Systematic review and meta-analysis of birth weight and PFNA exposures.

We used a systematic review that included risk of bias and study sensitivity analysis to identify 34 studies examining changes in birth weight (BWT) in relation to PFNA biomarker measures (e.g., maternal serum/plasma or umbilical cord samples). We fit a random effects model of the overall pooled estimate and stratified estimates based on sample timing and overall study confidence. We conducted a meta-regression to further examine the impact of gestational age at biomarker sample timing. We detected a -32.9 g (95%CI: -47.0, -18.7) mean BWT deficit per each ln PFNA increase from 27 included studies. We did not detect evidence of publication bias (pE = 0.30) or between-study heterogeneity in the summary estimate (pQ = 0.05; I2 = 36%). The twelve high confidence studies yielded a smaller pooled effect estimate (ß = -28.0 g; 95%CI: -49.0, -6.9) than the ten medium (ß = -39.0 g; 95%CI: -61.8, -16.3) or four low (ß = -36.9 g; 95%CI: -82.9, 9.1) confidence studies. The stratum-specific results based on earlier pregnancy sampling periods in 11 studies showed smaller deficits (ß = -22.0 g; 95%CI: -40.1, -4.0) compared to 10 mid- and late-pregnancy (ß = -44.2 g; 95%CI: -64.8, -23.5) studies and six post-partum studies (ß = -42.9 g; 95%CI: -88.0, 2.2). Using estimates of the specific gestational week of sampling, the meta-regression showed results consistent with the categorical sample analysis, in that as gestational age at sampling time increases across these studies, the summary effect estimate of a mean BWT deficit got larger. Overall, we detected mean BWT deficits for PFNA that were larger and more consistent across studies than previous PFAS meta-analyses. Compared to studies with later sampling, BWT deficits were smaller but remained sizeable for even the earliest sampling periods. Contrary to earlier meta-analyses for PFOA and PFOS, BWT deficits that were detected across all strata did not appear to be fully explained by potential bias due to pregnancy hemodynamics from sampling timing differences.

Fracture incidence and fracture-related mortality decreased with decreases in population mobility during the early days of the COVID-19 pandemic: an epidemiological study.

INTRODUCTION: We investigated the impact of coronavirus disease 2019 (COVID-19) social distancing measures on fracture incidence and fracture-related mortality, as well as associations with population mobility. METHODS: In total, 47 186 fractures were analysed across 43 public hospitals from 22 November 2016 to 26 March 2020. Considering the smartphone penetration of 91.5% in the study population, population mobility was quantified using Apple Inc's Mobility Trends Report, an index of internet location services usage volume. Fracture incidences were compared between the first 62 days of social distancing measures and corresponding preceding epochs. Primary outcomes were associations between fracture incidence and population mobility, quantified by incidence rate ratios (IRRs). Secondary outcomes included fracture-related mortality rate (death within 30 days of fracture) and associations between emergency orthopaedic healthcare demand and population mobility. RESULTS: Overall, 1748 fewer fractures than projected were observed during the first 62 days of COVID-19 social distancing (fracture incidence: 321.9 vs 459.1 per 100 000 person-years, P<0.001); the relative risk was 0.690, compared with mean incidences during the same period in the previous 3 years. Population mobility exhibited significant associations with fracture incidence (IRR=1.0055, P<0.001), fracture-related emergency department attendances (IRR=1.0076, P<0.001), hospital admissions (IRR=1.0054, P<0.001), and subsequent surgery (IRR=1.0041, P<0.001). Fracture-related mortality decreased from 4.70 (in prior years) to 3.22 deaths per 100 000 person-years during the COVID-19 social distancing period (P<0.001). CONCLUSION: Fracture incidence and fracture-related mortality decreased during the early days of the COVID-19 pandemic; they demonstrated significant temporal associations with daily population mobility, presumably as a collateral effect of social distancing measures.

Enantioselective oxidative boron Heck reactions.

This review highlights the use of the oxidative boron Heck reaction in enantioselective Heck-type couplings. The enantioselective oxidative boron Heck reaction overcomes several limitations of the traditional Pd(0)-catalysed Heck coupling and has subsequently allowed for intermolecular couplings of challenging systems such as cyclic enones, acyclic alkenes, and even site selectively on remote alkenes.

Dehydrative thiolation of allenols: indium vs gold catalysis.

Intermolecular additions of thiols to allenols via formal S(N)2' selectivity to produce functionalized dienes are described. Although this dehydrative reaction was initially developed using gold(I) catalysis, indium(III) proves to be a far superior catalyst in terms of selectivity and substrate scope.

Prediction of invasive candidal infection in critically ill patients with severe acute pancreatitis.

INTRODUCTION: Patients with severe acute pancreatitis are at risk of candidal infections carrying the potential risk of an increase in mortality. Since early diagnosis is problematic, several clinical risk scores have been developed to identify patients at risk. Such patients may benefit from prophylactic antifungal therapy while those patients who have a low risk of infection may not benefit and may be harmed. The aim of this study was to assess the validity and discrimination of existing risk scores for invasive candidal infections in patients with severe acute pancreatitis. METHODS: Patients admitted with severe acute pancreatitis to the intensive care unit were analysed. Outcomes and risk factors of admissions with and without candidal infection were compared. Accuracy and discrimination of three existing risk scores for the development of invasive candidal infection (Candida score, Candida Colonisation Index Score and the Invasive Candidiasis Score) were assessed. RESULTS: A total of 101 patients were identified from 2003 to 2011 and 18 (17.8%) of these developed candidal infection. Thirty patients died, giving an overall hospital mortality of 29.7%. Hospital mortality was significantly higher in patients with candidal infection (55.6% compared to 24.1%, P=0.02). Candida colonisation was associated with subsequent candidal infection on multivariate analysis. The Candida Colonisation Index Score was the most accurate test, with specificity of 0.79 (95% confidence interval [CI] 0.68 to 0.88), sensitivity of 0.67 (95% CI 0.41 to 0.87), negative predictive value of 0.91 (95% CI 0.82 to 0.97) and a positive likelihood ratio of 3.2 (95% CI 1.9 to 5.5). The Candida Colonisation Index Score showed the best discrimination with area under the receiver operating characteristic curve of 0.79 (95% CI 0.69 to 0.87). CONCLUSIONS: In this study the Candida Colonisation Index Score was the most accurate and discriminative test at identifying which patients with severe acute pancreatitis are at risk of developing candidal infection. However its low sensitivity may limit its clinical usefulness.

Effects of pulmonary rehabilitation in bronchiectasis: A retrospective study.

There is limited information about the benefits of pulmonary rehabilitation (PR) in patients with bronchiectasis. This study aimed to evaluate the effects of an out-patient PR program in patients with a primary diagnosis of bronchiectasis and to compare them with a matched COPD group who completed the same PR program. A retrospective review was conducted of patients with bronchiectasis or COPD who completed 6 to 8 weeks of PR at two tertiary institutions. The outcome measures were the 6-minute walk distance (6MWD) and Chronic Respiratory Disease Questionnaire (CRQ). Ninety-five patients with bronchiectasis completed the PR (48 male; FEV(1) 63 [24] % predicted; age 67 [10] years). Significant improvements in 6MWD (mean change 53.4 m, 95% CI 45.0 to 61.7) and CRQ total score (mean change 14.0 units, 95% CI 11.3 to 16.7) were observed immediately following PR. In patients with complete follow-up (n = 37), these improvements remained significantly higher than baseline at 12 months (20.5 m, 95% CI 1.4 to 39.5 for 6MWD; 12.1 points, 95% CI 5.7 to 18.4 for CRQ total score). The time trend and changes in the 6MWD and CRQ scores were not significantly different between the bronchiectasis and the COPD groups (all p > 0.05). This study supports the inclusion of patients with bronchiectasis in existing PR programs. Further prospective RCTs are warranted to substantiate these findings.

Diagnostic stewardship programme for urine culture: impact on antimicrobial prescription in a multi-centre cohort.

BACKGROUND: Restricting urine culture to patients with genuine urinary tract infection (UTI) reduces excessive antimicrobial prescription for asymptomatic bacteriuria. AIM: To evaluate the impact of urine culture diagnostic stewardship on antimicrobial consumption. METHODS: This quasi-study involved two general hospitals and 10 community clinics. In the pre-intervention (control) phase (25th November 2018-2nd February 2019), microscopy and culture results of all urine specimens were reported. In the post-intervention (study) phase (25th November 2019-2nd February 2020), urine cultures were processed and reported only if at least one of the following criteria were met: presence of white blood cells or bacteria on microscopy; patient from obstetrics, urology, paediatrics, oncology or renal transplant ward; specimen labelled as 'pregnancy', 'urological procedure', 'renal transplant' or 'neutropenic'; and ureteric, nephrostomy or suprapubic urine. For urine samples that did not fulfil these criteria, the microscopy results and a rejection comment were reported. FINDINGS: In total, 12,282 urine specimens were included in the intervention phase. Of these, 4757 (38.7%) specimens did not fulfil the screening criteria, and the microscopy result and a rejection comment were reported. One hundred and sixty-three (3.4%) of these non-reported urine cultures yielded significant bacterial growth, and the majority were Escherichia coli (N=58, 35.6%). Diagnostic stewardship was independently associated with lower antimicrobial consumption [adjusted odds ratio 0.76, 95% confidence interval (CI) 0.70-0.83, P<0.001] on multi-variable logistic regression across all healthcare settings. Diagnostic stewardship had no effect on patient mortality (adjusted hazard ratio=0.95, 95% CI 0.89-1.01, P=0.08). No patients with unreported urine culture developed bacteraemia from untreated UTI. CONCLUSION: Diagnostic stewardship of urine culture safely reduced excessive antimicrobial prescription for asymptomatic bacteriuria.

The six-minute walk test: a useful metric for the cardiopulmonary patient.

Measurement of exercise capacity is an integral element in assessment of patients with cardiopulmonary disease. The 6-min walk test (6MWT) provides information regarding functional capacity, response to therapy and prognosis across a range of chronic cardiopulmonary conditions. A distance less than 350 m is associated with increased mortality in chronic obstructive pulmonary disease, chronic heart failure and pulmonary arterial hypertension. Desaturation during a 6MWT is an important prognostic indicator for patients with interstitial lung disease. The 6MWT is sensitive to commonly used therapies in chronic obstructive pulmonary disease such as pulmonary rehabilitation, oxygen, long-term use of inhaled corticosteroids and lung volume reduction surgery. However, it appears less reliable to detect changes in clinical status associated with medical therapies for heart failure. A change in walking distance of more than 50 m is clinically significant in most disease states. When interpreting the results of a 6MWT, consideration should be given to choice of predictive values and the methods by which the test was carried out.

Restructuring the neuronal stress response with anti-glucocorticoid gene delivery.

Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.

Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5' untranslated region.

We have cloned and sequenced the 5' untranslated region of the transforming growth factor-beta 3 (TGF-beta 3) mRNA as well as the adjacent genomic sequence. S1 nuclease analysis identified a single transcription start site. We have thus determined that the 5' untranslated region is about 1.1 kb long and contains 11 open reading frames. In vitro translation of the TGF-beta 3 precursor coding sequence was markedly inhibited by the presence of the 5' untranslated region. Similarly, when the 5' untranslated region of TGF-beta 3 was introduced upstream of the coding sequence of chloramphenicol acetyltransferase, in vitro translation was inhibited. Furthermore, upon transfection into 293 cells, chloramphenicol acetyltransferase expression was inhibited by the 5' untranslated region of TGF-beta 3. The degree of translational inhibition was inversely proportional to the amount of transfected DNA. Mutation analysis implicated multiple segments of the 5' untranslated region as contributing to the inhibitory effect. Deletion of much of the 5'-most 640 nucleotides, including 8 of the 11 upstream ATGs, relieved much but not all of the inhibitory influence of the 5' untranslated region of TGF-beta 3 mRNA. The two upstream open reading frames closest to the initiator codon for the TGF-beta 3 coding sequence also decreased translational efficiency, since mutation of either ATG resulted in increased translation. Transfection results with T47-D cells, a cell line which expresses TGF-beta 3 mRNA, were similar to those obtained with the 293 cell line. Thus, TGF-beta 3 mRNA is a recent example of an expanding group of growth-related mRNAs in which the 5' untranslated region contains upstream open reading frames and other sequences which inhibit translation.

Dual gold and photoredox catalysed C-H activation of arenes for aryl-aryl cross couplings.

A mild and fully catalytic aryl-aryl cross coupling via gold-catalysed C-H activation has been achieved by merging gold and photoredox catalysis. The procedure is free of stoichiometric oxidants and additives, which were previously required in gold-catalysed C-H activation reactions. Exploiting dual gold and photoredox catalysis confers regioselectivity via the crucial gold-catalysed C-H activation step, which is not present in the unselective photocatalysis-only counterpart.

Prevalence and impact of urinary incontinence in men with chronic obstructive pulmonary disease: a questionnaire survey.

OBJECTIVES: To identify urinary incontinence and its impact on men with stable chronic obstructive pulmonary disease (COPD) and men without lung disease. DESIGN: Prospective questionnaire study. SETTING: Outpatients attending a public metropolitan hospital. PARTICIPANTS: Men with COPD (n=49) and age-matched men without lung disease (n=36). INTERVENTIONS: Validated questionnaires to identify the prevalence and impact of urinary incontinence. MAIN OUTCOME MEASURES: Prevalence of urinary incontinence and relationship with disease-specific factors, and relationship of urinary incontinence with anxiety and depression. RESULTS: The prevalence of urinary incontinence was higher in men with COPD (n=19/49) compared with men without lung disease (n=6/36; P=0.027). In men with COPD, symptoms of urgency were more prevalent in men with urinary incontinence (P=0.005), but this was not evident in men without lung disease (P=0.101). Only men with COPD reported symptoms of urgency associated with dyspnoea, and this did not vary between men with and without urinary incontinence (P=0.138). In men with COPD, forced expiratory volume in 1 second (FEV1) was lower in those with urinary incontinence compared with those without urinary incontinence {mean 38 [standard deviation (SD) 14] % predicted vs 61 (SD 24) % predicted; P=0.002}. The impact of urinary incontinence did not differ between the two groups (P=0.333). CONCLUSIONS: Incontinence is more prevalent in men with COPD than in men without lung disease. The prevalence of urinary incontinence increases with greater disease severity, as reflected by lower FEV1. Screening for urinary incontinence should be considered in men with COPD and compromised lung function.

Significance of Time-Zero Biopsy for Graft Renal Function After Deceased Donor Kidney Transplantation.

BACKGROUND: Donor organ quality from deceased donors affects graft survival after kidney transplantation. This study was performed to identify clinico-histological factors that affect early graft outcome, using time-zero biopsies of deceased donors. METHODS: Between December 2006 and July 2011, 135 recipients of deceased donor kidneys were included, and data concerning donor and recipient-related clinical characteristics and histological findings of time-zero biopsies categorized by use of the Banff 07 scoring system were included in the analysis. Mean donor age was 44.3 ± 12.3 years. Mean terminal serum creatinine level and cold ischemic time were 1.50 ± 0.96 mg/dL and 349 ± 166 minutes. Mean follow-up time after transplantation was 37 ± 16 months, and all recipients were followed for at least 1 year. RESULTS: Global glomerulosclerosis (38.5%), tubular atrophy (37.8%), arteriolar hyaline thickening (25.9%), interstitial fibrosis (23%), vascular fibrous intimal thickening (21.5%), and interstitial inflammation (20%) were the major pathologic findings of time-zero biopsies. The majority of pathologic scores were of mild degree. Among histological findings, arteriolar hyaline thickening and interstitial fibrosis were only significantly associated with early post-transplant renal function in multivariate analyses. CONCLUSIONS: Considerations of clinico-histological findings were found to be valuable for predicting early graft outcome after deceased donor kidney transplantation.

Sympathetic neurotransmission in the Watanabe heritable hyperlipidaemic rabbit mesentery artery.

STUDY OBJECTIVE: The aim was to examine sympathetic neurotransmission in the mesenteric artery of atherosclerotic (Watanabe heritable hyperlipidaemic, WHHL) rabbits. DESIGN: Contractile responses to perivascular nerve stimulation (8-64 Hz) and exogenous application of the cotransmitters noradrenaline (0.1-100 microM) and adenosine triphosphate (1 microM) were measured. Catecholamine containing nerves were localised using fluorescence histochemistry. EXPERIMENTAL MATERIAL: Female WHHL rabbits at 4, 6, and 12 months of age were used, with New Zealand white (NZW) rabbits as controls. MEASUREMENTS AND MAIN RESULTS: The contractile responses to nerve stimulation were significantly smaller in 12 month old WHHL compared to NZW rabbits, although there was no difference at 4 and 6 months of age. Contractile responses of WHHL vessels to noradrenaline (0.1-100 microM) were greater than NZW controls at 4 months, but no differences were seen at 6 and 12 months. Contractile responses to alpha, beta-methylene ATP (0.1 microM) were greater in WHHL rabbits at 6 months but were unchanged at 4 and 12 months. There was no difference in the contractile responses to potassium chloride (120 mM) between 4, 6, and 12 month old WHHL and NZW rabbits. There was no variation in either strain of rabbit in the density of catecholamine containing nerves between 4 and 12 months of age. CONCLUSIONS: The reduction of sympathetic neurotransmission in WHHL rabbits at 12 months of age may largely be due to a reduction in the release of the cotransmitters noradrenaline and ATP. The reduced contractile response to nerve stimulation in 12 month old WHHL rabbits is discussed in terms of "protection" of the mesenteric artery from potential vasospasm and atherogenesis.

Oxidative Heck desymmetrisation of 2,2-disubstituted cyclopentene-1,3-diones.

Oxidative Heck couplings have been successfully developed for 2,2-disubstituted cyclopentene-1,3-diones. The direct coupling onto the 2,2-disubstituted cyclopentene-1,3-dione core provides a novel expedient way of enantioselectively desymmetrising all-carbon quaternary centres.

Arterial response to mechanical injury: balloon catheter de-endothelialization.

Coronary angioplasty has been used clinically for over a decade. Its initial promise as an alternative to coronary bypass surgery has only partially been fulfilled because of the high rate of post-operative restenosis. A number of animal models have been devised to study this phenomenon and although none is entirely satisfactory, they have, together with recent advances in molecular biology provided an insight into the cellular mechanisms that may contribute to this complication. This knowledge may ultimately lead to a means of therapeutic intervention. This review summarises our present understanding of the pathology of post-angioplasty re-stenosis as revealed by studies using the balloon catheter de-endothelialization model, and discusses some of the intervention strategies that have been attempted.

X-irradiation attenuates relaxant responses in the rabbit ear artery.

1. The relaxant actions of acetylcholine, substance P and calcitonin gene-related peptide, and the levels of neuropeptide Y and calcitonin gene-related peptide were assessed in the rabbit central ear artery 1, 4 and 6 weeks after a single dose of 45 Gy X-irradiation, a dose similar to that used clinically in intraoperative radiotherapy. 2. Relaxant responses induced by acetylcholine and substance P (both endothelium-dependent) and calcitonin gene-related peptide (endothelium-independent) were reduced, and endogenous neuropeptide Y and calcitonin gene-related peptide levels were unaffected after X-irradiation. 3. The mechanism(s) by which a single dose of 45 Gy X-irradiation may selectively damage relaxant, but not direct, contractile responses of the smooth muscle (as we have shown previously) of the rabbit central ear artery are discussed.

Sympathetic neurotransmission in the rabbit isolated central ear artery is affected as early as one week following a single dose of X-irradiation.

1. The short-term effect of a single dose of 4500 rad X-irradiation on sympathetic neurotransmission (involving both noradrenergic and purinergic components) was assessed in the rabbit central ear artery, 1, 4 and 6 weeks post-irradiation. 2. Neurally mediated contractions were reduced as early as 1 week post-irradiation, with responses to lower frequency stimulation being initially most affected. This suggest that the purinergic component of the contractile response is affected earlier than the adrenergic component. 3. There was no change in the amplitude or sensitivity of treated preparations to the cumulative application of noradrenaline when compared with untreated preparations. In contrast, contractions to alpha, beta-methylene ATP (1 microM), a P2-purinoceptor agonist, were significantly increased at 4 and 6 weeks post-irradiation, although not at 1 week post-irradiation. 4. There were no apparent changes in the pattern of catecholamine fluorescence as a result of irradiation. However, the tissue content of noradrenaline was significantly reduced 6 weeks post-irradiation when compared with control preparations. 5. It is concluded that damage to sympathetic cotransmission is one of the early effects of irradiation, with initial impairment predominantly of the purinergic component.

The effect of atherosclerosis on neuromodulation of sympathetic neurotransmission by neuropeptide Y and calcitonin gene-related peptide in the rabbit mesenteric artery.

The neuromodulatory actions of neuropeptide Y (NPY) (0.1 microM) and calcitonin gene-related peptide (CGRP) (0.01 microM) on nerve-evoked contractions have been studied in the Watanabe heritable hyperlipidemic (WHHL) rabbit mesenteric artery from 4-, 6- and 12-month-old animals with New Zealand white (NZW) rabbits being used as age- and sex-matched controls. Nerve-evoked contractions in 12-month-old rabbits were smaller in WHHL in comparison to NZW rabbits, with no difference between the two strains of rabbit at 4 and 6 months of age. Both the potentiating effect of NPY and the inhibitory effect of CGRP on nerve-evoked contractions increased significantly at 12 months of age compared with responses measured in younger WHHL rabbits, and were greater than in 12-month-old control NZW rabbits. In contrast, the direct smooth muscle relaxant response of CGRP on raised-tone preparations was not different between the two strains of rabbit at any age. Both NPY-immunoreactive and CGRP-immunoreactive nerve fibres were less varicose in 6- and 12-month-old WHHL rabbits when compared with younger WHHL rabbits and NZW controls. In conclusion, this study shows that while nerve-evoked contractions are reduced, in the 12-month-old WHHL rabbit mesenteric artery, the neuromodulatory actions of NPY and CGRP are augmented.

Parental interventions and the development of the preterm infant.

OBJECTIVE: To review the current research on interventions to enhance the development of the preterm infant. DATA SOURCES: Searches were conducted on Medline and CINAHL for the previous 10 years. Classic articles also were included. STUDY SELECTION: Twenty-nine studies focusing on parental interventions were reviewed. CONCLUSION: Modeled interventions for the parent are effective.