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Purpose: To provide a comprehensive, evidence-based overview of the treatment for Dupuytren disease, specifically needle techniques, radiotherapy, primary conservative therapy, surgery, lipofilling, operative arthrolysis, salvage techniques, and the postoperative protocol and to make clinical recommendations for health care practitioners and patients.Methods: Comprehensive multidisciplinary guideline process funded by the Quality Foundation of the Dutch Federation of Medical Specialists. This process included a development, commentary, and authorization phase. Patients participated in every phase. Multiple databases and existing guidelines up to August 2020 were searched. Studies on Dupuytren disease were considered eligible. Specific eligibility criteria were described per module. To appraise the certainty of the evidence, reviewers extracted data, assessed the risk of bias, and used the Grading of Recommendations Assessment, Development and Evaluation method, where applicable. Important considerations were as follows: patient values and preferences, costs, acceptability of other stakeholders, and feasibility of implementation. Recommendations were made based on the evidence from the literature and the considerations. The primary and secondary outcome measures were defined per module based on the input of patients obtained in collaboration with the Netherlands Patient Federation and health care providers from different professions.Results: The following 8 specific modules were completed for Dupuytren disease: (1) needle techniques, (2) radiotherapy, (3) primary conservative therapy, (4) surgery, (5) lipofilling, (6) operative arthrolysis, (7) salvage techniques, and (8) the postoperative protocol.Conclusions: Our Dutch multidisciplinary guideline on Dupuytren disease provides 8 modules developed according to the standards of the Dutch Federation of Medical Specialists. Evidence-based recommendations for clinical practice are provided for needle techniques, radiotherapy, primary conservative therapy, surgery, lipofilling, operative arthrolysis, salvage techniques, and the postoperative protocol. This guideline can assist health care providers and patients in clinical practice.Type of study/level of evidence: Systematic review/I-II.

Background Treatment of locoregionally advanced penile squamous cell carcinoma (LAPSCC) is challenging. The exact role (in terms of oncological benefit) of extensive surgery is not well established. Moreover, surgery invariably leads to large defects requiring reconstructive surgery. Rectus abdominis myocutaneous (RAM) and abdominal advancement flaps have an independent and constant blood supply, are easily harvested, and provide substantial skin coverage and soft tissue. Objective To determine the surgical and oncological outcomes in patients with LAPSCC undergoing surgical resection with RAM flaps. Design, setting, and participants From 2002 to 2016, a multi-institutional database identified 15 LAPSCC patients undergoing flap reconstructions. Intervention Local surgical resection with RAM or abdominal advancement flap reconstruction. Outcome measurements and statistical analysis Perioperative and pathologic data were collected. Postoperative complications were identified using the Clavien-Dindo classification for surgical complications. Results and limitations Fifteen patients (median age 61 yr) were treated, ten with curative intent. Thirteen patients received induction chemotherapy. Thirteen of the 15 patients (87%) experienced wound complications, including five Clavien-Dindo grade III complications. In 11/15 patients (73%), the disease recurred (median recurrence-free interval 106 d). The majority of recurrences (91%) were locoregional, and in four cases the patient also had lesions in distant organs. Ten of the 15 patients (67%) died of their disease. The overall median follow-up interval was 10.5 mo. The study was limited by its retrospective design, the absence of quality-of-life measurements, and the cohort size. Conclusions The results of this study show that surgical resection with reconstruction is associated with a risk of perioperative complications, including high-grade Clavien-Dindo complications. With a cure rate of 27%, surgery must be carefully considered and there is a need for alternative treatments. Lack of robust quality-of-life-data is also a serious shortcoming in the decision process for this patient category. Patient summary Surgery in locoregionally advanced penile cancer has a low cure rate. Reconstruction of defects is surgically feasible, albeit with a high risk of complications. Furthermore, decision-making lacks robust data on quality of life after surgery.

Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to psychiatric morbidity. The aim of the present review is to integrate results from association studies between TPH2 single nucleotide polymorphisms (SNPs) and various psychiatric disorders, which we furthermore quantified with meta-analysis. We reviewed 166 studies investigating 69 TPH2 SNPs in a broad range of psychiatric disorders, including over 30,000 patients. According to our meta-analysis, TPH2 polymorphisms show strongest associations with mood disorders, suicide (attempt) and schizophrenia. Despite small effect sizes, we conclude that TPH2 SNPs in the coding and non-coding areas (rs4570625, rs11178997, rs11178998, rs10748185, rs1843809, rs4290270, rs17110747) are each associated with one or more psychopathological conditions. Our findings highlight the possible common serotonergic mechanisms of the investigated psychiatric disorders. Yet, the functional relevance of most TPH2 polymorphisms is unclear. Characterizing how exactly the different TPH2 variants influence the serotonergic neurotransmission is a next necessary step in understanding the psychiatric disorders where serotonin is implicated.

Despite evidence suggesting that parent involvement was beneficial for infant and parent outcomes, the Family Integrated Care (FICare) programme was one of the first pragmatic approaches to enable parents to become primary caregivers in the neonatal intensive care unit (NICU). We aimed to analyse the effect of FICare on infant and parent outcomes, safety, and resource use.In this multicentre, cluster-randomised controlled trial, we stratified 26 tertiary NICUs from Canada, Australia, and New Zealand by country and size, and assigned them, using a computer-generated random allocation sequence, to provide FICare or standard NICU care. Eligible infants were born at 33 weeks' gestation or earlier, and had no or low-level respiratory support; parents gave written informed consent for enrolment. To be eligible, parents in the FICare group had to commit to be present for at least 6 h a day, attend educational sessions, and actively care for their infant. The primary outcome, analysed at the individual level, was infant weight gain at day 21 after enrolment. Secondary outcomes were weight gain velocity, high frequency breastfeeding (≥6 times a day) at hospital discharge, parental stress and anxiety at enrolment and day 21, NICU mortality and major neonatal morbidities, safety, and resource use (including duration of oxygen therapy and hospital stay). This trial is registered with ClinicalTrials.gov, number NCT01852695.From Oct 1, 2012, 26 sites were randomly assigned to provide FICare (n=14) or standard care (n=12). One site assigned to FICare discontinued because of poor site enrolment. Parents and infants were enrolled between April 1, 2013, and Aug 31, 2015, with 895 infants being eligible in the FICare group and 891 in the standard care group. At day 21, weight gain was greater in the FICare group than in the standard care group (mean change in Z scores -0·071 [SD 0·42] vs -0·155 [0·42]; p0·0002). Average daily weight gain was significantly higher in infants receiving FICare than those receiving standard care (mean daily weight gain 26·7 g [SD 9·4] vs 24·8 g [9·5]; p0·0001). The high-frequency exclusive breastmilk feeding rate at discharge was higher for infants in the FICare group (279 [70%] of 396) than those in the standard care group (394 [63%] of 624; p=0·016). At day 21, parents in the FICare group had lower mean stress scores than did parents in the standard care group (2·3 [SD 0·8] vs 2·5 [0·8]; p0·00043), and lower mean anxiety scores (70·8 [20·1] vs 74·2 [19·9]; p=0·0045). There were no significant differences between groups in the rates of the secondary outcomes of mortality, major morbidity, duration of oxygen therapy, and duration of hospital stay. Although the safety assessment was not completed, there were no adverse events.FICare improved infant weight gain, decreased parent stress and anxiety, and increased high-frequency exclusive breastmilk feeding at discharge, which together suggest that FICare is an important advancement in neonatal care. Further research is required to examine if these results translate into better long-term outcomes for families.Canadian Institutes of Health Research Partnerships for Health System Improvement, and Ontario Ministry of Health and Long-Term Care.

To analyze the recurrence and survival outcomes of glansectomy in patients with penile squamous cell carcinoma.We performed a retrospective review of 410 patients across 5 international tertiary referral centers between 1999 and 2016. All patients had tumors involving the glans penis and underwent glansectomy as primary treatment. The Kaplan-Meier method and log-rank test were used to calculate survival and recurrence. Median follow-up was 42 months (interquartile range [IQR] 29-56).The median age was 64 years (IQR 53-72). Median tumor size was 2.2 cm (IQR 1.5-3.0). A total of 240 patients (58.5%) had pT2 disease, whereas only 43 patients (10.5%) had pT3 or pT4 disease. The majority of the cohort had poorly differentiated tumors (43.7%). Most recurrences were local at 7.6% (31 patients). Only 14 patients (3.4%) had regional recurrence and 9 patients (2.2%) had distant recurrence. When stratified by pathologic stage, tumors that were pT2 or higher were (P .001) and were more likely to be poorly differentiated (P .001). There were no differences in recurrence location among pathologic stages (P = .15). The 1-, 2-, and 5-year recurrence-free survival were 98%, 94%, and 78%, respectively. There were no differences in overall survival when stratified by stage (P = .67).Glansectomy is an oncologically safe treatment modality for squamous cell carcinoma of the glans in appropriately selected invasive tumors.

Introduction We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of sadness, the prevailing mood in major depression (MD), in a prospective, well-documented community sample followed since birth. Methods The children, comprising 136 children (65 boys and 71 girls) of mothers with varying levels of depressive symptomatology, were scanned – using a 1.5-Tesla system – while they watched 5 blocks of both sad and neutral film excerpts. Following scanning, they rated the emotions they experienced, and if they identified sadness, they were also asked to rate its intensity. Results In children whose mothers exhibited higher depressive symptomatology, compared to children whose mothers displayed lower depressive symptomatology, altered neural responses to sad film excerpts were noted in brain regions known to be involved in sadness and MD, notably the insula, anterior cingulate cortex and caudate nucleus, even though the children did not differ in current mood. Limitations Whether this represents genetic vulnerability or a consequence of exposure to maternal depressive symptoms at a young age is unknown. Discussion The results are consistent with the results of studies in healthy adults and MD patients. The present study suggests that an altered pattern of regional brain responses to sad stimuli, is already present in childhood and might represent vulnerability for MD later in life.

Measurement of mid-gestation cervix length has become a common screening tool for preterm birth. Our study was designed to assess the value of cervix length and serum relaxin in the prediction of spontaneous preterm birth at35 and37 weeks' gestation in a general obstetric population.A prospective cohort of women with a singleton pregnancy had blood collected at 24 and 28 weeks' gestation for determination of serum relaxin immediately before transvaginal ultrasound measurement of cervical length. Patients and referring physicians were blinded to cervix length and relaxin levels to preclude changes in management. The primary outcomes were spontaneous delivery at35 and37 weeks' gestation.A total of 1004 women entered the study. Delivery data were not available for 20 women who delivered elsewhere. Twenty women were excluded because preterm delivery was undertaken because of pregnancy abnormalities. Of the 964 women with known gestational age at delivery, 46 (4.8%) delivered at37 weeks and 16 (1.7%) at35 weeks' gestation. Mean cervix length at 28 weeks (36.7 +/- 7.3 mm) was significantly shorter than at 24 weeks (37.8 +/- 7.1 mm) (P0.001). Cervix length at 24 and 28 weeks' gestation was equally predictive of preterm birth. A cervix length ofor = 30 mm at 28 weeks had a sensitivity of 57.1%, a specificity of 81.8%, and a positive predictive value of 4.5% for birth at35 weeks. Serum relaxin levels were not correlated with cervix length at either 24 or 28 weeks. Serum relaxin at 24 and 28 weeks' gestation was not associated with preterm birth before or after controlling for patient characteristics and cervix length.Serum relaxin levels at 24 and 28 weeks' gestation are not associated with preterm birth. Although cervix length is associated with preterm birth, its positive predictive value is low. Given the lack of proven therapies for those at risk, cervix length does not appear to be a useful screening tool for preterm delivery in the general obstetric population.

We have previously reported in vivo preservation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, following treatment with physiological doses of melatonin, in a 6-hydroxydopamine model of Parkinson's disease. Based on these findings, we postulated that melatonin would similarly modulate the expression of TH in vitro. Therefore, using human SH-SY5Y neuroblastoma cells which can differentiate into dopaminergic neurons following treatment with retinoic acid, we first examined whether these cells express melatonin receptors. Subsequently, the physiological dose-dependent effects of melatonin on TH expression were examined in both undifferentiated and differentiated cells. The novel detection of the G protein-coupled melatonin MT(1) receptor in SH-SY5Y cells by RT-PCR was confirmed by sequencing and Western blotting. In addition, following treatment of SH-SY5Y cells with melatonin (0.1-100 nM) for 24h, Western analysis revealed a significant increase in TH protein levels. A biphasic response, with significant increases in TH protein at 0.5 and 1 nM melatonin and a reversal at higher doses was seen in undifferentiated cells; whereas in differentiated cells, melatonin was effective at doses of 1 and 100 nM. These findings suggest a physiological role for melatonin in modulating TH expression, possibly via the MT(1) receptor.

We have reported that valproic acid upregulates melatonin MT1 receptor expression in rat C6 glioma cells. In addition to its anticonvulsant and mood stabilizing properties, valproic acid can also inhibit the growth of cancer cells. Since the melatonin MT1 receptor has been implicated in the oncostatic action of melatonin on human MCF-7 breast cancer cells, the effect of valproic acid on its expression was examined in this cell line. Treatment of MCF-7 cells with valproic acid (0.5 or 1 mM) for 24 or 72 h caused a significant increase in melatonin MT1 receptor mRNA or protein expression, as shown by reverse transcription-polymerase chain reaction (RT-PCR) analysis and western blotting, respectively. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays revealed a concentration-dependent inhibition of MCF-7 cell proliferation by valproic acid (0.5, 1.0 or 5 mM), but melatonin (1 or 10 nM) was ineffective alone or in combination with valproic acid, in the first (MCF-7A) subline examined. However, in subsequent experiments using a different (MCF-7B) subline, which expressed higher levels of MT1 receptor mRNA and showed modest sensitivity to melatonin, a combination of this hormone with valproic acid produced a significant synergistic inhibition of cell proliferation. These findings indicate that clinically relevant concentrations of valproic acid upregulate melatonin MT1 receptor expression in human breast cancer cells. Moreover, the enhanced antiproliferative effect observed with a combination of valproic acid and melatonin suggests that a similar therapeutic approach may be beneficial in breast cancer.

A recently developed technique, based on ultrasonic wave propagation, was applied to study the effect of storage time on the retrogradation process of wheat starch extrudates during storage at room temperature. A specifically designed experimental set-up enabled to propagate in situ ultrasonic waves continuously for several days at constant water content and storage temperature (∼34% water and 25 °C). The velocity and the attenuation of the ultrasonic waves changed as a result of the recrystallisation process of amylopectin molecules of wheat starch samples during storage. The propagation of ultrasonic waves, acting as a dynamic mechanical deformation at high frequency (10 MHz), gave access to the complex longitudinal modulus that, compared to the complex Young modulus obtained from low frequency DMA, enabled a better insight of the changes in viscoelastic behaviour of starch extrudates during retrogradation. The results of the ultrasonic monitoring of starch retrogradation were correlated with those obtained from X-ray diffraction and differential scanning calorimetry. The present study demonstrated the potential of the ultrasonic technique in detecting the changes in physical properties of concentrated starch systems.

Outer-product analysis (OPA) is a method which makes it possible to emphasise co-evolutions of spectral regions in signals obtained for two different domains or even for the same domain. The calculation of the outer-product (OP) matrix, which links the two domains, corresponds to a mutual weighting of the two signals. Many statistical techniques – both univariate and multivariate – can be applied to these matrices to highlight these simultaneous variations. Applying partial least squares (PLS) regression to the OP matrix allows to direct the analysis and to visualise the simultaneous variations associated with a particular evolution of the samples. In this study, OPA is used to characterise the retrogradation of starch by time domain NMR, Fourier transform-MidInfraRed spectroscopy (MIR) and X-ray diffraction (XRD). During the process of retrogradation, the starch evolves from an amorphous state to a semi-crystalline state and this transformation affects these three signals. Three OP matrices are calculated corresponding to two-by-two combinations of the three signals. PLS regression is then performed to predict the retrogradation time. The B -coefficients obtained highlight the simultaneous variations in the pairs of signals as a result of retrogradation. The optimal regression model rank determined by “cross-validation” criterion applied to the B -coefficients vector indicated more components than the Durbin–Watson. Samples with a retrogradation time between 4 and 10 h (phase of the retrogradation process with visible changes in XRD) were characterised by the peak in the MIR spectrum at 998 cm −1 .

The retrogradation of amylopectin in a wheat starch and a wheat starch/gluten (10:1) blend prepared by extrusion and containing 34% water (wet weight basis) was studied using X-ray diffraction, differential scanning calorimetry and NMR relaxometry during storage at constant water content and temperature (25 °C). For both samples, amylopectin ‘fully’ retrograded after ∼2–3 days storage, i.e. the different parameters monitored with time to follow the retrogradation had reached their maximum value, and crystallised predominantly into the A polymorph. Under the experimental conditions used, there was no evidence of any significant effects of the presence of gluten on the kinetics, extent or polymorphism of amylopectin retrogradation.