What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review.

BACKGROUND: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD). OBJECTIVES: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. METHODS: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. RESULTS: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. CONCLUSIONS: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.

Celiac disease and bone health: is there a gap in the management of postmenopausal osteoporosis?

Malabsorption due to celiac disease (CD) may contribute to postmenopausal osteoporosis. This study aimed to survey participants with CD regarding their bone density, fractures, and bone-preserving medications; to compare tolerance of bone-preserving medications in participants with and without CD; and to review the evidence for CD screening and osteoporosis therapies in the setting of CD. We recruited 131 participants with CD and 102 participants without CD. Of those with CD, 87% were diagnosed in adulthood and 40% had no recognized gastrointestinal symptoms. In 21% CD was diagnosed after the diagnosis of osteoporosis and in 9% after a fracture. No difference was found in the tolerability of bone medications between participants with CD and those without. Review of the literature found that, although monitoring of bone health is recommended for patients with CD, screening for CD is not generally accepted for patients with osteoporosis, although studies of the prevalence of CD in osteoporosis had incomplete ascertainment methods. There is a lack of well-conducted studies and therefore insufficient data for the efficacy and tolerability of bone medication in CD. In conclusion, both CD and menopause lead to bone loss. Identifying CD in postmenopausal women should lead to modification of osteoporosis management.

Position Statement on Atopic Dermatitis in Sub-Saharan Africa: current status and roadmap.

BACKGROUND: The first International Society of Atopic Dermatitis (ISAD) global meeting dedicated to atopic dermatitis (AD) in Sub-Saharan Africa (SSA) was held in Geneva, Switzerland in April 2019. A total of 30 participants were present at the meeting, including those from 17 SSA countries, representatives of the World Health Organization (WHO), the International Foundation for Dermatology (IFD) (a committee of the International League of Dermatological Societies, ILDS www.ilds.org), the Fondation pour la Dermatite Atopique, as well as specialists in telemedicine, artificial intelligence and therapeutic patient education (TPE). RESULTS: AD is one of the most prevalent chronic inflammatory skin diseases in SSA. Besides neglected tropical diseases (NTDs) with a dermatological presentation, AD requires closer attention from the WHO and national Departments of Health. CONCLUSIONS: A roadmap has been defined with top priorities such as access to essential medicines and devices for AD care, in particular emollients, better education of primary healthcare workers for adequate triage (e.g. better educational materials for skin diseases in pigmented skin generally and AD in particular, especially targeted to Africa), involvement of traditional healers and to a certain extent also patient education, bearing in mind the barriers to effective healthcare faced in SSA countries such as travel distances to health facilities, limited resources and the lack of dermatological expertise. In addition, several initiatives concerning AD research in SSA were discussed and should be implemented in close collaboration with the WHO and assessed at follow-up meetings, in particular, at the next ISAD meeting in Seoul, South Korea and African Society of Dermatology and Venereology (ASDV) meeting in Nairobi, Kenya, both in 2020.

Altered walking strategy and increased unsteadiness in participants with impaired glucose tolerance and Type 2 diabetes relates to small-fibre neuropathy but not vitamin D deficiency.

AIMS: To investigate alterations in walking strategy and dynamic sway (unsteadiness) in people with impaired glucose tolerance and people with Type 2 diabetes in relation to severity of neuropathy and vitamin D levels. METHODS: A total of 20 people with Type 2 diabetes, 20 people with impaired glucose tolerance and 20 people without either Type 2 diabetes or impaired glucose tolerance (control group) underwent gait analysis using a motion analysis system and force platforms, and detailed assessment of neuropathy and serum 25 hydroxy-vitamin D levels. RESULTS: Ankle strength (P = 0.01) and power (P = 0.003) during walking and walking speed (P = 0.008) were preserved in participants with impaired glucose tolerance but significantly lower in participants with Type 2 diabetes compared with control participants; however, step width (P = 0.005) and dynamic medio-lateral sway (P = 0.007) were significantly higher and posterior maximal movement (P = 0.000) was lower in participants with impaired glucose tolerance, but preserved in those with Type 2 diabetes compared with the control group. Dynamic medio-lateral sway correlated with corneal nerve fibre length (P = 0.001) and corneal nerve branch density (P = 0.001), but not with vibration perception threshold (P = 0.19). Serum 25 hydroxy-vitamin D levels did not differ significantly among the groups (P = 0.10) and did not correlate with any walking variables or measures of dynamic sway. CONCLUSIONS: Early abnormalities in walking strategy and dynamic sway were evident in participants with impaired glucose tolerance, whilst there was a reduction in ankle strength, power and walking speed in participants with Type 2 diabetes. Unsteadiness correlated with small-, but not large-fibre neuropathy and there was no relationship between vitamin D levels and walking variables.

The developing landscape of diagnostic and prognostic biomarkers for spinal cord injury in cerebrospinal fluid and blood.

STUDY DESIGN: Review study. OBJECTIVES: The identification of prognostic biomarkers of spinal cord injury (SCI) will help to assign SCI patients to the correct treatment and rehabilitation regimes. Further, the detection of biomarkers that predict permanent neurological outcome would aid in appropriate recruitment of patients into clinical trials. The objective of this review is to evaluate the current state-of-play in this developing field. SETTING: Studies from multiple countries were included. METHODS: We have completed a comprehensive review of studies that have investigated prognostic biomarkers in either the blood or cerebrospinal fluid (CSF) of animals and humans following SCI. RESULTS: Targeted and unbiased approaches have identified several prognostic biomarkers in CSF and blood. These proteins associate with cellular damage following SCI and include components from neurons, oligodendrocytes and reactive astrocytes, that is, neurofilament proteins, glial fibrillary acidic protein, Tau and S100 calcium-binding protein ß. Unbiased approaches have also identified microRNAs that are specific to SCI, as well as other cell damage-associated proteins. CONCLUSIONS: The discovery and validation of stable, specific, sensitive and reproducible biomarkers of SCI is a rapidly expanding field of research. So far, few studies have utilised unbiased approaches aimed at the discovery of biomarkers within the CSF or blood in this field; however, some targeted approaches have been successfully used. Several studies using various animal models and some with small human patient cohorts have begun to pinpoint biomarkers in the CSF and blood with putative prognostic value. An increased sample size will be required to validate these biomarkers in the heterogeneous clinical setting.

Introductory anatomy and physiology in an undergraduate nursing curriculum.

Using an educational data mining approach, first-year academic achievement of undergraduate nursing students, which included two compulsory courses in introductory human anatomy and physiology, was compared with achievement in a final semester course that transitioned students into the workplace. We hypothesized that students could be grouped according to their first-year academic achievement using a two-step cluster analysis method and that grades achieved in the human anatomy and physiology courses would be strong predictors of overall achievement. One cohort that graduated in 2014 (n = 105) and one that graduated in 2015 (n = 94) were analyzed separately, and for both cohorts, two groups were identified, these being "high achievers" (HIGH) and "low achievers" (LOW). Consistently, the anatomy and physiology courses were the strongest predictors of group assignment, such that a good grade in these was much more likely to put a student into a high-achieving group. Students in the HIGH groups also scored higher in the Transition to Nursing course when compared with students in the LOW groups. The higher predictor importance of the anatomy and physiology courses suggested that if a first-year grade-point average was calculated for students, an increased weighting should be attributed to these courses. Identifying high-achieving students based on first-year academic scores may be a useful method to predict future academic performance.

Resistance exercise training increases lower limb speed of strength generation during stair ascent and descent in people with diabetic peripheral neuropathy.

AIM: To examine the effects of a 16-week resistance exercise training intervention on the speed of ankle and knee strength generation during stair ascent and descent, in people with neuropathy. METHODS: A total of 43 people: nine with diabetic peripheral neuropathy, 13 with diabetes but no neuropathy and 21 healthy control subjects ascended and descended a custom-built staircase. The speed at which ankle and knee strength were generated, and muscle activation patterns of the ankle and knee extensor muscles were analysed before and after a 16-week intervention period. RESULTS: Ankle and knee strength generation during both stair ascent and descent were significantly higher after the intervention than before the intervention in the people with diabetes who undertook the resistance exercise intervention (P < 0.05). Although muscle activations were altered by the intervention, there were no observable patterns that underpinned the observed changes. CONCLUSIONS: The increased speed of ankle and knee strength generation observed after the intervention would be expected to improve stability during the crucial weight acceptance phase of stair ascent and descent, and ultimately contribute towards reducing the risk of falling. Improvements in muscle strength as a result of the resistance exercise training intervention are likely to be the most influential factor for increasing the speed of strength generation. It is recommended that these exercises could be incorporated into a multi-faceted exercise programme to improve safety in people with diabetes and neuropathy.

People with diabetic peripheral neuropathy display a decreased stepping accuracy during walking: potential implications for risk of tripping.

AIM: To examine the stepping accuracy of people with diabetes and diabetic peripheral neuropathy. METHODS: Fourteen patients with diabetic peripheral neuropathy (DPN), 12 patients with diabetes but no neuropathy (D) and 10 healthy non-diabetic control participants (C). Accuracy of stepping was measured whilst the participants walked along a walkway consisting of 18 stepping targets. Preliminary data on visual gaze characteristics were also captured in a subset of participants (diabetic peripheral neuropathy group: n = 4; diabetes-alone group: n = 4; and control group: n = 4) during the same task. RESULTS: Patients in the diabetic peripheral neuropathy group, and patients in the diabetes-alone group were significantly less accurate at stepping on targets than were control subjects (P < 0.05). Preliminary visual gaze analysis identified that patients diabetic peripheral neuropathy were slower to look between targets, resulting in less time being spent looking at a target before foot-target contact. CONCLUSIONS: Impaired motor control is theorized to be a major factor underlying the changes in stepping accuracy, and potentially altered visual gaze behaviour may also play a role. Reduced stepping accuracy may indicate a decreased ability to control the placement of the lower limbs, leading to patients with neuropathy potentially being less able to avoid observed obstacles during walking.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Frequency, severity and risk factors for urinary and faecal incontinence at 4 years postpartum: a prospective cohort.

OBJECTIVES: To investigate frequency, severity and risk factors for urinary incontinence and faecal incontinence 4 years after a first birth. DESIGN: Prospective pregnancy cohort study. SETTING: Melbourne, Australia. SAMPLE: A total of 1011 nulliparous women recruited in early pregnancy. METHODS: Participants were followed up at 32 weeks of gestation; then at 3, 6, 9 and 12 months and 4 years postpartum. MAIN OUTCOME MEASURES: Frequency and severity of urinary and faecal incontinence. RESULTS: At 4 years, 29.6% of women reported urinary incontinence and 7.1% reported faecal incontinence. Compared with women having only spontaneous vaginal births, women who delivered exclusively by caesarean section were less likely to have urinary incontinence at 4 years postpartum (adjusted odds ratio 0.4, 95% confidence interval 0.3-0.6). Women who reported urinary incontinence before or during the index pregnancy, and those experiencing symptoms in the first year postpartum had increased odds of incontinence at 4 years, with the highest odds (6-12 times higher) among women who had previously reported moderate or severe symptoms. The odds of reporting faecal incontinence at 4 years were two to six times higher for women experiencing symptoms in pregnancy, and around four to eight times higher for those with symptoms in the first year postpartum. CONCLUSION: Urinary and faecal incontinence are prevalent conditions 4 years after a first birth. Women reporting urinary or faecal incontinence during pregnancy had markedly higher odds of reporting symptoms at 4 years postpartum, suggesting a need for further investigation and elucidation of aetiological pathways involving nonbirth-related risk factors. TWEETABLE ABSTRACT: Moderate/severe incontinence prevalent 4 years after first birth in population cohort. Prior symptoms are biggest predictor.

Vulnerability to intimate partner violence and poor mental health in the first 4-year postpartum among mothers reporting childhood abuse: an Australian pregnancy cohort study.

The purpose of this study was to investigate intergenerational patterns of abuse and trauma and the health consequences for women in the early childbearing years. A prospective pregnancy cohort of 1507 nulliparous women (≦24 weeks gestation) were recruited in Melbourne, Australia, 2003-2005. Follow-up was scheduled in late pregnancy, 3-, 6- and 12-month and 4-year postpartum. Childhood abuse was retrospectively reported at 4-year postpartum using the Child Maltreatment History Self Report. Intimate partner violence (IPV) was assessed at 1- and 4-year postpartum with the Composite Abuse Scale. Maternal depressive symptoms were assessed in all follow-ups using the Edinburgh Postnatal Depression Scale. Multivariable logistic regression was used to examine associations between childhood abuse, maternal mental health and IPV. Childhood abuse was reported by 41.1 % of women. In the 4 years after having their first child, 28.2 % of women reported IPV, 25.2 % depression and 31.6 % anxiety. Childhood abuse was associated with odds of depression or anxiety 1.5-2.6 times greater and 1.8-3.2 times greater for IPV. Childhood physical abuse remained significantly associated with depression and anxiety in pregnancy and postpartum after adjusting for IPV and stressful life events, while sexual abuse remained significantly associated only with anxiety. Women who begin childbearing with a history of childhood abuse are more vulnerable to IPV and poor mental health. All health care services and agencies in contact with children, young people and families should have adequate training to identify trauma associated with abuse and IPV and provide first line supportive care and referral.

Identification of translational dermatology research priorities in the U.K.: results of an electronic Delphi exercise.

BACKGROUND: Translational research is the direct application of basic and applied research to patient care. It is estimated that there are at least 2000 different skin diseases; thus, there are considerable challenges in seeking to undertake research on each of these disorders. OBJECTIVES: This electronic Delphi (e-Delphi) exercise was conducted in order to generate a list of translational dermatology research questions that are regarded as a priority for further investigations. METHODS: During the first phase of the e-Delphi exercise, 228 research questions were generated by an expert panel that included clinical academic dermatologists, clinical dermatologists, nonclinical scientists, dermatology trainees and representatives from patient support groups. RESULTS: Following completion of the second and third phases, 40 questions on inflammatory skin disease, 20 questions on structural skin disorders/genodermatoses, 37 questions on skin cancer and eight miscellaneous questions were designated as priority translational dermatology research questions (PRQs). In addition to PRQs on a variety of disease areas (including multiple PRQs on psoriasis, eczema, squamous cell carcinoma and melanoma), there were a number of cross-cutting themes that identified a need to investigate mechanisms/pathogenesis of disease and the necessity to improve treatments for patients with skin disease. CONCLUSIONS: It is predicted that this list of PRQs will help to provide a strategic direction for translational dermatology research in the U.K. and that addressing this list of questions will ultimately provide clinical benefit for substantial numbers of patients with skin disorders.

Dyspareunia and childbirth: a prospective cohort study.

OBJECTIVE: To investigate the relationship between mode of delivery, perineal trauma and dyspareunia. DESIGN: Prospective cohort study. SETTING: Six maternity hospitals in Melbourne, Australia. SAMPLE: A total of 1507 nulliparous women recruited in the first and second trimesters of pregnancy. METHOD: Data from baseline and postnatal questionnaires (3, 6, 12 and 18 months) were analysed using univariable and multivariable logistic regression. MAIN OUTCOME MEASURE: Study-designed self-report measure of dyspareunia at 18 months postpartum. RESULTS: In all, 1244/1507 (83%) women completed the baseline and all four postpartum questionnaires; 1211/1237 (98%) had resumed vaginal intercourse by 18 months postpartum, with 289/1211 (24%) women reporting dyspareunia. Compared with women who had a spontaneous vaginal delivery with an intact perineum or unsutured tear, women who had an emergency caesarean section (adjusted odds ratio [aOR] 2.41, 95% confidence interval [95% CI] 1.4-4.0; P = 0.001), vacuum extraction (aOR 2.28, 95% CI 1.3-4.1; P = 0.005) or elective caesarean section (aOR 1.71, 95% CI 0.9-3.2; P = 0.087) had increased odds of reporting dyspareunia at 18 months postpartum, adjusting for maternal age and other potential confounders. CONCLUSIONS: Obstetric intervention is associated with persisting dyspareunia. Greater recognition and increased understanding of the roles of mode of delivery and perineal trauma in contributing to postpartum maternal morbidities, and ways to prevent postpartum dyspareunia where possible, are warranted.

Maternal depression from early pregnancy to 4 years postpartum in a prospective pregnancy cohort study: implications for primary health care.

OBJECTIVE: To describe the prevalence of maternal depression from pregnancy to 4 years postpartum, and the risk factors for depressive symptoms at 4 years postpartum. DESIGN: Prospective pregnancy cohort study of nulliparous women. SETTING: Melbourne, Australia. SAMPLE: In all, 1507 women completed baseline data in pregnancy (mean gestation 15 weeks). METHODS: Women were recruited from six public hospitals. Questionnaires were completed at recruitment and 3, 6, 12 and 18 months postpartum, and 4 years postpartum. MAIN OUTCOME MEASURES: Scores ≥13 on the Edinburgh Postnatal Depression Scale were used to indicate depressive symptoms. RESULTS: Almost one in three women reported depressive symptoms at least once in the first 4 years after birth. The prevalence of depressive symptoms at 4 years postpartum was 14.5%, and was higher than at any time-point in the first 12 months postpartum. Women with one child at 4 years postpartum were more likely to report depressive symptoms at this time compared with women with subsequent children (22.9 versus 11.3%), and this association remained significant in adjusted models (Adjusted odds ratio 1.71, 95% confidence interval 1.12-2.63). CONCLUSIONS: Maternal depression is more common at 4 years postpartum than at any time in the first 12 months postpartum, and women with one child at 4 years postpartum report significantly higher levels of depressive symptoms than women with subsequent children. There is a need for scaling up of current services to extend surveillance of maternal mental health to cover the early years of parenting.

Tracking undergraduate student achievement in a first-year physiology course using a cluster analysis approach.

A cluster analysis data classification technique was used on assessment scores from 157 undergraduate nursing students who passed 2 successive compulsory courses in human anatomy and physiology. Student scores in five summative assessment tasks, taken in each of the courses, were used as inputs for a cluster analysis procedure. We aimed to group students into high-achieving (HA) and low-achieving (LA) clusters and to determine the ability of each summative assessment task to discriminate between HA and LA students. The two clusters identified in each semester were described as HA (n = 42) and LA (n = 115) in semester 1 (HA1 and LA1, respectively) and HA (n = 91) and LA (n = 42) in semester 2 (HA2 and LA2, respectively). In both semesters, HA and LA means for all inputs were different (all P < 0.001). Nineteen students moved from the HA1 group into the LA2 group, whereas 68 students moved from the LA1 group into the HA2 group. The overall order of importance of inputs that determined group membership was different in semester 1 compared with semester 2; in addition, the within-cluster order of importance in LA groups was different compared with HA groups. This method of analysis may 1) identify students who need extra instruction, 2) identify which assessment is more effective in discriminating between HA and LA students, and 3) provide quantitative evidence to track student achievement.

Altered glycosylation in donor mice causes rejection of strain-matched skin and heart grafts.

Differential protein glycosylation in the donor and recipient can have profound consequences for transplanted organs, as evident in ABO-incompatible transplantation and xenotransplantation. In this study, we investigated the impact of altered fucosylation on graft acceptance by using donor mice overexpressing human α1,2-fucosyltransferase (HTF). Skin and heart grafts from HTF transgenic mice were rapidly rejected by otherwise completely matched recipients (median survival times 16 and 14 days, respectively). HTF skin transplanted onto mice lacking T and B cells induced an natural killer cell-mediated innate rejection crisis that affected 50-95% of the graft at 10-20 days. However, in the absence of adaptive immunity, the residual graft recovered and survived long-term (>100 days). Experiments using "parked" grafts or MHC class II-deficient recipients suggested that indirect rather than direct antigen presentation plays a role in HTF skin graft rejection, although the putative antigen(s) was not identified. We conclude that altered glycosylation patterns on donor tissue can trigger a powerful rejection response comprising both innate and adaptive components. This has potential implications for allotransplantation, in light of increasing recognition of the variability of the human glycome, and for xenotransplantation, where carbohydrate remodeling has been a lynchpin of donor genetic modification.

Does method of birth make a difference to when women resume sex after childbirth?

OBJECTIVE: To investigate the timing of resumption of vaginal sex and assess associations with method of birth, perineal trauma and other obstetric and social factors. DESIGN: Prospective pregnancy cohort study of nulliparous women. SETTING: Melbourne, Australia. SAMPLE: A total of 1507 nulliparous women recruited in early pregnancy (≤24 weeks). METHOD: Women were recruited from six public hospitals. Data from hospital records and self-administered questionnaires at recruitment and 3, 6 and 12 months postpartum were analysed using univariable and multivariable logistic regression. MAIN OUTCOME MEASURE: Resumption of vaginal sex. RESULTS: Sexual activity was resumed earlier than vaginal sex, with 53% resuming sexual activity by 6 weeks postpartum, and 41% attempting vaginal sex. By 8 weeks a majority of women had attempted vaginal sex (65%), increasing to 78% by 12 weeks, and 94% by 6 months. Compared with women who had a spontaneous vaginal birth with an intact perineum, women who had a spontaneous vaginal birth with an episiotomy (adjusted odds ratio 3.43, 95% confidence interval 1.9-6.2) or sutured perineal tear (adjusted odds ratio 3.18, 95% confidence interval 2.1-4.9) were more likely not to have resumed vaginal sex by 6 weeks postpartum. Similarly, women who had an assisted vaginal birth or caesarean section had raised odds of delaying resumption of sex. CONCLUSIONS: Most women having a first birth do not resume vaginal sex until later than 6 weeks postpartum. Women who have an operative vaginal birth, caesarean section or perineal tear or episiotomy appear to delay longer.