Surgical sequence, timing and volume, and variation in dento-facial outcome, speech and secondary surgery in children with unilateral cleft lip and palate: The Cleft Care UK Study.

OBJECTIVES: To estimate both the association of surgical variables in complete unilateral cleft lip and palate (cUCLP) in the UK with outcomes at age 5 years, and the association of secondary speech surgery, volume of surgery, and surgeon with the same outcomes. SETTING AND SAMPLE POPULATION: The Cleft Care UK study, a cross-sectional study of 268 5-year-olds, born from 2005 to 2007, with cUCLP. MATERIALS AND METHODS: Information on surgical variables was extracted from a standardized questionnaire. Dento-facial outcomes were derived from dental study casts of dental arch relationships. Three speech outcomes - intelligibility, structure and articulation - were derived using the Cleft Audit Protocol for Speech-Augmented tool. RESULTS: Surgical and outcome data were available for 211 (79%) children from all cleft centres in the UK. Later soft palate surgery was associated with a 17% increased chance of a poor intelligibility score (P = .02), and high volume surgery with a 249% increased chance of a good articulation score (P = .01). There were no between surgeon effects identified. No association between the surgical variables examined and dento-facial outcome, or secondary speech surgery by the age of 5 years were found. CONCLUSION: This study found associations between surgical variables and speech outcomes at 5 years of age, but not between surgical variables and dento-facial outcome, nor between surgical variables and secondary speech surgery. High surgical volume should be maintained, and any changes towards later surgery monitored for changes in speech outcome.

The use of biomarkers and HPV genotyping to improve diagnostic accuracy in women with a transformation zone type 3.

BACKGROUND: Twenty percent of women referred to colposcopy have a type 3 transformation zone-where colposcopic assessment for high-grade dysplasia (CIN2+) is not possible. This study examines the effectiveness of HPV biomarkers and genotyping in combination with techniques that sample an endocervical TZ. METHODS: A prospective diagnostic accuracy study. Women booked for large-loop excision (LLETZ) with squamous dyskaryosis, high-risk HPV and a TZ3 were recruited. Immediately prior to LLETZ samples were collected for p16/Ki-67 dual-stained cytology, HPV genotyping and H&E, p16- and Ki-67-stained endocervical curettings. RESULTS: In women with low-grade screening (n = 64), 35.9% had CIN2+; dual-stained cytology had the greatest effect on the PPV of routine screening (76.1% vs 35.9%) and perfectly predicted the absence of CIN2+. In women with a high-grade screening result (n = 37); 75.6% had CIN2+ and dual-stained curettings improved the PPV (96.5 vs 75.6%). CONCLUSIONS: With high-grade screening and a TZ3, LLETZ appears safest as three quarters have CIN2+ . Women with low-grade screening and a TZ3 have a twofold increased risk of CIN2+ when compared to women where the TZ is visible. The use of dual-stained cytology may help identify those women who can be safely offered surveillance and those who require treatment.

The impact of changing cigarette smoking habits and smoke-free legislation on orofacial cleft incidence in the United Kingdom: Evidence from two time-series studies.

BACKGROUND: Both active and passive cigarette smoking have previously been associated with orofacial cleft aetiology. We aimed to analyse the impact of declining active smoking prevalence and the implementation of smoke-free legislation on the incidence of children born with a cleft lip and/or palate within the United Kingdom. METHODS AND FINDINGS: We conducted regression analysis using national administrative data in the United Kingdom between 2000-2018. The main outcome measure was orofacial cleft incidence, reported annually for England, Wales and Northern Ireland and separately for Scotland. First, we conducted an ecological study with longitudinal time-series analysis using smoking prevalence data for females over 16 years of age. Second, we used a natural experiment design with interrupted time-series analysis to assess the impact of smoke-free legislation. Over the study period, the annual incidence of orofacial cleft per 10,000 live births ranged from 14.2-16.2 in England, Wales and Northern Ireland and 13.4-18.8 in Scotland. The proportion of active smokers amongst females in the United Kingdom declined by 37% during the study period. Adjusted regression analysis did not show a correlation between the proportion of active smokers and orofacial cleft incidence in either dataset, although we were unable to exclude a modest effect of the magnitude seen in individual-level observational studies. The data in England, Wales and Northern Ireland suggested an 8% reduction in orofacial cleft incidence (RR 0.92, 95%CI 0.85 to 0.99; P = 0.024) following the implementation of smoke-free legislation. In Scotland, there was weak evidence for an increase in orofacial cleft incidence following smoke-free legislation (RR 1.16, 95%CI 0.94 to 1.44; P = 0.173). CONCLUSIONS: These two ecological studies offer a novel insight into the influence of smoking in orofacial cleft aetiology, adding to the evidence base from individual-level studies. Our results suggest that smoke-free legislation may have reduced orofacial cleft incidence in England, Wales and Northern Ireland.

Range and timing of surgery, and surgical sequences used, in primary repair of complete unilateral cleft lip and palate: The Cleft Care UK study.

OBJECTS: To describe the range of surgery used to repair the lip and palate in the UK with specific interest in the sequence/timing used in complete unilateral cleft lip and palate (cUCLP). SETTING AND SAMPLE POPULATION: The Cleft Care UK study, a cross-sectional study of 268 5-year-olds, born from 2005 to 2007, with complete unilateral cleft lip and palate. MATERIALS & METHODS: Information on surgery was extracted from medical notes by surgeons during research clinics and transcribed onto a standardized questionnaire. RESULTS: Surgical data were available for 251 (94%) children from all cleft centres in the UK (n = 18). Over a two-year period, 32 surgeons used 10 different surgical sequences in primary repair of the cleft lip and palate. The most frequently used sequence was repair of cleft lip and anterior hard palate followed by repair of posterior hard palate and soft palate (70%). Four surgical sequences were used only once. Most surgeons had a preferred sequence, but 38% (11/29) used more than one sequence during the study period. The timing of repair of the lip, the hard palate and the soft palate varied with surgical sequence, and also between surgeons, even adjusting for the different sequences used. CONCLUSION: Despite centralization of cleft services in the UK, there remains considerable variation in both the sequence and timing of surgical repair of cleft lip and palate in infancy. Further work is required to understand whether these factors are associated with differences in outcome.

Comparison of the Cervex-Brush alone to Cytobrush plus Cervex-Brush for detection of cervical dysplasia in women with a transformation zone type 3.

INTRODUCTION: Twenty percent of colposcopic assessments are inadequate due to a type 3 transformation zone (TZ3). In the absence of colposcopic or histological assessment, subsequent management is guided by the referral screening test. In the UK, routine cervical screening is completed by a Cervex-Brush alone. This study examines the effectiveness of a Cytobrush in addition to a standard Cervex-Brush when used in TZ3 assessment. METHODOLOGY: An 18-month diagnostic accuracy study in a single National Health Service (NHS) Trust. Women with a TZ3 booked for large loop excision of the transformation zone (LLETZ) with a referral cytology of high-risk HPV and squamous dyskaryosis were recruited. Immediately prior to LLETZ, a Cervex-Brush plus Cytobrush liquid-based cytology sample was taken. Presence of endocervical cells was compared. Predictability of high-grade cervical intra-epithelial neoplasia (CIN2+) was by blind standardised reporting of the LLETZ histology. RESULTS: One hundred and five women were recruited from a total eligible population of 153 cases (68.8%). Endocervical cell yield was increased with the Cervex-Brush plus Cytobrush when compared to the Cervex-Brush alone (99.1% vs 79.1%, P < .001). Irrespective of cytological grade, age or parity, there was no difference in predictability of CIN2+ between sampling methods. CONCLUSIONS: When compared to Cervex-Brush sampling alone, the addition of a Cytobrush improves endocervical sampling but does not improve cytological predictability of CIN2+ in women with a TZ3. These data suggest that women who will reliably attend for cytological follow-up can be safely referred to primary care for a Cervex-Brush alone.

Hidden magnetic order in plutonium dioxide nuclear fuel.

A thorough understanding of the chemistry of PuO2 is critical to the design of next-generation nuclear fuels and the long-term storage of nuclear materials. Despite over 75 years of study, the ground-state magnetic structure of PuO2 remains a matter of much debate. Experimental studies loosely indicate a diamagnetic (DM) ground-state, whereas theoretical methods have proposed either a collinear ferromagnetic (FM) or anti-ferromagnetic (AFM) ground-state, both of which would be expected to cause a distortion from the reported Fm3[combining macron]m symmetry. In this work, we have used accurate calculations based on the density functional theory (DFT) to systematically investigate the magnetic structure of PuO2 to resolve this controversy. We have explicitly considered electron-correlation, spin-orbit interaction and noncollinear magnetic contributions to identify a hereto unknown longitudinal 3k AFM ground-state that retains Fm3[combining macron]m crystal symmetry. Given the broad interest in plutonium materials and the inherent experimental difficulties of handling this compound, the results presented in this paper have considerable implications for future computational studies relating to PuO2 and related actinide structures. As the crystal structure is coupled by spin-orbit interactions to the magnetic state, it is imperative to consider relativity when creating computational models.

Adherence to the New Nordic Diet during pregnancy and subsequent maternal weight development: a study conducted in the Norwegian Mother and Child Cohort Study (MoBa).

The rising prevalence of overweight and obesity is a worldwide public health challenge. Pregnancy and beyond is a potentially important window for future weight gain in women. We investigated associations between maternal adherence to the New Nordic diet (NND) during pregnancy and maternal BMI trajectories from delivery to 8 years post delivery. Data are from the Norwegian Mother and Child Cohort. Pregnant women from all of Norway were recruited between 1999 and 2008, and 55 056 are included in the present analysis. A previously constructed diet score, NND, was used to assess adherence to the diet. The score favours intake of Nordic fruits, root vegetables, cabbages, potatoes, oatmeal porridge, whole grains, wild fish, game, berries, milk and water. Linear spline multi-level models were used to estimate the association. We found that women with higher adherence to the NND pattern during pregnancy had on average lower post-partum BMI trajectories and slightly less weight gain up to 8 years post delivery compared with the lower NND adherers. These associations remained after adjustment for physical activity, education, maternal age, smoking and parity (mean diff at delivery (high v. low adherers): -0·3 kg/m2; 95 % CI -0·4, -0·2; mean diff at 8 years: -0·5 kg/m2; 95 % CI -0·6, -0·4), and were not explained by differences in energy intake or by exclusive breast-feeding duration. Similar patterns of associations were seen with trajectories of overweight/obesity as the outcome. In conclusion, our findings suggest that the NND may have beneficial properties to long-term weight regulation among women post-partum.

Evaluation of variables influencing success and complication rates in canine total hip replacement: results from the British Veterinary Orthopaedic Association Canine Hip Registry (collation of data: 2010-2012).

The objective of this study was to assess the variables associated with complications of total hip replacement (THR) and report owner-assessed outcomes. Entries into the British Veterinary Orthopaedic Association-Canine Hip Registry (BVOA-CHR) between September 2011 and December 2012 were reviewed separately and in conjunction with previous data (January 2010-August 2011). An outcomes assessment questionnaire was used to collect data from owners. Incidences of surgeon-reported and owner-reported complications were 8.2 per cent and 4.3 per cent, respectively. THR using the BioMedtrix BFX cup/stem prosthesis had a greater incidence of complications compared with THR using the BioMedtrix CFX cup/stem prosthesis (P=0.002); complications were 4.48 times more likely when using the BioMedtrix BFX cup/stem prosthesis versus the BioMedtrix CFX cup/stem prosthesis. THR using the BioMedtrix BFX cup/stem prosthesis had a higher incidence of complications compared with THR using a hybrid prosthesis (BioMedtrix BFX cup/CFX stem, BioMedtrix CFX cup/BFX stem) (P=0.046); complications were 2.85 times more likely when using the BioMedtrix BFX cup/stem prosthesis versus a hybrid prosthesis. In 95 per cent of cases, owner satisfaction with the outcome of THR was 'very good' or 'good'. Complication rates from the BVOA-CHR are similar to previous studies. The data suggest that prosthesis type is associated with complication rate, with BioMedtrix BFX (circa 2012) having a high short-term complication rate.

Stem Cells in the Trabecular Meshwork for Regulating Intraocular Pressure.

Intraocular pressure (IOP) is still the main treatment target for glaucoma. Outflow resistance mainly exists at the trabecular meshwork (TM) outflow pathway, which is responsible for IOP regulation. Changes of TM cellularity and TM extracellular matrix turnover may play important roles in IOP regulation. In this article, we review basic anatomy and physiology of the outflow pathway and TM stem cell characteristics regarding the location, isolation, identification and function. TM stem cells are localized at the insert region of the TM and are label-retaining in vivo. They can be isolated by side-population cell sorting, cloning culture, or sphere culture. TM stem cells are multipotent with the ability to home to the TM region and differentiate into TM cells in vivo. Other stem cell types, such as adipose-derived stem cells, mesenchymal stem cells and induced pluripotent stem cells have been discovered for TM cell differentiation and TM regeneration. We also review glaucomatous animal models, which are suitable to study stem cell-based therapies for TM regeneration.

Environmental Tobacco Smoke Exposure in Pregnancy is Associated With Earlier Delivery and Reduced Birth Weight.

The association between maternal smoking and preterm birth (PTB) has been known for more than 50 years but the effect of passive smoking is controversial. This retrospective cohort study in Bristol, United Kingdom, examines the effect of environmental tobacco smoke exposure (ETSE) on gestational age at delivery, birth weight, PTB, and being small-for-gestational age (SGA). Environmental tobacco smoke exposure was defined by either self-report or exhaled carbon monoxide (eCO) levels, and exposed women were compared with unexposed controls. Two models were used: The first included all women with adjustment for maternal smoking, and the second considered nonsmokers alone. Both models were further adjusted for maternal age, body mass index, parity, ethnicity, employment status, socioeconomic position, asthma, preeclampsia, and offspring sex. Logistic regression and likelihood ratio tests were used to test for any association between exposure and the binary outcomes (PTB and SGA), while linear regression and F tests were used to test for associations between exposure and the continuous outcomes. There were 13 359 deliveries in 2012 to 2014, with complete data for 5066 and 4793 women in the self-reported and eCO-measured exposure groups, respectively. Self-reported exposure was associated with earlier delivery (-0.19 weeks; 95% confidence interval [CI]: -0.32 to -0.05) and reduced birth weight (-56 g, 95% CI: -97 to -16 g) but no increase in the risk of PTB or SGA. There was no evidence for an association between eCO-measured exposure and any of the outcome measures. This information is important when advising women and their families and adds further support to continued public health efforts to reduce exposure to tobacco smoke.

Do repeated risk factor measurements influence the impact of education on cardiovascular mortality?

OBJECTIVE: It has been questioned if the excess cardiovascular disease (CVD) mortality by lower educational level can be fully explained by conventional modifiable CVD risk factors. Our objective was to examine whether repeated measures over time of risk factors (smoking, physical inactivity, blood pressure, total cholesterol and body mass index) explain more of the socioeconomic gradient in CVD mortality than if they are measured only once. METHODS: A cohort of 34 884 men and women attended all three screenings (1974-1978, 1977-1983 and 1985-1988) in the Norwegian Counties Study and were followed for CVD mortality through 2009 by linkage to the Norwegian Cause of Death Registry. RESULTS: Age-adjusted and sex-adjusted HR of CVD mortality was 2.32 (95% CI 1.93 to 2.80) for basic relative to tertiary educated individuals. The HR was attenuated by 48% (HR 1.54 (1.28 to 1.87)) when adjusted for CVD risk factors measured at baseline and by 56% (HR 1.45 (1.20 to 1.75)) when two repeated measurements ascertained 5 years apart were added to the model. Similarly, absolute risk difference in CVD mortality by education was attenuated by 62% when adjusted for baseline and by 72% when adjusted for repeated measurements of risk factors. CONCLUSIONS: In this cohort, repeated measurements of risk factors seemed to explain more of the educational gradient in CVD mortality. This suggests that a substantial part of the excess CVD mortality among those with lower education might be explained by conventional risk factors.

Skin pigmentation, sun exposure and vitamin D levels in children of the Avon Longitudinal Study of Parents and Children.

BACKGROUND: It has been hypothesised that light skin pigmentation has arisen to ensure adequate levels of vitamin D as human populations moved out of Africa and into higher latitudes. Vitamin D, which is primarily obtained through exposure to sunlight (specifically ultraviolet radiation B (UVR-B)), has been inversely associated with several complex diseases. Greater sun exposure, on the other hand, is a well-known cause of skin cancer. The potential of UVR to be beneficial for some health outcomes but detrimental for others has prompted a public health debate on how to balance the positive and negative consequences of sun exposure. In this study we aimed to determine the validity of the evolutionary hypothesis linking lighter skin with higher vitamin D concentrations in a European population. Additionally, we aimed to examine the influence of pigmentation on personal behaviour towards sunlight exposure and the effects of this behaviour on vitamin D. METHODS: We combined genetic variants strongly associated with skin colour, tanning or freckling to create genetic scores for each of these phenotypes. We examined the association of the scores with pigmentary traits, sun exposure and serum 25-hydroxyvitamin D (25(OH)D) levels among children of the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 661 to 5649). RESULTS: We found that fairer-skinned children, i.e. those with higher pigmentation score values, had higher levels of 25(OH)D (0.6 nmol/l; 95% CI 0.2, 1.0; per unit increase in skin colour score; N = 5649). These children also used more protection against the damaging effects of UVR. CONCLUSIONS: In this population taking protective measures against sunburn and skin cancer does not seem to remove the positive effect that having a less pigmented skin has on vitamin D production. Our findings require further replication as skin pigmentation showed only a small effect on circulating 25(OH)D.

Complications and owner assessment of canine total hip replacement: a multicenter internet based survey.

OBJECTIVE: To assess the variables associated with the complications of total hip replacement (THR) and report owner-assessed outcomes, through surgeon-based registration of cases via an online database, informed owner consent, and prospective outcomes assessment using a client-administered clinical metrology instrument. STUDY DESIGN: Prospective case series ANIMALS: Dogs (n = 170) METHODS: Entries into the British Veterinary Orthopaedic Association-Canine Hip Registry (BVOA-CHR) between January 2010 and August 2011 were reviewed. Variables evaluated included dog age, body weight, breed, and indication for THR and prosthesis. Associations between each variable and the incidence of complications were assessed using logistic regression. Additionally, an on-line, owner-administered outcomes assessment questionnaire (modified from the Liverpool Osteoarthritis in Dogs (LOAD) questionnaire) was used to collect data from owners. RESULTS: One hundred and seventy cases met the inclusion criteria. Surgical indications included hip dysplasia and coxofemoral osteoarthritis (n = 150), Legg-Calves-Perthes disease (7), coxofemoral luxation (6), fracture (4), slipped capital physis (2), and femoral head and neck ostectomy revision (1). Surgical implants were from 4 systems. The incidence of surgeon-reported complication was 9.4%. No significant association was identified between weight, age, sex, breed, indication for THR, surgical technique and prosthesis, and the incidence of complications. In 82% of the cases, owners described their satisfaction with the outcome of THR as "very good" and a total of 20% complication rate was reported. There was a statistically significant improvement in owner-assessed questionnaire score before and after THR (P < .001). CONCLUSIONS: The BVOA-CHR offers a novel framework for the prospective studies on THR and on a national/international scale. Initial complication rates from the BVOA-CHR are similar to previous studies.

Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase.

Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K(i) = 2 µM.