Severe asphyxia due to delivery-related malpractice in Sweden 1990–2005

Aim The objective of the thesis was to describe the most common causes of substandard care during labour contributing to severe asphyxia or neonatal death, to study risk factors related to asphyxia associated with substandard care and to explore the occurrence of substandard care during labour. Background There are about 100 000 infants born every year in Sweden. Most infants are born healthy after uncomplicated deliveries. However, 20-50 claims for financial compensation are made annually to the Patients Advisory Committee (PA C) on suspicion that substandard care during labour has contributed to severe asphyxia causing cerebral palsy or death. Even if this group of patients is notably small, asphyxia causes life-long impairment and immeasurable suffering to the patients and their families. In addition, the insurance costs are substantial and amount to 25% of all costs related to substandard care in Sweden. With the exception of this group of patients, and claims to the Health Services Disciplinary Board, the frequency of substandard care in relation to childbirth is fairly unknown. Material and methods Inclusion criteria were pregnancies with a gestational length ≥ 33 weeks, a spontaneous or induced start of labour, a normal CTG at admission for labour, and Apgar score < 7 at 5 minutes of age (Papers I-IV). 472 case records of deliveries from 1990-2005, filed at the PAC were scrutinised. In Paper I and II the deliveries and acts of neonatal resuscitation procedures are described. In Paper III, maternal characteristics, factors related to care and infant characteristics for patients receiving lifelong financial compensation from PAC are compared with all infants with full Apgar score at 5 minutes of age born after a vaginal start during the same time period in Sweden (n=1.141 059). In Paper IV deliveries and risk factors from 313 infants with Apgar score < 7at 5 minutes of age, born in the Stockholm County are compared with 313 infants with full Apgar score at five minutes of age, matched for year of birth. Results One-hundred and seventy-seven infants were considered to have been severely asphyxiated due to substandard care during labour (Paper I-III). The most common occurrences of malpractice in conjunction with labour were neglecting to supervise fetal well-being (98%), neglecting signs of fetal asphyxia (71%), including incautious use of oxytocin (71%) and choosing a non-optimal mode of delivery (52%) (Paper I). Resuscitation of the 177 severely asphyxiated infants was unsatisfactory in 47%. The most important flaw was the defective compliance with the guidelines concerning ventilation and prompt paging for skilled personnel in cases of imminent asphyxia (Paper II). Risk factors associated with asphyxia included maternal age ≥ 30 years, short maternal stature (< 159 cm), previous caesarean delivery, insulin-dependent diabetes, induced deliveries and night deliveries, where the increases in risk were doubled to a four-fold. In addition, dystocia of labour was associated with a five-fold increase in risk, which was further increased if epidural anaesthesia or opioids were used. Small- and large-for-gestational age infants, post-term (> 42 weeks) births, twins and breech deliveries had a three to eight-fold increase in risk of asphyxia when there was substandard care during labour (Paper III). Two thirds of infants born in the Stockholm region 2004-2006, with Apgar score < 7 at 5 minutes but also one third of the healthy controls were subjected to some kind of substandard care during labour (Paper IV). The main causes of substandard care during labour were related to misinterpretation of CTG, not acting timely on abnormal CTG, and incautious use of oxytocin. The risk of asphyxia increased with duration of abnormal CTG and was increased fifteen-fold when this was abnormal for ≥ 90 minutes. Oxytocin was provided without sign of inertia in 20% of cases and controls and the risk of asphyxia was increased more than fivefold in cases of tachysystole. Infants born after a spontaneous vaginal delivery with abnormal CTG for more than 45 minutes had a more than sevenfold risk of low Apgar score. In instrumental deliveries that were considered complex, there was a more than seventeen-fold risk of an Apgar score < 7 at 5 minutes of age. Assuming that substandard care is causative for low Apgar score, we estimate that 42% of the cases could be prevented by avoiding substandard care (Paper IV). Conclusion It is possible to improve patient safety during labour by applying educational efforts on fetal surveillance and increasing awareness of risk factors associated with asphyxia. The main causes of substandard care during labour are related to misinterpretation of CTG, not acting timely on abnormal CTG, misinterpretation of guidelines and misuse of oxytocin. Low Apgar score at 5 minutes of age can substantially, be prevented by avoiding substandard care

Altered expression of T cell Immunoglobulin-Mucin (TIM) molecules in bronchoalveolar lavage CD4+ T cells in sarcoidosis

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Transferable MARTINI Model of Poly(ethylene Oxide)

Motivated by the deficiencies of the previous MARTINI models of poly(ethylene oxide) (PEO), we present a new model featuring a high degree of transferability. The model is parametrized on (a) a set of 8 free energies of transfer of dimethoxyethane (PEO dimer) from water to solvents of varying polarity; (b) the radius of gyration in water at high dilution; and (c) matching angle and dihedral distributions from atomistic simulations. We demonstrate that our model behaves well in five different areas of application: (1) it produces accurate densities and phase behavior or small PEO oligomers and water mixtures; (2) it yields chain dimensions in good agreement with the experiment in three different solvents (water, diglyme, and benzene) over a broad range of molecular weights ( 3c1.2 kg/mol to 21 kg/mol); (3) it reproduces qualitatively the structural features of lipid bilayers containing PEGylated lipids in the brush and mushroom regime; (4) it is able to reproduce the phase behavior of several PEO-based nonionic surfactants in water; and (5) it can be combined with the existing MARTINI PS to model PS-PEO block copolymers. Overall, the new PEO model outperforms previous models and features a high degree of transferability

CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing

BACKGROUND: Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects. METHODS: CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs. RESULTS: All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing. CONCLUSION: Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing

Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients

<p>Abstract</p> <p>Background</p> <p>A strong genetic influence by the MHC class II region has been reported in sarcoidosis, however in many studies with different results. This may possibly be caused by actual differences between distinct ethnic groups, too small sample sizes, or because of lack of accurate clinical subgrouping.</p> <p>Subjects and methods</p> <p>In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with Löfgren's syndrome (LS) (n = 302) and those without (non-Löfgren's) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.</p> <p>Results</p> <p>There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 × 10^-36). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).</p> <p>Conclusions</p> <p>We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.</p