How to Handle In-Flight Death in International Patient Repatriation and Air Ambulance Operations.

In-flight cardiac arrest is a rare event that occurs at a rate of approximately 1 event in 3.8 to 4.7 million commercial airline passengers and at a rate of approximately 1 event in 1,500 to 3,000 patients transported by fixed wing international air medical transport. Only 13% to 19% of victims of in-flight cardiac arrest can be successfully resuscitated. The arrival of an aircraft with a deceased patient/passenger on board triggers a country-specific procedure that focuses on public health and medicolegal considerations. In most jurisdictions, these procedures are detailed in the respective national Aeronautical Information Publication, which are commonly based on the International Civil Aviation Organization International Standards and Recommended Practices, Annex 9 to the Convention on International Civil Aviation. Awareness among medical and flight crews on such procedures will support appropriate documentation of the event and enable effective cooperation with the relevant local authorities.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1ß, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face.

BNP, troponin I, and YKL-40 as screening markers in extremely preterm infants at risk for pulmonary hypertension associated with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is often complicated by pulmonary hypertension (PH). We investigated three biomarkers potentially suitable as screening markers for extremely preterm infants at risk of BPD-associated PH. In this prospective observational cohort study conducted in a tertiary neonatal intensive care unit, 83 preterm infants with BPD born <28-wk gestation and still inpatients at 36-wk corrected age received an echocardiogram and blood tests of B-type natriuretic peptide (BNP), troponin I, and YKL-40. Infants were analyzed according to echocardiographic evidence of tricuspid regurgitation (TR). Thirty infants had evidence of TR on echocardiogram at 36-wk corrected age. Infants with or without TR had similar baseline demographics: mean ± SD gestational age 261 ± 12 vs. 261 ± 11 wk and birth weight 830 ± 206 vs. 815 ± 187 g, respectively. There was no difference in duration of respiratory support. The right ventricular systolic pressure of infants with evidence of TR was 40 ± 16 mmHg. BNP was the only biomarker that proved to be significantly higher in infants with evidence of TR: median (interquartile range) serum level 54.5 (35-105) vs. 41.5 (30-59) pg/ml, P = 0.043. Subgroup analysis of infants with severe BPD requiring discharge on home oxygen or BPD-related mortality revealed similar results. There was no difference between groups for troponin I and YKL-40. In conclusion, increased serum levels of BNP were associated with evidence of TR at 36-wk corrected gestational age in extremely preterm infants, suggesting a potential role as a screening biomarker for BPD-associated PH.

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. METHODS: In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 µg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. FINDINGS: Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. INTERPRETATION: cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. FUNDING: German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia.

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short- and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65% or 85% O2). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60%, alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65%, but not 85% O2. Hyperoxia depleted pulmonary immune cells by 67%; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63%, and abolished the unexpected persistence of IL-1α and IL-1ß on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1α/ß in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1α and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.

A percutaneous fetal cardiac catheterization technique for pulmonary valvuloplasty and valvulotomy in a mid-gestation lamb model.

OBJECTIVE: We aimed to assess the feasibility of using a percutaneous transhepatic cardiac catheterization technique to perform fetal pulmonary valvuloplasty and valvulotomy under ultrasound guidance at mid-gestation. METHOD: In 13 mid-gestation fetal lambs without cardiac pathology, percutaneous transhepatic cardiac catheterization was used to position a coronary angioplasty catheter within the pulmonary valve. The balloon was inflated/deflated several times, simulating pulmonary valvuloplasty. In another two fetal lambs, a guidewire tip was positioned against the pulmonary valve, and unipolar diathermy was applied to simulate perforation of an atretic valve. RESULTS: Percutaneous access followed by right heart catheterization was successful in all cases. One fetus died following right ventricle perforation. Simulated pulmonary valvuloplasty was successful in nine cases using catheters with 6-mm-long balloons but unsuccessful in two cases (both survived) using 12-mm-long balloons. In one case, the catheter could not be inserted as the cannula became dislodged. Diathermy of the pulmonary valve was successful in both attempts. CONCLUSION: We successfully simulated in utero perforation and dilation of the pulmonary valve using percutaneous transhepatic access in fetal lambs. The technique has potential for clinical translation into treatment for human fetuses with critical pulmonary stenosis or pulmonary atresia with intact ventricular septum.

Using a modified Seldinger technique is an effective way of placing femoral venous catheters in critically ill infants.

AIM: Femoral venous catheters (FVCs) provide multilumen access in critically ill infants with difficult venous access. This study reports our experiences of using a modified Seldinger technique to insert FVCs in our neonatal unit. METHODS: This was a retrospective case series of 34 infants who had FVCs inserted using the modified Seldinger technique during a 4-year period. RESULTS: The median (range) post-natal age and weight at the time of insertion were 66 days (1-314) and 3080 g (865-8000). The FVC remained in situ for a median duration of 21 days (1-63). There were nine infants who died while the FVC remained in situ. The FVCs were removed from four infants due to complications. In three cases, they became dislodged, and in one case, the line became blocked. In 16 infants, the FVC was removed when it was no longer required and one infant was transferred out of the unit with the FVC in situ. Transient venous congestion of the distal limb occurred in four infants. In one infant, the FVC was accidently placed in the femoral artery and removed without complications. CONCLUSIONS: Femoral venous catheter insertion using a modified Seldinger technique appeared to provide alternate and immediate central venous access in critically ill infants.

Does milk fortification increase the risk of necrotising enterocolitis in preterm infants with congenital heart disease?

Prematurity and low birth weight adds to the risk of serious congenital heart disease in infants. It may also delay surgical intervention, especially when cardiopulmonary bypass is required, or where an aortopulmonary shunt is necessary to maintain adequate oxygenation. In this setting, neonatologists are faced with the challenge of accelerating the infant's growth to allow for early surgery. We describe the cases of two infants in whom an attempt to fortify the feeds was associated with necrotising enterocolitis, with a lethal outcome in one. The outcome suggests caution in fortifying feeds in premature infants with serious congenital heart disease.

Stratification of patients in long-distance, international, fixed-wing aircraft.

INTRODUCTION: A growing number of individuals with significant medical histories travel for business and holidays. Precise anticipation and stratification of transport-relevant illness severity in the planning stage of an air medical evacuation is crucial for mission success and patient safety. METHODS: We developed a staging system (ie, Stratification of Air Medical Transport by Expression of Symptoms in Patients [STEP]) and applied it to 356 patients transported by a fixed wing aircraft between January 2010 and June 2011. Patients were stratified before transport, and the transport team performed independent staging of each patient during the actual transport. Data on transport modes, transport time, age, sex, diagnosis, the need for mechanical ventilation, and transport-related complications were collected. Data were analyzed for significant differences in STEP categories between operations staging and staging by the flight crew and for the correlation between operations STEP staging and actual transport acuity. RESULTS: Complete datasets were available in 353 of 356 patients. Differences between staging by operations and flight crew were documented in 31 cases (P = .809); in 18 of them, the flight crew considered the patient to be more severely affected than previously estimated. Decisions for specific transport mode and configuration were found to be adequate in all but 3 cases (99.15%). CONCLUSION: STEP is a useful tool to assess patient's illness/injury severity in the planning stage of a long distance, international, air ambulance transport and assists in choosing the appropriate mode and configuration of transport.

Please get me out of here: The difficult decision making in fit-to-fly assessments for international fixed-wing air ambulance operations.

INTRODUCTION: With international travel for leisure and business almost back to pre-pandemic levels, demand for repatriation due to illness and injury abroad is increasing [1,2]. In any repatriation, there is considerable pressure on all involved to organize a rapid transport back home. Delay in such action may be perceived by the patient, relatives, and the public as an attempt by the underwriter to hold off on an expensive air ambulance mission [3-5]. METHODS: Review of the available literature and analysis of assistance and air ambulance Companies' infrastructure and processes to identify risk and benefit of executing or delaying aeromedical transport for international travellers. KEY FINDINGS: While patients of almost any severity can be safely transported over great distances in modern air ambulance aircraft, immediate transport is not always in the patient's best interest. Each call for assistance requires a complex and dynamic risk-benefit analysis with multiple stakeholders involved to achieve an optimized outcome. Opportunities for risk mitigation within the assistance team include active case management with clearly assigned ownership, as well as medical and logistical experience with knowledge on local treatment opportunities and limitations. On the air ambulance side, modern equipment, experience, standards and procedures as well as accreditation can reduce risk. CONCLUSIONS: Each patient evaluation remains a highly individual risk-benefit assessment. Optimal outcomes require a clear understanding of responsibilities, flawless communication and significant expertise among the key decision-makers. Negative outcomes are mostly associated with insufficient information, communication, inadequate experience or a lack of ownership/assigned responsibility.

Safety and Feasibility of Long-Distance Aeromedical Transport of Neonates and Children in Fixed-Wing Air Ambulance.

In cases of critical injury or illness abroad, fixed-wing air ambulance aircraft is employed to repatriate children to their home country. Air ambulance aircraft also transport children to foreign countries for treatment not locally available and newborns back home that have been born prematurely abroad. In this retrospective observational study, we investigated demographics, feasibility, and safety and outcomes of long-distance and international aeromedical transport of neonates and children. The study included 167 pediatric patients, 56 of those preterm neonates. A total of 41 patients were ventilated, 45 requiring oxygen prior to the transport, 57 transferred from an intensive care unit (ICU), and 48 to an ICU. Patients were transported by using Learjet 31A, Learjet 45, Learjet 55, and Bombardier Challenger 604, with a median transport distance of 1,008 nautical miles (NM), median transport time of 04:45 hours (median flight time = 03:00 hours), flight time ≥8 hours in 15 flights, and transport time ≥8 hours in 29 missions. All transports were accompanied by a pediatric physician/nurse team. An increase in FiO 2 during the transport was documented in 47/167 patients (28%). Therapy escalation (other than increased oxygen) was reported in 18 patients, and technical adverse events in 3 patients. No patient required CPR or died during the transport. Clinical transport outcome was rated by the accompanying physician as unchanged in 163 transports, improved in 4, and deteriorated in none. In summary, international, long-distance transport of neonatal and pediatric patients performed by experienced and well-equipped transport teams is feasible. Neither major adverse events nor physician-rated clinical deteriorations were observed in this group of patients.

Subgaleal hemorrhage: risk factors and outcomes.

Subgaleal hemorrhage in the newborn is a serious adverse event that is often unrecognized and under-appreciated. This retrospective case series aimed to determine perinatal factors associated with subgaleal hemorrhage and subsequent neonatal outcomes. Obstetric and neonatal details of 21 infants with subgaleal hemorrhage over a 10-year period were collected. The mother was primiparous in 95% cases, 48% had a prolonged second stage (>120 minutes) and 43% had prolonged rupture of membranes (>12 hours). Thirteen infants (62%) were born by instrumental vaginal delivery. Ten infants (48%) required resuscitation at delivery. The severity of subgaleal hemorrhage was mild in four infants (19%), moderate in 10 (48%) and severe in seven (33%). Hypovolemic shock developed in 10 infants (48%), encephalopathy in 13 (62%) and coagulopathy was present in five infants (24%). There were three (14%) deaths. Long-term outcomes were good in the surviving infants.

The Use of Off-Label Medications in Newborn Infants Despite an Approved Alternative Being Available-Results of a National Survey.

Neonates continue to be treated with off-label or unlicensed drugs while in hospital. However, some medications that have previously been used in adults underwent clinical testing and licensure for use with a different indication in the neonatal and pediatric population. Almost always, the marketing of these newly approved substances in a niche indication is accompanied by a steep increase in the price of the compound. We investigated the use of the approved formulation or the cheaper off-label alternative of Ibuprofen (Pedea®), Propanolol (Hemangiol®) and Caffeine Citrate (Peyona®) in neonatal clinical practice by conducting a National Survey of 214 Perinatal Centers in Germany. We also assessed price differences between on- and off-label alternatives and the extend of the clinical development program of the on-label medication in the neonatal population. On-label medication was more frequently used than the off-label alternative in all indications (PDA: on-label to off-label ratio 1:0.26, Apnea: 1:0.56, Hemangioma 1:0.76). All sponsors did conduct placebo-controlled Phase III trials with efficacy and safety endpoints in the target population and the number of participants in the target population varied between 82 and 497. Costs for the three drugs in their approved and marketed formulations increased in median 405-fold compared with the corresponding off-label alternative. Overall, about one out of three neonatologists prescribed an off-label or non-approved drug to patients despite an alternative medication that is approved for the indication in the target population being available.

Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants.

Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1ß and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.

Disseminated intravascular coagulation in term and preterm neonates.

Among critically ill patients, the risk of developing disseminated intravascular coagulation (DIC) is probably highest in neonates. Low plasma reserves in pro- and anticoagulant coagulation factors, intravascular volume contraction after birth, and a high incidence of hypoxia and sepsis in critically ill newborns rapidly lead to a decompensation of the coagulation system in this population. Global coagulation tests and single-factor plasma levels have to be interpreted in the context of age-corrected normal ranges. Platelet consumption and reduced protein C plasma levels have diagnostic value; the latter also has prognostic potential in neonates with DIC and sepsis. Therapeutic success relies heavily on reversal of the underlying condition. Some coagulation-specific therapies have been explored in small studies and case series with varying success and sometimes conflicting results. Therefore, larger controlled trials in this common and serious condition are urgently needed.

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients.

INTRODUCTION: Purpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels. METHODS: In Germany, patients receiving protein C concentrate (Ceprotin, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study. RESULTS: Complete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03). CONCLUSIONS: This retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial.

Long-Distance Aeromedical Transport of Patients with COVID-19 in Fixed-Wing Air Ambulance Using a Portable Isolation Unit: Opportunities, Limitations and Mitigation Strategies.

INTRODUCTION: Aeromedical transport of patients with highly-infectious diseases, particularly over long distances with extended transport times, is a logistical, medical and organizational challenge. Following the 2014-2016 Ebola Crisis, sophisticated transport solutions have been developed, mostly utilizing large civilian and military airframes and the patient treated in a large isolation chamber. In the present COVID-19 pandemic, however, many services offer aeromedical transport of patients with highly-infectious diseases in much smaller portable medical isolation units (PMIU), with the medical team on the outside, delivering care through portholes. METHODS: We conducted a retrospective review of all transports of patients with proven or suspected COVID-19 disease, transported by Jetcall, Idstein, Germany, between April 1 and August 1, 2020, using a PMIU (EpiShuttle, EpiGuard AS, Oslo, Norway). Demographics and medical data were analyzed using the services' standardized transport protocols. Transport-associated challenges and optimization strategies were identified by interviewing and debriefing all transport teams after each transport. RESULTS: Thirteen patients with COVID-19 have been transported in a PMIU over distances up to 7,400 kilometers (km), with flight times ranging from 02:15 hours to 11:10 hours. We identified the main limitations of PMIU transports as limited access to the patient and reduced manual dexterity when delivering care through the porthole gloves and disconnection of lines and tubes during loading and unloading procedures. Technical solutions such as bluetooth-enabled stethoscopes, cordless ultrasound scanners and communication devices, meticulous preparation of the PMIU and the patient following standardized protocols and scenario-based training of crew members can reduce some of the risks. DISCUSSION: Transporting a patient with COVID-19 or any other highly infectious disease in a PMIU is a feasible option even over long distances, but adding a significant layer of additional risk, thus requiring a careful and individualized risk-benefit analysis for each patient prior to transport.

Induction of left ventricular hypoplasia by occluding the foramen ovale in the fetal lamb.

Disturbed fetal haemodynamics often affects cardiac development and leads to congenital cardiac defects. Reduced left ventricular (LV) preload in the fetus may result in hypoplastic LV, mitral and aortic valve, mimicking a moderate form of hypoplastic left heart complex. We aimed to induce LV hypoplasia by occluding the foramen ovale (FO) to reduce LV preload in the fetal sheep heart, using percutaneous trans-hepatic catheterisation. Under maternal anaesthesia and ultrasound guidance, hepatic venous puncture was performed in six fetal lambs (0.7-0.75 gestation). A coronary guidewire was advanced into the fetal inferior vena cava, right and left atrium. A self-expandable stent was positioned across the FO. An Amplatzer Duct Occluder was anchored within the stent for FO occlusion. Euthanasia and post-mortem examination was performed after 3 weeks. Nine fetuses were used as age-matched controls. Morphometric measurements and cardiac histopathology were performed. Compared with controls, fetal hearts with occluded FO had smaller LV chamber, smaller mitral and aortic valves, lower LV-to-RV ratio in ventricular weight and wall volume, and lower number of LV cardiomyocyte nuclei. We conclude that fetal FO occlusion leads to a phenotype simulating LV hypoplasia. This large animal model may be useful for understanding and devising therapies for LV hypoplasia.

Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities.

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46-RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.