Salivary uric acid as a predictive test of preeclampsia, pregnancy-induced hypertension and preterm delivery: A pilot study.

INTRODUCTION: There remains a need for a non-invasive, low-cost and easily accessible way of identifying women at risk of developing hypertensive disorders in pregnancy. This study evaluated the predictive value of longitudinal salivary uric acid measurement. MATERIAL AND METHODS: Pregnant women (n = 137) from 20 weeks of gestation were recruited at St Richards Hospital, Chichester, UK, for this prospective cohort study. Weekly samples of salivary uric acid were analyzed until delivery. Information regarding pregnancy and labor were obtained from the patient's record after delivery. Independent t tests were used to compare mean levels of salivary uric acid in women with hypertensive complications and adverse fetal outcomes with women with normal pregnancies. Main outcome measures were preeclampsia, pregnancy-induced hypertension, spontaneous preterm delivery and small-for-gestational-age babies. RESULTS: From 21 weeks of gestation until delivery, levels of salivary uric acid increased significantly in women who subsequently developed preeclampsia and pregnancy-induced hypertension compared with women with normal pregnancies (preeclampsia-mean at gestational age 21-24, 95% confidence interval [95% CI] [mean GA21-24 ): 108 [63-185] vs 47 (39-55) µmol/L; P = .005; pregnancy-induced hypertension-mean GA21-24 : 118 [54-258] vs 47 [39-55] µmol/L; P = .004). In women who had spontaneous preterm delivery, salivary uric acid levels increased significantly from 29 to 32 weeks of gestation compared with women with normal pregnancies (mean GA29-32 : 112 (57-221) vs 59 (50-71) µmol/L; P = .04). In women who had babies small-for-gestational-age <10th percentile and small-for-gestational-age <3rd percentile, differences in salivary uric acid levels were insignificant. CONCLUSIONS: Elevated levels of salivary uric acid precede the onset of preeclampsia, pregnancy-induced hypertension and preterm delivery. Salivary uric acid may prove to be an early biomarker of hypertensive complications of pregnancy and spontaneous preterm delivery.

Does Late Hip Dysplasia Occur After Normal Ultrasound Screening in Breech Babies?

BACKGROUND: Recent literature has raised concern regarding the occurrence of late dysplasia after normal screening in breech babies. One paper states a late dysplasia incidence of 29%. This finding is in contrast with other published work, which suggests breech presentation is predictive of spontaneous stabilization of the unstable neonatal hip. We decided to identify the rate of late dysplasia after normal screening in our patient cohort and also to investigate the use of a prophylactic abduction diaper. METHODS: During the study period of December 2012 to June 2014, breech babies referred to the screening program at our institution were identified. Ninety babies were prospectively enrolled into the study and randomized to either the observational arm or prophylactic treatment with the Healthy Hip Diaper (HALO, Minnetonka, MN). All babies had a normal initial clinical examination and ultrasound. Regular follow-up including clinical and ultrasound examination was undertaken culminating in pelvic x-rays performed at 13±1 months. A total of 63% of patients elected against their randomization to prophylactic treatment, 28% opted for prophylactic treatment against their randomization to observation only, meaning a total of 40% of babies proceeded against their initial randomization. In total, 75% of recruited babies completed follow-up. Dysplasia was defined as an acetabular index >2 SD from the mean sex, age, and side-specific values. RESULTS: The overall rate of radiographic dysplasia at 13 months was 7.4%. The rate was 5% in those using a Healthy Hip Diaper and 8.3% in those under observation only. This was not a statistically significant difference. Two patients required operative intervention, one requiring capsulorraphy with acetabuloplasty, the other requiring an arthrogram. Overall compliance with the abduction diaper was low. CONCLUSIONS: We conclude that late radiographic dysplasia does occur after normal clinical and ultrasound screening in breech babies, although not to the same extent as recently published data. We cannot recommend prophylactic abduction devices for breech babies who have a normal hip ultrasound at 6 weeks of age. Consideration must be given to further clinical and radiographic follow-up for hip dysplasia when the risk factor of breech presentation is present. LEVEL OF EVIDENCE: Level II-prospective comparative trial.

Vitamin D Deficiency in Slipped Upper Femoral Epiphysis: Time to Physeal Fusion.

BACKGROUND: Slipped upper femoral epiphysis (SUFE) has an incidence of 1 to 7 per 100,000 adolescents in the United Kingdom and its link with obesity is well established. With an increasing number of pediatric orthopaedic patients presenting with vitamin D deficiency, the aim of our study was to establish the prevalence of vitamin D deficiency in SUFE patients presenting to an orthopaedic department in the United Kingdom and whether a low vitamin D level increases the time to proximal femoral physeal fusion after surgical fixation. METHODS: A total of 27 pediatric patients, with a female to male ratio of 17:10 and a mean age of 11.5 years (SD=1.99), range 8 to 16 years, presented with a SUFE and their vitamin D level was assessed during the study period, June 2007 to July 2012 (inclusive). The majority of these patients (85.2%) were assessed as vitamin D deficient, with a serum 25-(OH)D<52 nmol/L. The time taken for >50% physeal fusion on anteroposterior radiography after surgical fixation reported in the literature is 9.6 months, with no reported vitamin D deficiency or insufficiency. RESULTS: In our study, the median time to physeal fusion in the vitamin D-deficient and vitamin D-insufficient patients was 25 months (interquartile range, 17 to 43 mo; mean of 29 mo, SD=16.8). A negative correlation was also observed between vitamin D level and the time taken for physeal fusion after surgical fixation. CONCLUSIONS: We conclude that a high prevalence of vitamin D deficiency has been observed in our SUFE patients. Comparing the time taken for physeal closure of 9.6 months in the literature with vitamin D-deficient patients, this is prolonged. Indeed, a negative correlation has been shown between vitamin D level and time to physeal fusion. This study highlights the need for regular vitamin D status assessment in SUFE patients to allow early implementation of treatment with vitamin D supplementation. The impact of vitamin D screening and supplementation on SUFE outcomes should be investigated further.

Failed Pavlik harness treatment for DDH as a risk factor for avascular necrosis.

BACKGROUND: Avascular necrosis (AVN) of the femoral head is an irreversible complication seen in the treatment of developmental dysplasia of hip (DDH) with the Pavlik harness. Its incidence is reported to be low after successful reduction of the hip but high if the hip is not concentrically relocated. We aim to investigate its incidence after failed Pavlik harness treatment. METHODS: We prospectively followed up a group of children who failed Pavlik harness treatment for DDH treated at our institution by the senior author between 1988 and 2001 and compared their rates of AVN with a group of children who presented late and hence were treated surgically. AVN was graded as described by Kalamchi and MacEwen and only grade 2 to 4 AVN was considered significant and included in the analysis. RESULTS: Thirty-seven hips were included in the failed Pavlik group (group 1) and 86 hips in the no Pavlik group (group 2). Ten hips in group 1 developed AVN (27%), whereas only 7 hips in group 2 (8%) developed AVN; the odds of developing AVN after failed Pavlik treatment was 4.7 (95% confidence interval, 1.3-14.1) (P=0.009) with a relative risk of 3.32 (range, 1.37 to 8.05). CONCLUSIONS: There was no statistically significant association observed with duration of splintage and severity of AVN (Spearman's correlation, -0.46; P=0.18). However, there was a positive correlation noted with age at presentation and severity of AVN. Therefore, we advise close monitoring of hips in the Pavlik harness and discontinue its use if the hips are not reduced within 3 weeks. LEVEL OF EVIDENCE: Level III.

A hyperinflammation clinical risk tool, HI5-NEWS2, stratifies hospitalised COVID-19 patients to associate risk of death and effect of early dexamethasone in an observational cohort.

BACKGROUND: The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. METHODS: Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FINDINGS: Of 1265 patients, high risk of HI (high HI5-NEWS2) (n = 367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n = 455, 36.0%). An intermediate risk group (n = 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p = 0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p = 0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p = 0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p = 0.31). INTERPRETATION: Higher HI5-NEWS2 scores measured at COVID-19 diagnosis, strongly associate with increased mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention in all cases.

Prevention of Morbidity in Sickle Cell Disease (POMS2a)-overnight auto-adjusting continuous positive airway pressure compared with nocturnal oxygen therapy: a randomised crossover pilot study examining patient preference and safety in adults and children.

DESIGN: This randomised crossover trial compared nocturnal auto-adjusting continuous positive airway pressure (APAP) and nocturnal oxygen therapy (NOT) in adults and children with sickle cell anaemia, with patient acceptability as the primary outcome. Secondary outcomes included pulmonary physiology (adults), safety, and daily pain during interventions and washout documented using tablet technology. METHODS: Inclusion criteria were age > 8 years and the ability to use an iPad to collect daily pain data. Trial participation was 4 weeks; week 1 involved baseline data collection and week 3 was a washout between interventions, which were administered for 7 days each during weeks 2 and 4 in a randomised order. Qualitative interviews were transcribed verbatim and analysed for content using a funnelling technique, starting generally and then gaining more detailed information on the experience of both interventions. Safety data included routine haematology and median pain days between each period. Missing pain day values were replaced using multiple imputation. RESULTS: Ten adults (three female, median age 30.2 years, range 18-51.5 years) and eleven children (five female, median age 12 years, range 8.7-16.9 years) enrolled. Nine adults and seven children completed interviews. Qualitative data revealed that the APAP machine was smaller, easier to handle, and less noisy. Of 16 participants, 10 preferred APAP (62.5%, 95% confidence interval (CI) 38.6-81.5%). Haemoglobin decreased from baseline on APAP and NOT (mean difference -3.2 g/L (95% CI -6.0 to -0.2 g/L) and -2.5 g/L (95% CI -4.6 to 0.3 g/L), respectively), but there was no significant difference between interventions (NOT versus APAP, 1.1 (-1.2 to 3.6)). Pulmonary function changed little. Compared with baseline, there were significant decreases in the median number of pain days (1.58 for APAP and 1.71 for NOT) but no significant difference comparing washout with baseline. After adjustment for carry-over and period effects, there was a non-significant median difference of 0.143 (95% CI -0.116 to 0.401) days additional pain with APAP compared with NOT. CONCLUSION: In view of the point estimate of patient preference for APAP, and no difference in haematology or pulmonary function or evidence that pain was worse during or in washout after APAP, it was decided to proceed with a Phase II trial of 6 months APAP versus standard care with further safety monitoring for bone marrow suppression and pain. TRIAL REGISTRATION: ISRCTN46078697 . Registered on 18 July 2014.

Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial.

BACKGROUND: In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. METHODS/DESIGN: Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of < 90% for < 30% of the night (i.e. not meeting current criteria for overnight oxygen therapy). Key exclusion criteria are: overnight respiratory support; respiratory or decompensated cardiac failure; chronic transfusion; or contraindications to APAP therapy or magnetic resonance imaging (MRI). Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8-11, 12-15, 16-22 and > 23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or < 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment. DISCUSSION: Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events. TRIAL REGISTRATION: ISRCTN46012373 . Registered on 10 July 2015. Protocol Version: 6.0 Date: 24th December 2015 Sponsor: University Hospital Southampton. Sponsor's protocol code: RHMCHIOT53.

Prevention of Morbidity in sickle cell disease--qualitative outcomes, pain and quality of life in a randomised cross-over pilot trial of overnight supplementary oxygen and auto-adjusting continuous positive airways pressure (POMS2a): study protocol for a randomised controlled trial.

BACKGROUND: Sickle cell anaemia (SCA) is an inherited disorder of haemoglobin. Patients experience long-term health care problems, affecting quality of life (QOL) including frequent acute pain, which is difficult to document in trials except as hospital admissions. Pilot data suggests that overnight respiratory support, either supplementary oxygen or auto-adjusting continuous positive airways pressure (APAP), is safe and may have clinical benefit. This pilot trial aims to determine which intervention is more acceptable to participants and whether there are other advantages of one over the other, e.g. in respiratory function or haematological parameters, before conducting the Phase 2 trial of overnight respiratory support funded by the National Institutes of Health Research. METHODS/DESIGN: This is a pilot cross-over interventional trial with the order of interventions decided by simple randomization. Ten adults (age over 18 years) and 10 children (aged between 8 and 18 years) with homozygous sickle cell disease (haemoglobin SS, HbSS), recruited regardless of symptoms of sleep-disordered breathing, will undergo overnight pulse oximetry and will have two interventions, overnight oxygen and APAP, for a week each in randomised order with a washout week between interventions. Participants will complete online diaries via an iPad throughout the 29 days of the study and will complete QOL questionnaires and have measurement of haematology, biochemistry, spirometry and lung volumes (adults only) at 3 time points, at baseline and after each intervention, as well as in-depth semi-structured qualitative interviews after each intervention, carried out by an experienced psychologist. Both qualitative and statistical methods will be used to analyze the data. The primary outcome is qualitative data looking at participant experience from the transcribed interviews after each intervention. The participant's view on feasibility, acceptability and preference will specifically be explored. The QOL, laboratory and lung function data will be compared with baseline for each arm. DISCUSSION: Patient and public involvement is an integral part of this trial and the key outcome is the qualitative result, which is dependent on obtaining good quality data to advise on participant feasibility, acceptability and preference. This is being addressed by using a standard interview. The development of a pain endpoint is another important outcome and collecting daily measurements is likely to be challenging. Research results will be used to inform design of the Phase 2 trial. TRIAL REGISTRATION: ISRCTN46078697 18 July 2014.

Twenty years experience of selective secondary ultrasound screening for congenital dislocation of the hip.

OBJECTIVES: The authors report the results of a selective ultrasound screening programme for congenital dislocation of the hip (CDH) over a period of 20 years, with the aim of defining the rate of screening, conservative treatment and late presentation requiring surgery. METHODS: All neonates born from June 1988 to December 2008 (inclusive) were included in the prospective cohort, with a minimum follow-up of 12 months. All underwent an early clinical examination of the hips and those with clinical instability were referred for ultrasound at 2 weeks; those with risk factors were sonographically examined at 6 weeks. Risk factors were defined as breech presentation, family history or foot deformity. RESULTS: 107 440 live births were clinically examined, 20 344 (18.9%) were referred for ultrasound assessment at either 2 weeks (due to clinical signs) or 6 weeks (due to risk factors). 774 (3.8%) were diagnosed with dysplasia with a crude overall treatment rate of 7.2 per 1000 live births. 37 (0.34 per 1000) presented late, that is, after 12 weeks of age; none had detectable clinical signs or risk factors. There were no false negatives. CONCLUSION: Elective screening for developmental dysplasia of the hip in association with one stop treatment and monitoring is an effective programme. The number of infants referred increased statistically significantly year on year over the study period and generated more activity. Pavlik harness treatment rates remained acceptable and steady over the period, despite the increase in referrals. The incidence of late presenting cases ranged from 0 to 4 per year, with no secular trend and there were no ultrasound false negatives.