Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

UV-activated bioadhesive composite for bone repair

Current surgical procedures to stabilize fractured bones involve the use of fixation devices like screws and plates, and often supplemented with the administration of bone cement to improve anchorage. However, issues leading to the need of an undesirable second surgery have been reported. This project investigates the structure-activity relationships of UV-activated bioadhesive and Bioglass composite and assesses its suitability for orthopaedic applications. UV activated bioadhesive allows better control over crosslinking process, enabling the tuning of mechanical properties. Bioglass promotes bone-bonding and acts as the reinforcing phase. Rheological measurements show that shear modulus and shear strength are positively correlated to Bioglass concentration and UV dose. The optimum formulation with 20 wt% Bioglass is shown to have a storage modulus of 142 kPa and a shear strength of 57.6 kPa. In an experiment where photocuring is done ex-vivo, a lap shear strength of 42.7 kPa is obtained. Although the mechanical properties of the current formulation can not match the modulus and strength of a bone, and the current adhesion strength can not match that of bone cement’s, structure-activity relationships show that there is a potential for improvement upon further research.Bachelor of Engineering (Materials Engineering

Fixation of transparent bone pins with photocuring biocomposites

Bone fractures are in need of rapid fixation methods, but the current strategies are limited to metal pins and screws, which necessitate secondary surgeries upon removal. New techniques are sought to avoid surgical revisions, while maintaining or improving the fixation speed. Herein, a method of bone fixation is proposed with transparent biopolymers anchored in place via light-activated biocomposites based on expanding CaproGlu bioadhesives. The transparent biopolymers serve as a UV light guide for the activation of CaproGlu biocomposites, which results in evolution of molecular nitrogen (from diazirine photolysis), simultaneously expanding the covalently cross-linked matrix. Osseointegration additives of hydroxyapatite or Bioglass 45S5 yield a biocomposite matrix with increased stiffness and pullout strength. The structure-property relationships of UV joules dose, pin diameter, and biocomposite additives are assessed with respect to the apparent viscosity, shear modulus, spatiotemporal pin curing, and lap-shear adhesion. Finally, a model system is proposed based on ex vivo investigation with bone tissue for the exploration and optimization of UV-active transparent biopolymer fixation.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)Nanyang Technological UniversityAccepted versionMinistry of Education Tier 1 Grant RG17/18 (S): Novel light activated, diazo protecting groups, Ministry of Education Tier 2 Grant (MOE2018-T2-2-114): CaproGlu, Double sided wettissue adhesives, NTUitive POC (Gap) Fund NGF/2018/05: Aesthetic Applications of CaproGlu Bioadhesives, and A*Star IAF PP Grant (H19/01/a0/0II9): CathoGlu Bioadhesivespreventing catheter extravasation and skin infections

Stories of experiences of care for growth hormone deficiency: the CRESCERE project

Aims: Growth hormone deficiency therapy is demanding for patients and caregivers. Teams engaged in the clinical management of growth hormone deficiency therapy need to know how families live with this condition, to provide an adequate support and prevent the risk of withdrawal from therapy. Methods: Using Narrative Medicine, testimonies from patients, their parents and providers of care were collected from 11 Italian centers. Narrations were analyzed throughout an elaboration of recurring words and expressions. Results: Although care management and outcomes were considered satisfying in the 182 collected narratives, recurring signals of intolerance among adolescents and the worry of not being well informed about side effects among parents are open issues. Conclusion: Narratives found that communication issues could decrease adherence and influence the physicians’ clinical practice. Lay abstract: Using Narrative Medicine, testimonies from children and adolescents with growth hormone deficiency, their parents and providers of care were collected in 11 Italian Centers. Although the general high level of satisfaction for the results of the treatment, the analysis of the narrations revealed that adolescents can show recurring signals of intolerance and parents can feel worried and not well informed about side effects. Communication issues could decrease the adherence to therapy, and teams engaged in the clinical management of growth hormone deficiency need to strengthen their communication with all the family members, to provide an adequate support and prevent the risk of withdrawal from therapy

Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes

The scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated that human SC islets reaggregated from cryopreserved cells display glucose-stimulated insulin secretion in vitro. Importantly, we showed that conformally coated SC islets displayed comparable in vitro function with unencapsulated SC islets, with conformal coating permitting physiological insulin secretion. Transplantation of SC islets into the gonadal fat pad of diabetic NOD-scid mice revealed that both unencapsulated and conformal-coated SC islets could reverse diabetes and maintain human-level euglycemia for more than 80 days. Overall, these results provide support for further evaluation of safety and efficacy of conformal-coated SC islets in larger species. •Reaggregated human SC islets display glucose-stimulated insulin secretion in vitro•Conformal-coated human SC islets displayed physiological insulin secretion•Conformal-coated human SC islets in mice reversed diabetes to human euglycemic levels Scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Islet encapsulation may eliminate the need for chronic immunosuppression. Conformal coating seeks to overcome limitations of traditional microencapsulation. Transplantation of conformal-coated stem cell-derived islets might extend the applicability of islet transplantation to a larger cohort of patients

Ah, the apple trees, blossoms in the breeze, that we walked [first line of chorus]

Performers: Bing Crosby, Toni Arden, Bob Sands, Felicia Sanders, Polly Bergen, Leo MarjanePiano, Voice and Chord

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort

none54noBackgroundMoyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). MethodsWe conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. ResultsA total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (&gt;= 2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed &gt;= 1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS &gt; 2. The proportion of final mRS &gt; 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age &lt;4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS &gt; 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). ConclusionsMoyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS &gt; 2).openPo', Chiara; Nosadini, Margherita; Zedde, Marialuisa; Pascarella, Rosario; Mirone, Giuseppe; Cicala, Domenico; Rosati, Anna; Cosi, Alessandra; Toldo, Irene; Colombatti, Raffaella; Martelli, Paola; Iodice, Alessandro; Accorsi, Patrizia; Giordano, Lucio; Savasta, Salvatore; Foiadelli, Thomas; Sanfilippo, Giuseppina; Lafe, Elvis; Thyrion, Federico Zappoli; Polonara, Gabriele; Campa, Serena; Raviglione, Federico; Scelsa, Barbara; Bova, Stefania Maria; Greco, Filippo; Cordelli, Duccio Maria; Cirillo, Luigi; Toni, Francesco; Baro, Valentina; Causin, Francesco; Frigo, Anna Chiara; Suppiej, Agnese; Sainati, Laura; Azzolina, Danila; Agostini, Manuela; Cesaroni, Elisabetta; De Carlo, Luigi; Di Rosa, Gabriella; Esposito, Giacomo; Grazian, Luisa; Morini, Giovanna; Nicita, Francesco; Operto, Francesca Felicia; Pruna, Dario; Ragazzi, Paola; Rollo, Massimo; Spalice, Alberto; Striano, Pasquale; Skabar, Aldo; Lanterna, Luigi Alberto; Carai, Andrea; Marras, Carlo Efisio; Manara, Renzo; Sartori, StefanoPo', Chiara; Nosadini, Margherita; Zedde, Marialuisa; Pascarella, Rosario; Mirone, Giuseppe; Cicala, Domenico; Rosati, Anna; Cosi, Alessandra; Toldo, Irene; Colombatti, Raffaella; Martelli, Paola; Iodice, Alessandro; Accorsi, Patrizia; Giordano, Lucio; Savasta, Salvatore; Foiadelli, Thomas; Sanfilippo, Giuseppina; Lafe, Elvis; Thyrion, Federico Zappoli; Polonara, Gabriele; Campa, Serena; Raviglione, Federico; Scelsa, Barbara; Bova, Stefania Maria; Greco, Filippo; Cordelli, Duccio Maria; Cirillo, Luigi; Toni, Francesco; Baro, Valentina; Causin, Francesco; Frigo, Anna Chiara; Suppiej, Agnese; Sainati, Laura; Azzolina, Danila; Agostini, Manuela; Cesaroni, Elisabetta; De Carlo, Luigi; Di Rosa, Gabriella; Esposito, Giacomo; Grazian, Luisa; Morini, Giovanna; Nicita, Francesco; Operto, Francesca Felicia; Pruna, Dario; Ragazzi, Paola; Rollo, Massimo; Spalice, Alberto; Striano, Pasquale; Skabar, Aldo; Lanterna, Luigi Alberto; Carai, Andrea; Marras, Carlo Efisio; Manara, Renzo; Sartori, Stefan