Intrapartum-related perinatal deaths in births planned in midwifery-led settings in Great Britain: findings and recommendations from the ESMiE confidential enquiry.

OBJECTIVE: To review quality of care in births planned in midwifery-led settings, resulting in an intrapartum-related perinatal death. DESIGN: Confidential enquiry. SETTING: England, Scotland and Wales. SAMPLE: Intrapartum stillbirths and intrapartum-related neonatal deaths in births planned in alongside midwifery units, freestanding midwifery units or at home, sampled from national perinatal surveillance data for 2015/16 (alongside midwifery units) and 2013-16 (freestanding midwifery units and home births). METHODS: Multidisciplinary panels reviewed medical notes for each death, assessing and grading quality of care by consensus, with reference to national standards and guidance. Data were analysed using thematic analysis and descriptive statistics. RESULTS: Sixty-four deaths were reviewed, 30 stillbirths and 34 neonatal deaths. At the start of labour care, 23 women were planning birth in an alongside midwifery unit, 26 in a freestanding midwifery unit and 15 at home. In 75% of deaths, improvements in care were identified that may have made a difference to the outcome for the baby. Improvements in care were identified that may have made a difference to the mother's physical and psychological health and wellbeing in 75% of deaths. Issues with care were identified around risk assessment and decisions about planning place of birth, intermittent auscultation, transfer during labour, resuscitation and neonatal transfer, follow up and local review. CONCLUSIONS: These confidential enquiry findings do not address the overall safety of midwifery-led settings for healthy women with straightforward pregnancies, but suggest areas where the safety of care can be improved. Maternity services should review their care with respect to our recommendations. TWEETABLE ABSTRACT: Confidential enquiry of intrapartum-related baby deaths highlights areas where care in midwifery-led settings can be made even safer.

Comparison of poisonings managed at military and Veterans Administration hospitals reported to Texas poison centers.

OBJECTIVES: There is little information on poisonings managed at military and Veterans Administration (VA) hospitals. This investigation described and compared poisonings reported to Texas poison centers that were managed at military and VA hospitals. STUDY DESIGN: Retrospective analysis of poison centre data. METHODS: Cases were poisonings among patients aged 18 years or more reported to Texas poison centers during 2000-2015 where management occurred at a military or VA hospital. The distribution of exposures for various demographic and clinical factors was determined for military and veterans hospitals and comparisons were made between the two groups. RESULTS: There were 4353 and 1676 poisonings managed at military and VA hospitals, resepctively. Males accounted for 50.5% of the military hospital patients and 84.9% of the VA hospital patients. The mean age for military hospital patients was 31 years and for VA hospital patients was 50 years. The proportion of poisonings managed at military hospitals and VA hospitals, respectively, were intentional (70.0% vs 64.1%), particularly suspected attempted suicide (57.3% vs 47.7%), and unintentional (25.0% vs 30.5%). More than one substance was reported in 37.7% of military and 33.2% of VA hospital poisonings. The most commonly reported substance categories for poisonings managed at military and VA hospitals, respectively, were analgesics (28.4% vs 19.7%), sedatives/hypnotics/antipsychotics (24.7% vs 23.4%), antidepressants (18.7% vs 19.7%) and alcohol (11.3% vs 10.6%). CONCLUSIONS: A number of differences were observed between poisonings managed at military and VA hospitals. These differing patterns of poisonings may need to be taken into account in the education, prevention and treatment of poisonings at these hospitals and among the populations they serve.

Increased urinary CD80 excretion and podocyturia in Fabry disease.

BACKGROUND: Certain glomerulopathies are associated with increased levels of CD80 (B7-1). We measured the urinary excretion of CD80, podocyturia and proteinuria in controls and in subjects with Fabry disease either untreated or on enzyme replacement therapy (ERT). METHODS: Cross-sectional study including 65 individuals: controls (n = 20) and Fabry patients (n = 45, 23 of them not on ERT and 22 on ERT). Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), urinary uCD80/creatinine ratio (uCD80) and podocyturia. CD80 mRNA expression in response to lyso-Gb3, a bioactive glycolipid accumulated in Fabry disease, was studied in cultured human podocytes. RESULTS: Controls and Fabry patients did not differ in age, eGFR and gender. However, UPCR, uCD80 and podocyturia were significantly higher in Fabry patients than in controls. As expected, Fabry patients not on ERT were younger and a higher percentage were females. Non-ERT Fabry patients had less advanced kidney disease than ERT Fabry patients: UPCR was lower and eGFR higher, but uCD80 and podocyturia did not differ between non-ERT or ERT Fabry patients. There was a significant correlation between uCD80 and UPCR in the whole population (r 0.44, p 0.0005) and in Fabry patients (r 0.42, p 0.0046). Lyso-Gb3 at concentrations found in the circulation of Fabry patients increased uCD80 expression in cultured podocytes. CONCLUSIONS: Fabry disease is characterized by early occurrence of increased uCD80 excretion that appears to be a consequence of glycolipid accumulation. The potential for uCD80 excretion to reflect early, subclinical renal Fabry involvement should be further studied.

Human interleukin-27: wide individual variation in plasma levels and complex inter-relationships with interleukin-17A.

Although it is widely believed that interleukin (IL)-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with T helper type 17 (Th)17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and proinflammatory cytokines, including IL-17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein-Barr virus-induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other proinflammatory cytokines. We verified that IL-27 inhibited IL-17A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.

Pattern of ziprasidone exposures reported to Texas poison centers, 2001-2005.

Information on potentially adverse exposures to the atypical antipsychotic drug ziprasidone is limited. This study described the pattern of exposures involving only ziprasidone (isolated exposures) reported to Texas poison control centers during 2001-2005. The mean dose was 666 mg. The patient age distribution was or=20 years (60%). The exposures were intentional in 53% of the cases. Seventy-five percent of the exposures were managed at health care facilities. The final medical outcome was classified as no effect for 39% of the cases and minor effects for 40% of the cases. Adverse clinical effects were listed for 53% of the patients; the most frequently reported being neurological (42%), cardiovascular (13%), and gastrointestinal (5%). The most frequently listed treatment was decontamination by charcoal (34%) or cathartic (28%). Potentially adverse ziprasidone exposures reported to poison control centers are likely to involve management at a health care facility and involve some sort of adverse clinical effect. With proper treatment, the outcomes of such exposures are generally favorable.

Adult metformin ingestions reported to Texas poison control centers, 2000-2006.

Metformin is an oral hypoglycemic agent used in the management of type 2 diabetes mellitus. Limited information exists on adult metformin ingestions reported to poison control centers. The distribution of adult metformin ingestions reported to Texas poison control centers during 2000-2006 was determined for various factors. In addition, triage guidelines for the management of isolated ingestions were drafted. Of 1528 total metformin ingestions, 58% involved coingestants. Of the 264 ingestions of metformin alone, where the final medical outcome was known, dose ingested was reported for 66%. The mean reported dose was 4739 mg (range 500-60,000 mg). Ingestions of < or =2500 mg and >5000 mg reported doses differed with respect to the proportion involving suspected attempted suicide (6% versus 81%), serious final medical outcome (3% versus 19%), and referral to a health care facility (3% versus 83%). Using 5000 mg as a threshold dose for referral to a health care facility, 91% of cases not already at or en route to a health care facility were managed according drafted triage guidelines.

Plasminogen activator inhibitor-1 activity and 4G/5G polymorphism in hemodialysis.

INTRODUCTION: Chronic insufficiency alters homeostasis, in part due to endothelial inflammation. Plasminogen activator inhibitor-1 (PAI-1) is increased in renal disease, contributing to vascular damage. We assessed PAI-1 activity and PAI-1 4G/5G polymorphism in hemodialysis (HD) subjects and any association between thrombotic vascular access (VA) events and PAI-1 polymorphism. METHODS: Prospective, observational study in 36 HD patients: mean age: 66.6 +/- 12.5 yr, males n=26 (72%), time on HD: 28.71 +/- 22.45 months. Vascular accesses: 10 polytetrafluoroethylene grafts (PTFEG), 22 arteriovenous fistulae (AVF), four dual lumen catheters (CAT). Control group (CG): 40 subjects; mean age: 60.0 +/- 15 yrs, males n=30 (75%). Group A (GA): thrombotic events (n=12), and group B (GB): No events (n=24). Groups were no different according to age (69.2 +/- 9.12 vs. 65.3 +/- 14.5 yrs), gender (males: 7; 58.3% vs. 18; 81.8%), time on HD (26.1 +/- 14.7 vs. 30.1 +/- 38.7 months), causes of renal failure. Time to follow-up for access thrombosis: 12 months. RESULTS: PAI-1 levels in HD: 7.21 +/- 2.13 vs. CG: 0.42 +/- 0.27 U/ml (p<0.0001). PAI-1 4G/5G polymorphic variant distribution in HD: 5G/5G: 6 (17%), 4G/5G: 23 (64%); 4G/4G: 7 (19%) and in CG: 5G/5G: 14 (35%); 4G/5G: 18 (45%); 4G/4G: 8 (20%). C-reactive protein (CRP) in HD: 24.5 +/- 15.2 mg/L vs. in CG 2.3 +/- 0.2 mg/L (p<0.0001). PAI-1 4G/5G variants: GA: 5G/5G: 3; 4G/5G: 8; 4G/4G: 1; GB: 5G/5G: 3; 4G/5G: 15; 4G/4G: 6. Thrombosis occurred in 8/10 patients (80%) with PTFEG, 3/22 (9%) in AVF, and 1/4 (25%) in CAT. Among the eight PTFEG patients with thrombosis, seven were PAI 4G/5G. CONCLUSIONS: PAI-1 levels were elevated in HD patients, independent of their polymorphic variants, 4G/5G being the most prevalent variant. Our data suggest that in patients with PTFEG the 4G/5G variant might be associated with an increased thrombosis risk.

Pediatric Nandina domestica ingestions reported to poison centers.

Nandina domestica is grown as an ornamental plant in the United States but has also been reported as an invasive plant in a number of states. Parts of the plant, particularly the berries, contain cyanogenic glycosides that convert to hydrogen cyanide when ingested. This investigation characterized N. domestica ingestions involving patients of age 5 years and less reported to Texas poison centers during 2000-2015. There were 875 total N. domestica ingestions. A seasonal pattern was observed with the highest proportion of ingestions occurring in March (18.5%) and April (14.7%). The patients were male in 55.0% of the cases; 40.8% of the patients were of age 1 and 37.0% of age 2. Berries were specifically mentioned in 709 ingestions, of which 57.3% involved one berry and 28.5% an unknown number of berries. The ingestion occurred at the patient's own residence in 92.9% of the cases, and the patient was managed on site in 97.0%. The most frequently reported clinical effects were vomiting (3.7%), abdominal pain (1.0%), diarrhea (0.9%), and nausea (0.7%). In conclusion, N. domestica ingestions among young children generally do not result in serious outcomes and can be managed successfully outside of a healthcare facility.

Mucin-1 Gene Mutation and the Kidney: The Link between Autosomal Dominant Tubulointerstitial Kidney Disease and Focal and Segmental Glomerulosclerosis.

Glomerular diseases are one of the most frequent causes of chronic kidney disease, focal and segmental glomerulosclerosis being one of the commonest glomerulopathies. However, the etiology of this glomerular entity, which merely depicts a morphologic pattern of disease, is often not established and, in most of the patients, remains unknown. Nephrologists tend to assume focal and segmental glomerulosclerosis as a definitive diagnosis. However, despite the increasing knowledge developed in the field, genetic causes of glomerular diseases are currently identified in fewer than 10% of chronic kidney disease subjects. Moreover, unexplained familial clustering among dialysis patients suggests that genetic causes may be underrecognized. Secondary focal and segmental glomerulosclerosis due to genetic mutations mainly located in the podocyte and slit diaphragm can occur from childbirth to adulthood with different clinical presentations, ranging from mild proteinuria and normal renal function to nephrotic syndrome and renal failure. However, this histopathological pattern can also be due to primary defects outside the glomerulus. The present report illustrates an adult case of secondary focal and segmental glomerulosclerosis with a dominant tubulointerstitial damage that led to the pursue of its cause at the tubular level. In this patient with an undiagnosed family history of adult kidney disease, a genetic study unraveled a mutation in the mucin-1 gene and a final diagnosis of adult dominant tubular kidney disease-MUC1 was made.

Escitalopram ingestions reported to Texas poison control centers, 2002-2005.

Limited information exists on potentially adverse escitalopram ingestions reported to poison control centers. Using isolated escitalopram ingestions reported to Texas poison control centers during 2002-2005, the proportion of cases involving serious medical outcomes was determined for selected variables and evaluated for statistical significance by calculating the rate ratio (RR) and 95% confidence interval (CI). Of 1179 cases identified, 234 (20%) involved serious outcomes. Serious outcomes were significantly more likely to occur with a maximum dose of >100 mg (RR 4.69, CI 2.52-9.29) or >5 tablets (RR 4.96, CI 2.94-8.93), where the circumstances of the exposures involved self-harm or malicious intent (RR 3.21, CI 2.42-4.29), or when the patient was already at or en route to a health care facility when the poison control center was contacted (RR 7.88, CI 4.31-15.79) or referred to a health care facility by the poison control center (RR 15.91, CI 8.78-31.64). The severity of the outcome associated with isolated escitalopram ingestions depended on the dose and the circumstances of the ingestion. The management of patients with serious outcomes were more likely to involve health care facilities. Such information is useful for creating triage guidelines for the management of escitalopram ingestions.

Pediatric lisinopril ingestions reported to Texas poison control centers.

Lisinopril is not recommended for use by young children. This study attempted to identify factors associated with serious outcomes in pediatric lisinopril ingestions. Cases for this study were lisinopril ingestions by children age < or =5 years reported to Texas poison control centers during 1998-2005. The percentage of cases involving serious medical outcomes was identified for selected variables and evaluated for statistical significance by calculating the rate ratio (RR) and 95% confidence interval (CI). Of 691 total cases, 26 (3.8%) involved a serious outcome. Higher serious outcome rates were found with a maximum dose of >4 mg/kg (RR: 2.54, CI: 0.05-25.62), or >80 mg (RR: 7.85; CI: 1.73-29.29), or five or more tablets (RR: 8.18; CI: 2.73-22.54), or the patient was already at or en route to a health care facility when the poison control center was contacted (RR: 13.93; CI: 3.68-77.78), or referred to a health care facility by the poison control center (RR: 33.49; CI: 9.04-194.94). The management of patients with severe outcomes was more likely to involve health care facilities. This information is useful for drafting triage guidelines for the management of pediatric lisinopril ingestions.

Adult glyburide ingestions reported to Texas poison control centers, 1998 2005.

Limited information exists on potentially adverse adult glyburide ingestions reported to poison control centers. Using adult glyburide ingestions reported to Texas poison control centers during 1998-2005, the proportion of cases involving serious outcomes was determined for selected variables and evaluated for statistical significance by calculating the rate ratio (RR) and 95% confidence interval (CI). Of 126 cases identified, 49 (39%) involved serious outcomes. Serious outcomes were significantly more likely to occur with a maximum dose>24 mg (RR 4.74, 95% CI 1.74-14.90) or >4 tablets (RR 3.27, CI 1.57-7.31), where the circumstances of the exposures involved self-harm or malicious intent (RR 2.44, CI 1.33-4.46), or the patient was already at or en route to a health care facility when the poison control center was contacted (RR 12.89, CI 4.00-66.12) or referred to a health care facility by the poison control center (RR 12.21, CI 3.53-65.01). The severity of the outcome associated with adult glyburide ingestions depended on the dose and the circumstances of the ingestion. The management of patients with severe outcomes was more likely to involve health care facilities. Such information is useful for creating triage guidelines for the management of adult glyburide ingestions.

Human exposures to pentobarbital-phenytoin combination veterinary drugs.

A combination of pentobarbital and phenytoin is used as a veterinary euthanasia drug. Because of its lethal effect, this study described pentobarbital-phenytoin combination veterinary drug human exposures reported to Texas poison centers during 2000-2015. Of 66 exposures, 73% involved female and 27% male patients. The distribution by patient age was 3% 0-5 years, 5% 6-19 years, 91% 20+ years, and 2% unknown. The most common routes were ocular (41%), ingestion (32%), injection (23%), and dermal (18%). The exposure reasons were unintentional (77%) and intentional (23%). The exposure site was the workplace (52%), patient's own residence (38%), health-care facility (2%), and other/unknown (9%). The management site was managed on site (48%), at/en route to health-care facility (45%), referred to health-care facility (5%), and other (2%). The medical outcomes were no effect (23%), minor effect (30%), moderate effect (8%), major effect (8%), not followed nontoxic (3%), not followed minimal effects (24%), unable to follow potentially toxic (2%), and unrelated (3%). The most common adverse effects were ocular irritation/pain (18%), drowsiness/lethargy (15%), and coma (9%). The most common treatments were dilution/irrigation (70%), intravenous fluids (21%), and oxygen (14%). This study found few pentobarbital-phenytoin combination veterinary drug exposures were reported to Texas poison centers during a 16-year period. Although meant to be administered intravenously, the most common exposure routes were ocular and ingestion. Many of the exposures appeared to be unintentional and occurred at the workplace.

In Acute IgA Nephropathy, Proteinuria and Creatinine Are in the Spot, but Podocyturia Operates in Silence: Any Place for Amiloride?

IgA nephropathy is the most frequent cause of primary glomerulonephritis, portends erratic patterns of clinical presentation, and lacks specific treatment. In general, it slowly progresses to end-stage renal disease. The clinical course and the response to therapy are usually assessed with proteinuria and serum creatinine. Validated biomarkers have not been identified yet. In this report, we present a case of acute renal injury with proteinuria and microscopic hematuria in a young male. A kidney biopsy disclosed IgA nephropathy. Podocyturia was significantly elevated compared to normal subjects. Proteinuria, renal function, and podocyturia improved promptly after steroids and these variables remained normal after one year of follow-up, when steroids had already been discontinued and patient continued on valsartan and amiloride. Our report demonstrates that podocyturia is critically elevated during an acute episode of IgA nephropathy, and its occurrence may explain the grim long-term prognosis of this entity. Whether podocyturia could be employed in IgA nephropathy as a trustable biomarker for treatment assessment or even for early diagnosis of IgA nephropathy relapses should be further investigated.

Epidemiology of jellyfish stings reported to poison centers in Texas.

This study examined the relationship between selected factors and all human exposures involving jellyfish stings reported to Texas poison centers. Cases were obtained retrospectively from calls to poison centers in Texas and included all reported human exposures during 1998-2004 involving jellyfish stings. The distribution of cases was determined for a variety of demographic and clinical parameters. There were 423 total cases. Among the cases with a known patient age, 19.8% were <6 years of age, 53.5% were age 6-19 years, and 26.7% were >19 years of age. Males accounted for 52% of the cases. Of the 118 cases with a known clinical outcome, 0.8% had no effect, 80.5% had minor effects, and 18.6% had moderate effects. Counties along the Gulf Coast accounted for 72.3% of the calls. This information can be used to identify those portions of the population most at need of education regarding the prevention and treatment of jellyfish stings.

Celecoxib exposures reported to Texas poison control centers from 1999 to 2004.

Concerns have been raised about the safety of celecoxib. This study described the pattern of exposures involving only celecoxib (isolated exposures) reported to Texas poison control centers from 1999 to 2004. The mean dose was 701 mg. The patient age distribution was < or = 5 years (48%), 6-19 years (8%), and > or = 20 years (44%). In 78% of cases, exposure was unintentional. Of the exposures, 74% were managed outside of health care facilities. The final medical outcome was classified as no effect for 82% of the cases, and minor effects for 12% of the cases. Adverse clinical effects were listed for 5% of the patients, the most frequently reported being rash (3%), drowsiness (3%), pruritus (2%), and vomiting (2%). The most frequently listed treatment was decontamination by dilution (43%) or food (32%). The majority of isolated celecoxib exposures could be managed outside of health care facilities, and the outcome was generally favorable.

Bibliometric analysis of poison center-related research published in peer-review journals.

Poison centers advance knowledge in the field of toxicology through publication in peer-review journals. This investigation describes the pattern of poison center-related publications. Cases were poison center-related research published in peer-review journals during 1995-2014. These were identified through searching the PubMed database, reviewing the tables of contents of selected toxicology journals, and reviewing abstracts of various national and international meetings. The following variables for each publication were identified: year of publication, journal, type of publication (meeting abstract vs. other, i.e. full article or letter to the editor), and the country(ies) of the poison center(s) included in the research. Of the 3147 total publications, 62.1% were meeting abstracts. There were 263 publications in 1995-1999, 536 in 2000-2004, 999 in 2005-2009, and 1349 in 2010-2014. The publications were in 234 different journals. The journals in which the highest number of research was published were Clinical Toxicology (69.7%), Journal of Medical Toxicology (2.2%), and Veterinary and Human Toxicology (2.1%). The research was reported from 62 different countries. The countries with the highest number of publications were the United States (67.9%), United Kingdom (6.5%), Germany (3.9%), France (2.5%), and Italy (2.4%). The number of publications increased greatly over the 20 years. Although the publications were in a large number of journals, a high proportion of the publications were in one journal. While the research came from a large number of countries, the preponderance came from the United States.

Podocyturia: A Clue for the Rational Use of Amiloride in Alport Renal Disease.

No specific or efficient treatment exists for Alport syndrome, an X-linked hereditary disease caused by mutations in collagen type IV, a crucial component of the glomerular basement membrane. Kidney failure is usually a major complication of the disease, and patients require renal replacement therapy early in life. Microhematuria and subsequently proteinuria are hallmarks of kidney involvement, which are due to primary basement membrane alterations that mainly cause endothelial thrombosis and podocyte contraction and ulterior irreversible detachment. Commonly drug-based approaches include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are employed to reduce proteinuria and thus retard kidney disease progression and cardiovascular morbidity and mortality. However, as any hereditary disease, it is expressed as early as in the intrauterine life, and usually an index case is helpful to detect family-related cases. As no specific treatment exists, pathophysiologically based approaches are useful. The present case illustrates the reduction rate of urinary podocyte loss and proteinuria after amiloride administration and suggests the molecular pathways involved in Alport renal disease. Finally, podocyturia rather than proteinuria should be considered as an earlier biomarker of kidney involvement and disease progression in Alport disease.

Computer-assisted molecular modeling of benzodiazepine and thyromimetic inhibitors of the HepG2 iodothyronine membrane transporter.

T3 cellular uptake is inhibited in the presence of benzodiazepines (BZs). The structure-activity relationship of BZ inhibition correlates strongly with halogen substitution of the nonfused phenyl ring and indicates that this ring is required for activity. A structure-activity series of thyromimetic (TH) inhibitors of the HepG2 iodothyronine transporter further point out the critical importance of the amino group of the alanine side chain, its L-stereo configuration, and the size of the substituents of the inner and outer phenyl rings. A third series of compounds, reported to interact at related sites, were inactive as HepG2 iodothyronine transport inhibitors, and therefore the potent inhibitors were restricted to the BZ and TH compounds. Using both of these BZ and TH structure-activity series along with computer-assisted molecular modeling techniques, we determined which chemical structural components were important at the transporter interaction site. By superimposing structures from active chemicals, excluding residues from poor inhibitors, and incorporating molecular electropotential data, we developed a five-point model of BZ conformational similarity to the endogenous transporter ligand, L-T3: the alkyl substitution at the N1 of the BZ ring seems to simulate the alanine side chain of T3, and the electro-negative halogen and oxygen atoms of substituents at R3/R7/R2'/R4' of BZ form a pyramidal pharmacophore that seems to correspond with the 3-l/5-l/3'-l/4'-OH substituents of T3, respectively. These points, suggesting a tilted cross-bow formation, may be sites for ligand interaction with the iodothyronine transporter.