office visits. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S26-S34.].

Generation and Regulation of Spontaneous Contractions in the Prostate.

Spontaneous myogenic contractions have been shown to be significantly upregulated in prostate tissue collected from men with Benign Prostatic Hyperplasia (BPH), an extremely common disorder of the ageing male. Although originally thought likely to be involved in 'housekeeping' functions, mixing prostatic secretions to prevent stagnation, these spontaneous myogenic contractions provide a novel opportunity to understand and treat BPH. This treatment potential differs from previous models, which focused exclusively on attenuating nerve-mediated neurogenic contractions. Previous studies in the rodent prostate have provided an insight into the mechanisms underlying the regulation of myogenic contractions. 'Prostatic Interstitial Cells' (PICs) within the prostate appear to generate pacemaker potentials, which arise from the summation of number of spontaneous transient depolarisations triggered by the spontaneous release of Ca2+ from internal stores and the opening of Ca2+-activated Cl- channels. Pacemaker potentials then conduct into neighbouring smooth muscle cells to generate spontaneous slow waves. These slow waves trigger the firing of 'spike-like' action potentials, Ca2+ entry and contraction, which are not attenuated by blockers of neurotransmission. However, these spontaneous prostatic contractions can be modulated by the autonomic nervous system. Here, we discuss the mechanisms underlying rodent and human prostate myogenic contractions and the actions of existing and novel pharmacotherapies for the treatment of BPH. Understanding the generation of human prostatic smooth muscle tone will confirm the mechanism of action of existing drugs, inform the identification and effectiveness of new pharmacotherapies, as well as predict patient outcomes.

The Antitussive Benzonatate Is Not Tumorigenic in Rodent Carcinogenicity Studies.

Benzonatate is a peripheral oral antitussive that dampens the activity of cough stretch receptors. Rodent carcinogenicity studies were performed in Tg.rasH2 mice and Wistar Han rats. Mice were orally gavaged benzonatate at 10, 30, 75, and 100 mg/kg/day for males and 5, 15, and 50 mg/kg/day for females. Rats were gavaged at 10, 30, and 90 mg/kg/day for males and 5, 15, and 50 mg/kg/day for females. Higher doses in males were due to differences in maximum tolerated doses in dose-ranging studies. In both species, benzonatate was not detected in plasma because of rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol polymer. This metabolism was similar in human plasma; therefore, plasma BBA was used to show systemic exposure. Both species had no evidence of a benzonatate-related increase in any neoplasm. A slight increase in nasal cavity exudative inflammation was present in benzonatate-dosed male mice. Retinal atrophy was observed in male rats at ≥30 mg/kg/day, but the incidence was within historical control data range and not related to benzonatate. In conclusion, benzonatate and its 2 major metabolites were not carcinogenic in rodent carcinogenicity studies at BBA exposures of ≥32 and 70 times a 200 mg human benzonatate dose, respectively.

Diabetes-induced alterations in urothelium function: Enhanced ATP release and nerve-evoked contractions in the streptozotocin rat bladder.

Up to 80% of patients with diabetes mellitus develop lower urinary tract complications, most commonly diabetic bladder dysfunction (DBD). The aim of this study was to investigate the impact of diabetes on the function of the inner bladder lining (urothelium). Bladder compliance and intraluminal release of urothelial mediators, adenosine triphosphate (ATP) and acetylcholine (ACh) in response to distension were investigated in whole bladders isolated from 2- and 12-week streptozotocin (STZ)-diabetic rats. Intact and urothelium-denuded bladder strips were used to assess the influence of the urothelium on bladder contractility. Intraluminal ATP release was significantly enhanced at 2 weeks of diabetes, although not at 12 weeks. In contrast, intraluminal ACh release was unaltered by diabetes. Bladder compliance was also significantly enhanced at both 2 and 12 weeks of diabetes, with greatly reduced intravesical pressures in response to distension. Nerve-evoked contractions of bladder strips were significantly greater at 2 weeks of diabetes. When the urothelium was absent, nerve-evoked contractions were reduced, but contractions remained significantly elevated at lower frequencies of stimulation (<5 Hz) in diabetics. Interestingly, although relaxations of bladder strips to isoprenaline were unaltered by diabetes, removal of the urothelium unmasked significantly enhanced relaxations in strips from 2- and 12-week diabetic animals. In conclusion, diabetes alters urothelial function. Enhanced urothelial ATP release may be involved in the hypercontractility observed at early time points of diabetes. These alterations are time-dependent and may contribute to the mechanisms at play during the development of diabetic bladder dysfunction.

Role of IGF1R(+) MSCs in modulating neuroplasticity via CXCR4 cross-interaction.

To guide the use of human mesenchymal stem cells (MSCs) toward clinical applications, identifying pluripotent-like-markers for selecting MSCs that retain potent self-renewal-ability should be addressed. Here, an insulin-like growth factor 1 receptor (IGF1R)-expressing sub-population in human dental pulp MSCs (hDSCs), displayed multipotent properties. IGF1R expression could be maintained in hDSCs when they were cultured in 2% human cord blood serum (hUCS) in contrast to that in 10% fetal calf serum (FCS). Cytokine array showed that hUCS contained higher amount of several growth factors compared to FCS, including IGF-1 and platelet-derived growth factor (PDGF-BB). These cytokines modulates the signaling events in the hDSCs and potentially enhances engraftment upon transplantation. Specifically, a bidirectional cross-talk between IGF1R/IGF1 and CXCR4/SDF-1α signaling pathways in hDSCs, as revealed by interaction of the two receptors and synergistic activation of both signaling pathways. In rat stroke model, animals receiving IGF1R(+) hDSCs transplantation, interaction between IGF1R and CXCR4 was demonstrated to promote neuroplasticity, therefore improving neurological function through increasing glucose metabolic activity, enhancing angiogenesis and anti-inflammatiory effects. Therefore, PDGF in hUCS-culture system contributed to the maintenance of the expression of IGF1R in hDSCs. Furthermore, implantation of IGF1R(+) hDSCs exerted enhanced neuroplasticity via integrating inputs from both CXCR4 and IGF1R signaling pathways.

Gastrointestinal surgery in cystic fibrosis: a 20-year review.

OBJECTIVES: The purpose of this study was to evaluate outcomes of the surgical management for meconium ileus (MI) and Distal Intestinal Obstruction Syndrome (DIOS) in Cystic Fibrosis (CF). METHODS: Children born between 1990 and 2010 were identified using a regional CF database. Retrospective case note analysis was performed. Outcome measures for MI were mortality, relaparotomy rate, length of stay (LOS), time on parental nutrition (TP), and time to full feeds (TFF). Outcome measures for DIOS were: age of onset, number of episodes, and need for laparotomy. RESULTS: Seventy-five of 376 neonates presented with MI. Fifty-four (92%) required laparotomy. Contrast enema decompression was attempted in nineteen. There were no post-operative deaths. Thirty-nine (72%) neonates with MI were managed with stomas. LOS was longer in those managed with stomas (p=0.001) and in complex MI (p=0.002). Thirty-five patients were treated for DIOS. Twenty-five patients were managed with gastrograffin. Ten patients underwent surgical management of DIOS. Overall, MI did not predispose to later development of DIOS. There was a significantly greater incidence of laparotomy for DIOS in children who had MI. CONCLUSION: The proportion of neonates with complex meconium ileus was high (49%) and may explain the infrequent utilisation of radiological decompression. Complex MI or management with stomas both significantly increase LOS. Re-laparotomy rate is high (22%) in MI irrespective of the type of management. DIOS is not a benign condition, particularly when the child has had previous abdominal surgery. Early referral to a surgical team is essential in these children.