The complex circumstellar environment of supernova 2023ixf.

The early evolution of a supernova (SN) can reveal information about the environment and the progenitor star. When a star explodes in vacuum, the first photons to escape from its surface appear as a brief, hours-long shock-breakout flare1,2, followed by a cooling phase of emission. However, for stars exploding within a distribution of dense, optically thick circumstellar material (CSM), the first photons escape from the material beyond the stellar edge and the duration of the initial flare can extend to several days, during which the escaping emission indicates photospheric heating3. Early serendipitous observations2,4 that lacked ultraviolet (UV) data were unable to determine whether the early emission is heating or cooling and hence the nature of the early explosion event. Here we report UV spectra of the nearby SN 2023ixf in the galaxy Messier 101 (M101). Using the UV data as well as a comprehensive set of further multiwavelength observations, we temporally resolve the emergence of the explosion shock from a thick medium heated by the SN emission. We derive a reliable bolometric light curve that indicates that the shock breaks out from a dense layer with a radius substantially larger than typical supergiants.

North Pacific freshwater events linked to changes in glacial ocean circulation.

There is compelling evidence that episodic deposition of large volumes of freshwater into the oceans strongly influenced global ocean circulation and climate variability during glacial periods1,2. In the North Atlantic region, episodes of massive freshwater discharge to the North Atlantic Ocean were related to distinct cold periods known as Heinrich Stadials1-3. By contrast, the freshwater history of the North Pacific region remains unclear, giving rise to persistent debates about the existence and possible magnitude of climate links between the North Pacific and North Atlantic oceans during Heinrich Stadials4,5. Here we find that there was a strong connection between changes in North Atlantic circulation during Heinrich Stadials and injections of freshwater from the North American Cordilleran Ice Sheet to the northeastern North Pacific. Our record of diatom δ18O (a measure of the ratio of the stable oxygen isotopes 18O and 16O) over the past 50,000 years shows a decrease in surface seawater δ18O of two to three per thousand, corresponding to a decline in salinity of roughly two to four practical salinity units. This coincided with enhanced deposition of ice-rafted debris and a slight cooling of the sea surface in the northeastern North Pacific during Heinrich Stadials 1 and 4, but not during Heinrich Stadial 3. Furthermore, results from our isotope-enabled model6 suggest that warming of the eastern Equatorial Pacific during Heinrich Stadials was crucial for transmitting the North Atlantic signal to the northeastern North Pacific, where the associated subsurface warming resulted in a discernible freshwater discharge from the Cordilleran Ice Sheet during Heinrich Stadials 1 and 4. However, enhanced background cooling across the northern high latitudes during Heinrich Stadial 3-the coldest period in the past 50,000 years7-prevented subsurface warming of the northeastern North Pacific and thus increased freshwater discharge from the Cordilleran Ice Sheet. In combination, our results show that nonlinear ocean-atmosphere background interactions played a complex role in the dynamics linking the freshwater discharge responses of the North Atlantic and North Pacific during glacial periods.

EuroGuiderm guideline on lichen sclerosus-introduction into lichen sclerosus.

INTRODUCTION: Lichen sclerosus (LS) is an inflammatory skin disease affecting all ages. LS typically involves the anogenital site where it causes itching and soreness. It may lead to sexual and urinary dysfunction in females and males; however, it may be asymptomatic. First signs of LS are redness and oedema, typically followed by whitening of the genital skin; sometimes fissuring, scarring, shrinkage and fusion of structures may follow in its course. LS is associated with an increased risk of genital cancer. LS has a huge impact on the quality of life of affected patients, and it is important to raise more awareness of this not uncommon disease in order to diagnose and treat it early. OBJECTIVES: The guideline intends to provide guidance on the diagnostic of LS, highlight important aspects in the care of LS patients (part 1), generate recommendations and treatment algorithms (part 2) on topical, interventional and surgical therapy, based on the latest evidence, provide guidance in the management of LS patients during pregnancy, provide guidance for the follow-up of patients with LS and inform about new developments and potential research aspects. MATERIALS AND METHODS: The guideline was developed in accordance with the EuroGuiDerm Methods Manual v1.3 https://www.edf.one/de/home/Guidelines/EDF-EuroGuiDerm.html. The wording of the recommendations was standardized (as suggested by the GRADE Working Group). The guideline development group is comprised of 34 experts from 16 countries, including 5 patient representatives. RESULTS: Ultrapotent or potent topical corticosteroids in females and males, adults and children remain gold standard of care for genital LS; co-treatment with emollients is recommended. If standard treatment fails in males, a surgical intervention is recommended, complete circumcision may cure LS in males. UV light treatment is recommended for extragenital LS; however, there is limited scientific evidence. Topical calcineurin inhibitors are second line treatment. Laser treatment, using various wave lengths, is under investigation, and it can currently not be recommended for the treatment of LS. Treatment with biologics is only reported in single cases. CONCLUSIONS: LS has to be diagnosed and treated as early as possible in order to minimize sequelae like scarring and cancer development. Topical potent and ultrapotent corticosteroids are the gold standard of care; genital LS is often a lifelong disease and needs to be treated long-term.

EuroGuiderm guideline on lichen sclerosus-Treatment of lichen sclerosus.

INTRODUCTION: Lichen sclerosus (LS) is an inflammatory skin disease affecting all ages. LS typically involves the anogenital site where it causes itching and soreness; it may lead to sexual and urinary dysfunction in females and males; however, it may be asymptomatic. First signs of LS are usually a whitening of the genital skin, sometimes preceded by redness and oedema; fissuring, scarring, shrinkage and fusion of structures may follow in its course. LS is associated with an increased risk of genital cancer. LS has a huge impact on the quality of life of affected patients, and it is important to raise more awareness of this not uncommon disease in order to diagnose and treat it early. OBJECTIVES: The guideline intends to provide guidance on the diagnostic of LS (part 1), highlight important aspects in the care of LS patients, generate recommendations and treatment algorithms (part 2) on topical, interventional and surgical therapy, based on the latest evidence, provide guidance in the management of LS patients during pregnancy, provide guidance for the follow-up of patients with LS and inform about new developments and potential research aspects. MATERIALS AND METHODS: The guideline was developed in accordance with the EuroGuiDerm Methods Manual v1.3 https://www.edf.one/de/home/Guidelines/EDF-EuroGuiDerm.html. The wording of the recommendations was standardized (as suggested by the GRADE Working Group). The guideline development group is comprised of 34 experts from 16 countries, including 5 patient representatives. RESULTS: Ultrapotent or potent topical corticosteroids in females and males, adults and children remain gold standard of care for genital LS; co-treatment with emollients is recommended. If standard treatment fails in males, a surgical intervention is recommended, complete circumcision may cure LS in males. UV light treatment is recommended for extragenital LS; however, there is limited scientific evidence. Topical calcineurin inhibitors are second line treatment. Laser treatment, using various wave lengths, is under investigation, and it can currently not be recommended for the treatment of LS. Treatment with biologics is only reported in single cases. CONCLUSIONS: LS has to be diagnosed and treated as early as possible in order to minimize sequelae like scarring and cancer development. Topical potent and ultrapotent corticosteroids are the gold standard of care; genital LS is often a lifelong disease and needs to be treated long-term.

Peroperative extent of peritoneal metastases affects the surgical outcome and survival in advanced ovarian cancer.

OBJECTIVE: Determining whether cytoreductive surgery (CRS) is feasible in patients with advanced ovarian cancer and whether extensive surgery is justified is challenging. Accurate patient selection for CRS based on pre- and peroperative parameters will be valuable. The aim of this study is to assess the association between the extent of peritoneal metastases as determined during surgery and completeness of interval CRS and survival. METHODS: This single-center observational cohort study included consecutive patients with newly diagnosed stage III-IV epithelial ovarian cancer who received neoadjuvant chemotherapy and underwent interval CRS. The 7 Region Count (7RC) was recorded during surgical exploration to systematically quantify the extent of peritoneal metastases. Logistic regression analysis was performed to predict surgical outcomes, and Cox regression analysis was done for survival outcomes. RESULTS: A total of 316 patients were included for analyses. The median 7RC was 4 (interquartile range: 2-6). Complete CRS was performed in 58%, optimal CRS in 30%, and incomplete CRS in 12% of patients. A higher 7RC was independently associated with lower odds of complete or optimal CRS in multivariable analysis (odds ratio [OR] = 0.45, 95% confidence interval [CI]: 0.33-0.63, p < 0.001). Similarly, a higher 7RC was independently associated with worse progression-free survival (hazard ratio [HR] = 1.17, 95% CI 1.08-1.26, p < 0.001) and overall survival (HR = 1.14, 95% CI 1.04-1.25, p = 0.007). CONCLUSION: The extent of peritoneal metastases, as expressed by the 7RC during surgery, is an independent predictor for completeness of CRS and has independent prognostic value for progression-free survival and overall survival in addition to completeness of CRS.

iNKT cells are increased in children with severe therapy-resistant asthma.

BACKGROUND: Invariant natural killer T (iNKT) cells play complex functions in the immune system, releasing both Th1 and Th2 cytokines. The role of iNKT cells in human asthma is still controversial and never described in severe therapy-resistant asthma in children. The objective of this work was to analyse iNKT frequency in peripheral blood of children with severe therapy-resistant asthma (STRA), compared to children with milder asthma and healthy controls. METHODS: Children with asthma (n=136) (non-severe and STRA) from a referral centre and healthy controls (n=40) were recruited. Peripheral blood mononuclear cells were isolated, stained with anti-CD3 and anti-iNKT (Vα24Jα18), and analysed through flow cytometry. Atopic status was defined by measuring specific IgE in serum. Airway inflammation was assessed by induced sputum. RESULTS: Children with asthma presented an increased frequency of CD3+iNKT+ cells (median 0.38% IQR 0.18-1.9), compared to healthy controls (median 0.26% IQR 0.10-0.43) (p=0.025). Children with STRA also showed an increased frequency of iNKT cells (1.5% IQR 1.05-2.73) compared to healthy controls and non-severe asthmatic children (0.35% IQR 0.15-1.6; p=0.002). The frequency of iNKT cells was not different between atopic and non-atopic children. In addition, iNKT cells were not associated with any inflammatory pattern of induced sputum studied. CONCLUSION: Our data suggests that iNKT cells play a role in paediatric asthma, which is also associated with the severity of disease, but independent of the atopic status.

Discrepancies in central review re-testing of patients with ER-positive and HER2-negative breast cancer in the OPTIMA prelim randomised clinical trial.

BACKGROUND: There is limited data on results of central re-testing of samples from patients with invasive breast cancer categorised in their local hospital laboratories as oestrogen receptor (ER) positive and human epidermal growth factor receptor homologue 2 (HER2) negative. METHODS: The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) was the feasibility phase of a randomised controlled trial to validate the use of multiparameter assay-directed chemotherapy decisions in the UK National Health Service (NHS). Eligibility criteria included ER positivity and HER2 negativity. Central re-testing of receptor status was mandatory. RESULTS: Of the 431 patients tested centrally, discrepant results between central and local laboratory results were identified in only 19 (4.4%; 95% confidence interval 2.5-6.3%) patients (with 21 tumours). On central review, seven patients had cancers that were ER-negative (1.6%) and 13 (3.0%) patients with 15 tumours had HER2-positive disease, including one tumour discrepant for both biomarkers. CONCLUSIONS: Central re-testing of receptor status of invasive breast cancers in the UK NHS setting shows a high level of reproducibility in categorising tumours as ER-positive and HER2-negative, and raises questions regarding the cost effectiveness and clinical value of central re-testing in this sub-group of breast cancers in this setting.

Termites and large herbivores influence seed removal rates in an African savanna.

Seed removal can influence plant community dynamics, composition, and resulting vegetation characteristics. In the African savanna, termites and large herbivores influence vegetation in various ways, likely including indirect effects on seed predators and secondary dispersers. However, the intensity and variation of seed removal rates in African savannas has seldom been studied. We experimentally investigated whether termites and large herbivores were important factors in the mechanisms contributing to observed patterns in tree species composition on and off mounds, in Lake Mburo National Park, Uganda. Within fenced (excluding large herbivores) and unfenced termite mound and adjacent savanna plots, we placed seeds of nine native tree species within small open "cages," accessed by all animals, roofed cages that only allowed access to small vertebrates and invertebrates, and closed cages that permitted access by smaller invertebrates only (5 mm wire mesh). We found that mean seed removal rate was high (up to 87.3% per 3 d). Mound habitats experienced significantly higher removal rates than off-mound habitats. The mean removal rate of native seeds from closed cages was 11.1% per 3 d compared with 19.4% and 23.3% removed per 3 d in the roofed and open cages, respectively. Smaller seeds experienced higher removal rates than larger seeds. Large herbivore exclusion on mounds reduced native seed removal rates by a mean of 8.8% in the open cages, but increased removal rates by 1.7% in the open cages when off-mound habitats were fenced. While removal rates from open cages were higher on active mounds (30.9%) than on inactive mounds (26.7%), the removal rates from closed cages were lower on active vs. inactive mounds (6.1% vs. 11.6%, respectively). Thus, we conclude that large herbivores and Macrotermes mounds influence seed removal rates, though these effects appear indirect.

Bowel function in patients with urinary diversion: a gender-matched comparison of continent urinary diversion with the ileocecal pouch and ileal conduit.

PURPOSE: To evaluate stool habits and associated quality of life (QoL) in a matched pair analysis of patients who underwent continent cutaneous diversion using the ileocecal segment [Mainz pouch I (MzPI)] with an intussuscepted ileal nipple as efferent segment with those receiving an ileal conduit (IC) after radical cystectomy. METHODS: We identified 250 patients who underwent radical cystectomy and urinary diversion (UD) with either MzPI with an ileal nipple or IC in our database. A detailed history of stool habits using the modified Wexner score was obtained, and questions addressing general lifestyle, comparison of symptom differences before and after surgery considering bowel function as well as bowel-associated QoL were assessed. RESULTS: Forty-five age- and sex-matched pairs could be compared. Overall, stool incontinence (p = 0.481) and the Wexner score (p = 0.464) revealed no differences between both groups. However, patients with MzPI as compared to those with IC had significant higher rates of stool frequency (53 vs 31 %), softer stool consistencies (60 vs 13 %), diarrhea (62 vs 20 %) and a lower rate of constipation (4 vs 22 %). Patients with MzPI had a trend toward lower bowel-associated QoL compared with patients with IC. Similarly, the MzPI group reported a significantly impaired overall postoperative QoL (51 %) compared to the IC group (29 %) (p = 0.024). CONCLUSIONS: Patients following UD by MzPI have an increased stool frequency and softer stool consistency. However, there is no difference between both groups in terms of de novo stool incontinence. Change in bowel habits should be part of preoperative informed consent in any kind of UD. Careful patient selection is of paramount importance.

IL-8/IL-17 gene variations and the susceptibility to severe viral bronchiolitis.

Clinical manifestations of acute bronchiolitis (AB) vary from minimal disease to severe respiratory failure. The response to respiratory viral infections is possibly influenced by genetic polymorphisms linked to the regulation of the inflammatory response. In the present study, we investigated whether interleukin-8 (IL-8) and interleukin-17 (IL-17) genetic variants are associated with the severity of AB. A group of Brazilian infants hospitalized with AB and a control group (infants with no or mild AB, without hospitalization) were genotyped for four IL-8/IL-17 variations. For replication, we studied an Argentinean population sample of infants with mild and severe AB. IL-8 polymorphism (rs 2227543) and IL-17 (rs2275913) variants showed significant associations with the severity of AB. The effect of the IL-8 variation could be replicated in the Argentinean sample. This finding suggests that IL-8 variations may influence the severity of AB in young infants. Further genetic association studies in low- or middle-income populations are necessary with the aim of expanding knowledge in this area.

Immune response of toddlers with history of prematurity.

BACKGROUND: It is not quite well established how immune responses differ in term and preterm infants beyond the first year of life. This study aimed to evaluate aspects of the innate and adaptive immune responses in a group of preterm infants in comparison with their term peers. METHODS: In this cross-sectional study peripheral blood mononuclear cells (PBMC) were isolated from preterm and term children at age three years. Innate immune response was evaluated by the analysis of TLR receptors expression on CD11c+HLADRhigh cells and inflammatory cytokine production after PBMC stimulation with Toll like receptors (TLR) ligands. Adaptive immune response was evaluated by T cells' phenotyping and function after stimulation with polyclonal conventional T cell stimulus. CONCLUSION: We have found that the patterns of innate and adaptive immune responses at 3 years of age were not affected by the fact of the children having being born preterm or at term.

Respiratory syncytial virus induces phosphorylation of mTOR at ser2448 in CD8 T cells from nasal washes of infected infants.

Respiratory syncytial virus (RSV)-specific CD8(+) T cell responses do not protect against reinfection. Activation of mammalian target of rapamycin (mTOR) impairs memory CD8(+) T cell differentiation. Our hypothesis was that RSV inhibits the formation of CD8(+) T cells memory responses through mTOR activation. To explore this, human and mouse T cells were used. RSV induced mTOR phosphorylation at Ser2448 in CD8 T cells. mTOR activation by RSV was completely inhibited using rapamycin. RSV-infected children presented higher mTOR gene expression on nasal washes comparing to children infected with metapneumovirus and rhinovirus. In addition, RSV-infected infants presented a higher frequency of CD8(+) pmTORser2448(+) T cells in nasal washes compared to RSV-negative infants. Rapamycin treatment increased the frequency of mouse CD8 RSV-M282-90 pentamer-positive T cells and the frequency of RSV-specific memory T cells precursors. These data demonstrate that RSV is activating mTOR directly in CD8 T cells, indicating a role for mTOR during the course of RSV infection.

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

Pubic symphysitis after transurethral resection of the prostate.

PURPOSE: Pubic symphysitis (PS) after urological operations is uncommon. This is a systematic single-institution review of patients with transurethral resection of the prostate (TUR-P) with the aim to determine the incidence of PS after TUR-P and to identify a risk profile. MATERIALS AND METHODS: In the past 15 years, 12,118 transurethral operations were performed in our department, 33.4% (n = 4045) were TUR-P, and 84.6% (n = 3421) had routine suprapubic trocar placement. A systematic retrospective analysis identified 12 patients, who developed PS (0.297%). RESULTS: Median age was 69.5 years (64-83). All patients had voiding difficulties. Urine culture had been positive in three cases. All 12 TUR-Ps were monopolar resections, and n = 11 patients had a suprapubic trocar. Median resection weight was 47.5 g (10-100). Two patients had a perforation of the capsule. Histopathological examination revealed chronic prostatitis in nine cases. After 1.0 ± 1.2 months, all patients developed pain in the pubic region. All patients underwent MRI, which suggested PS. Symptomatic and antibiotic medications were administered. Final outcome was resolution of symptoms in all patients after 3.8 ± 5.6 months. No patient retained voiding difficulties. CONCLUSION: PS remains a rare complication after TUR-P. We could not identify a single cause for developing PS. In our study, suprapubic trocar placement (11/12), chronic prostatic inflammation (9/12), previous UTI (3/12) and extended resection (2/12) were overrepresented. Inflammatory, thermic and/or surgical damage of the capsule may be causative. Patients require antibiotic and symptomatic medication. However, prognosis for remission is excellent.

Impact of Pdx1-associated chromatin modifiers on islet ß-cells.

Diabetes mellitus arises from insufficient insulin secretion from pancreatic islet ß-cells. In type 2 diabetes (T2D), ß-cell dysfunction is associated with inactivation and/or loss of transcription factor (TF) activity, including Pdx1. Notably, this particular TF is viewed as a master regulator of pancreas development and islet ß-cell formation, identity and function. TFs, like Pdx1, recruit coregulators to transduce activating and/or repressing signals to the general transcriptional machinery for controlling gene expression, including modifiers of DNA, histones and nucleosome architecture. These coregulators impart a secondary layer of control that can be exploited to modulate TF activity. In this review, we describe Pdx1-recruited coregulators that impact chromatin structure, consequently influencing normal ß-cell function and likely Pdx1 activity in pathophysiological settings.

The relative importance of vertical soil nutrient heterogeneity, and mean and depth-specific soil nutrient availabilities for tree species richness in tropical forests and woodlands.

The relative importance of resource heterogeneity and quantity on plant diversity is an ongoing debate among ecologists, but we have limited knowledge on relationships between tree diversity and heterogeneity in soil nutrient availability in tropical forests. We expected tree species richness to be: (1) positively related to vertical soil nutrient heterogeneity; (2) negatively related to mean soil nutrient availability; and (3) more influenced by nutrient availability in the upper than lower soil horizons. Using a data set from 60, 20 × 40-m plots in a moist forest, and 126 plots in miombo woodlands in Tanzania, we regressed tree species richness against vertical soil nutrient heterogeneity, both depth-specific (0-15, 15-30, and 30-60 cm) and mean soil nutrient availability, and soil physical properties, with elevation and measures of anthropogenic disturbance as co-variables. Overall, vertical soil nutrient heterogeneity was the best predictor of tree species richness in miombo but, contrary to our prediction, the relationships between tree species richness and soil nutrient heterogeneity were negative. In the moist forest, mean soil nutrient availability explained considerable variations in tree species richness, and in line with our expectations, these relationships were mainly negative. Soil nutrient availability in the top soil layer explained more of the variation in tree species richness than that in the middle and lower layers in both vegetation types. Our study shows that vertical soil nutrient heterogeneity and mean availability can influence tree species richness at different magnitudes in intensively utilized tropical vegetation types.

Bacterial extract (OM-85) with human-equivalent doses does not inhibit the development of asthma in a murine model.

BACKGROUND: OM-85 is an immunostimulant bacterial lysate, which has been proven effective in reducing the number of lower airways infections. We investigated the efficacy of the bacterial lysate OM-85 in the primary prevention of a murine model of asthma. METHODS: In the first phase of our study the animals received doses of 0.5µg, 5µg and 50µg of OM-85 through gavage for five days (days -10 to -6 of the protocol), 10 days prior to starting the sensitisation with ovalbumin (OVA), in order to evaluate the results of dose-response protocols. A single dose (5µg) was then chosen in order to verify in detail the effect of OM-85 on the pulmonary allergic response. Total/differential cells count and cytokine levels (IL-4, IL-5, IL-13 and IFN-γ) from bronchoalveolar lavage fluid (BALF), OVA-specific IgE levels from serum, lung function and lung histopathological analysis were evaluated. RESULTS: OM-85 did not reduce pulmonary eosinophilic response, regardless of the dose used. In the phase protocol using 5µg/animal of OM-85, no difference was shown among the groups studied, including total cell and eosinophil counts in BALF, serum OVA-specific IgE, lung histopathologic findings and lung resistance. However, OM-85 decreased IL-5 and IL-13 levels in BALF. CONCLUSIONS: OM-85, administered in early life in mice in human-equivalent doses, does not inhibit the development of allergic pulmonary response in mice.

A molecular genetic time scale demonstrates Cretaceous origins and multiple diversification rate shifts within the order Galliformes (Aves).

The phylogeny of Galliformes (landfowl) has been studied extensively; however, the associated chronologies have been criticized recently due to misplaced or misidentified fossil calibrations. As a consequence, it is unclear whether any crown-group lineages arose in the Cretaceous and survived the Cretaceous-Paleogene (K-Pg; 65.5 Ma) mass extinction. Using Bayesian phylogenetic inference on an alignment spanning 14,539 bp of mitochondrial and nuclear DNA sequence data, four fossil calibrations, and a combination of uncorrelated lognormally distributed relaxed-clock and strict-clock models, we inferred a time-calibrated molecular phylogeny for 225 of the 291 extant Galliform taxa. These analyses suggest that crown Galliformes diversified in the Cretaceous and that three-stem lineages survived the K-Pg mass extinction. Ideally, characterizing the tempo and mode of diversification involves a taxonomically complete phylogenetic hypothesis. We used simple constraint structures to incorporate 66 data-deficient taxa and inferred the first taxon-complete phylogenetic hypothesis for the Galliformes. Diversification analyses conducted on 10,000 timetrees sampled from the posterior distribution of candidate trees show that the evolutionary history of the Galliformes is best explained by a rate-shift model including 1-3 clade-specific increases in diversification rate. We further show that the tempo and mode of diversification in the Galliformes conforms to a three-pulse model, with three-stem lineages arising in the Cretaceous and inter and intrafamilial diversification occurring after the K-Pg mass extinction, in the Paleocene-Eocene (65.5-33.9 Ma) or in association with the Eocene-Oligocene transition (33.9 Ma).

Resource utilization and productivity loss in persons with spina bifida­an observational study of patients in a tertiary urology clinic in Germany.

BACKGROUND AND PURPOSE: To investigate resource use and burden associated with spina bifida (SB) in Germany. METHODS: A questionnaire was used to obtain information on SB-related healthcare resource use and assistive technologies used for the last 1 and 10 years. Individuals with SB were recruited at a tertiary specialist clinic. To participate, persons with SB required the cognitive ability to respond or a caregiver to answer questions on their behalf. They could use personal medical charts or other records to answer. The analyses included assessment of frequency and extent of resource use for both time frames. RESULTS: Data on 88 persons with a diagnosis of SB were collected (44% female). During the last year, 88.6% (N = 78) reported at least one visit to a general practitioner's (GP's) office, 77.3% (N = 68) to a urologist and 69.3% (N = 61) to a physiotherapist. The annual average number of visits was 7.6 GP, 3.6 urologist and 65.3 physiotherapist visits. Amongst those hospitalized, a single hospitalization lasted 7.3 days on average, whereas the average annual number of hospital days was 14.8 days. During the previous 10 years, 67.0% (N = 59) of responders used a wheelchair, 64.7% (N = 57) used glasses and 59.1% (N = 52) used orthopaedic shoes, with an average of 2.5, 2.8 and 6.1 new items used, respectively. CONCLUSIONS: The results indicate that persons with SB require a substantial amount of interaction with healthcare providers, as well as other healthcare-related resource use, both in the shorter and longer terms.