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Objective: Individuals with 45,X/46,XY or 46,XY gonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone (AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. Design, Patients and Measurements: Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999–2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. Results: Thirteen males and 16 females were included, 20 with 46,XY and 9 with 45,X/46,XY DSD. Three females had dysgerminoma alongside gonadoblastoma; two gonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. Conclusions: Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XY or 46,XY gonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

Background & objectives: The comparison of the incidence of gonadal germ cell tumors among males and females can provide insights that cannot be gained by separately studying these tumors. Material and methods: Incidence data on male and female gonadal germ cell tumors were drawn from the cancer registries of North Rhine-Westphalia, Germany, and the United States Surveillance, Epidemiology and End Results program, for non-Hispanic White persons only, for the years 2008–2016. We estimated age-standardized and age-, and histology-specific incidence rates. Results: We included 21,840 male and 716 female gonadal germ cell tumors. Incidence rates among males were higher in Germany (95.8 per million, standard error [SE] 1.1) than in the United States (68.0, SE 0.6), while incidence rates among females were lower in Germany (1.9, SE 0.2) than in the United States (2.6, SE 0.1). The characteristic peak of infantile (age 0–4 years) germ cell tumors among males were missing among females. The age peak of ovarian germ cell tumors occurred 15–20 years earlier (Germany: 10–14 years, United States: 15–19 years) than the age peak of testicular germ cell tumors (30–34 years). The three most common testicular germ cell tumors histologies were seminoma, mixed germ cell tumors, and embryonal carcinoma Among females, the three most common ovarian germ cell tumors histologies were teratoma, yolk sac tumor, monodermal teratomas, and somatic-type tumors arising from dermoid cysts in both countries. Discussion: The characteristic peak of infantile (age 0–4 years) germ cell tumors among males was missing among females. The shapes of the age-specific incidence curves are similar for males and females in Germany and the United States, though with much lower incidence rates in females, suggesting a common pathogenesis. Conclusion: The lower rates among females may be due to the lower number of initiated tumors in the absence of the Y-chromosome, and the earlier peak among females may be due to a younger age at puberty.

Staphylococcus aureus generates biofilms during many chronic human infections, which contributes to its growth and persistence in the host. Multiple genes and pathways necessary for S. aureus biofilm production have been identified, but knowledge is incomplete, and little is known about spontaneous mutations that increase biofilm formation as infection progresses.

Objective Suprainguinal re-resection of the proximal nerve stump can be performed in case of persistent or recurrent symptoms of meralgia paresthetica after previous transection of the lateral femoral cutaneous nerve (LFCN). Currently, no long-term results for this procedure have been reported in the literature. Methods In this study, 20 consecutive patients with persistent (13 cases) or recurrent (7 cases) symptoms of meralgia paresthetica were reoperated at a mean interval of 16 months after the first transection of the LFCN. The proximal nerve stump was sent for histopathologic analysis of a potential traumatic neuroma. Outcome was assessed using a 5-point Likert scale, which was obtained at a mean interval of 3.5 years after the suprainguinal re-resection. Results The proximal stump of the LFCN was identified in 90% of the cases. Successful pain relief (Likert 1 or 2) was obtained in 65% of the patients. A neuroma was found in 11 cases (55%), mostly in recurrent cases after a pain-free interval. The indication for recurrence of symptoms more frequently resulted in successful pain relief (71%) compared with results for the indication for persistence of symptoms (62%). There was no correlation between the presence of a neuroma and the chance for pain relief. Conclusions Suprainguinal re-resection of the LFCN can be a successful procedure, both for persistence and recurrence of symptoms of meralgia paresthetica after previous transection, with long-lasting pain relief. Several factors, however, should be considered before performing this relatively new technique in patients that are discussed in this article.

Defects may display high reactivity because the specific arrangement of atoms differs from crystalline surfaces. We demonstrate that high-temperature steam pretreatment of palladium catalysts provides a 12-fold increase in the mass-specific reaction rate for carbon-hydrogen (C–H) activation in methane oxidation compared with conventional pretreatments. Through a combination of experimental and theoretical methods, we demonstrate that an increase in the grain boundary density through crystal twinning is achieved during the steam pretreatment and oxidation and is responsible for the increased reactivity. The grain boundaries are highly stable during reaction and show specific rates at least two orders of magnitude higher than other sites on the palladium on alumina (Pd/Al

We investigate the inkjet printing of liquid silicon ink to form in situ doped and structured passivating contacts. The ink consists of neopentasilane oligomers in solvents and decomposes into amorphous silicon with a short anneal. By printing boron- and phosphorus-doped ink on silicon oxide, polycrystalline silicon on oxide (POLO) junctions for both p-type and n-type polarities (POLO²) are formed and the saturation current densities as low as 5 fA/cm2 are achieved for n+-POLO junctions. We perform a structured printing in interdigitated back contact (IBC) geometry achieving emitter and base fingers with an average finger height of up to 103 nm. The application of inkjet printing allows for a simplification of POLO and POLO2 solar cell processing. In particular, for POLO2-IBC cells, a lean process flow is facilitated.

Rationale: Staphylococcus aureus is the most common respiratory pathogen isolated from patients with cystic fibrosis (CF) in the United States. Although modes of acquisition and genetic adaptation ...

Summary Background Staphylococcus aureus is the bacterium cultured most often from respiratory secretions of people with cystic fibrosis. Both meticillin-susceptible S aureus and meticillin-resistant S aureus (MRSA) can adapt to form slow-growing, antibiotic-resistant isolates known as small-colony variants that are not routinely identified by clinical laboratories. We aimed to determine the prevalence and clinical significance of S aureus small-colony variants and their subtypes among children with cystic fibrosis. Methods The Small Colony Variant Staphylococcus aureus (SCVSA) study was a 2-year longitudinal study of children aged 6–16 years at five US cystic fibrosis centres, using culture methods sensitive for small-colony variants. Children were eligible if they had a documented diagnosis of cystic fibrosis and a minimum of two cystic fibrosis clinic visits and two respiratory cultures in the previous 12 months at enrolment. Participants attended clinic visits quarterly, at which respiratory tract samples were taken and measures of lung function (percentage of predicted forced expiratory volume in 1 s [FEV1] and frequency of respiratory exacerbations) were recorded. We determined the prevalence of small-colony variants and their subtypes, and assessed their independent associations with lung function and respiratory exacerbations using linear mixed-effects and generalised estimating equation logistic regression models. Analyses included both univariate models (unadjusted) and multivariate models that adjusted for potential confounders, including age, sex, race, baseline microbiology, treatment with CFTR modulator, and CTFR genotype. Findings Between July 1, 2014, and May 26, 2015, we enrolled 230 children. Participants were followed-up for 2 years, with a mean of 6·4 visits (SD 1·14) per participant (range 2–9 visits) and a mean interval between visits of 3·94 months (SD 1·77). Across the 2-year period, S aureus small-colony variants were detected in 64 (28%) participants. Most (103 [56%] of 185) of the small-colony variants detected in these participants were thymidine dependent. Children with small-colony variants had significantly lower mean percentage of predicted FEV1 at baseline than did children without small-colony variants (85·5 [SD 19] vs 92·4 [SD 18·6]; p=0·0145). Small-colony variants were associated with significantly lower percentage of predicted FEV1 throughout the study in regression models, both in univariate analyses (regression coefficient −7·07, 95% CI −12·20 to −1·95; p=0·0068) and in multivariate analyses adjusting for potential confounders (−5·50, −10·51 to −0·48; p=0·0316). Small colony variants of the thymidine-dependent subtype had the strongest association with lung function in multivariate regression models (regression coefficient −10·49, −17·25 to −3·73; p=0·0024). Compared with children without small-colony variants, those with small-colony variants had significantly increased odds of respiratory exacerbations in univariate analyses (odds ratio 1·73, 95% CI 1·19 to 2·52; p=0·0045). Children with thymidine-dependent small-colony variants had significantly increased odds of respiratory exacerbations (2·81, 1·69–4·67; p=0·0001), even after adjusting for age, sex, race, genotype, CFTR modulator, P aeruginosa culture status, and baseline percentage of predicted FEV1 (2·17, 1·33–3·57; p=0·0021), whereas those with non-thymidine-dependent small-colony variants did not. In multivariate models including small-colony variants and MRSA status, P aeruginosa was not independently associated with lung function (regression coefficient −4·77, 95% CI −10·36 to 0·83; p=0·10) and was associated with reduced odds of exacerbations (0·54, 0·36 to 0·81; p=0·0028). Only the small-colony variant form of MRSA was associated with reduced lung function (−8·44, −16·15 to −0·72; p=0·0318) and increased odds of exacerbations (2·15, 1·24 to 3·71; p=0·0061). Interpretation Infection with small-colony variants, and particularly thymidine-dependent small-colony variants, was common in a multicentre paediatric population with cystic fibrosis and associated with reduced lung function and increased risk of respiratory exacerbations. The adoption of small-colony variant identification and subtyping methods by clinical laboratories, and the inclusion of small-colony variant prevalence data in cystic fibrosis registries, should be considered for ongoing surveillance and study. Funding The Cystic Fibrosis Foundation and the National Institutes of Health.

Rationale: Staphylococcus aureus and Pseudomonas aeruginosa often infect the airways in cystic fibrosis (CF). Because registry studies show higher prevalence of P. aeruginosa versus S. aureus in older patients with CF, a common assumption is that P. aeruginosa replaces S. aureus over time. In vitro, P. aeruginosa can outgrow and kill S. aureus. However, it is unknown how rapidly P. aeruginosa replaces S. aureus in patients with CF. Methods: We studied a longitudinal cohort of children and adults with CF who had quantitative sputum cultures. We determined the abundance of P. aeruginosa and S. aureus in cfu/ml. We determined the duration and persistence of infections and measured longitudinal changes in culture positivity and abundance for each organism. Measurements and Main Results: Between 2004 and 2017, 134 patients had ≥10 quantitative cultures, with median observation time of 10.15 years. One hundred twenty-four patients had at least one positive culture for P. aeruginosa, and 123 had at least one positive culture for S. aureus. Both species had median abundance of >10(6) cfu/ml. Culture abundance was stable over time for both organisms. There was an increase in the prevalence of S. aureus/P. aeruginosa coinfection but no decrease in S. aureus prevalence within individuals over time. Conclusions: S. aureus and P. aeruginosa are abundant in CF sputum cultures. Contrary to common assumption, we found no pattern of replacement of S. aureus by P. aeruginosa. Many patients with CF have durable long-term coinfection with these organisms. New strategies are needed to prevent and treat these infections.

Late Pleistocene permafrost of the Yedoma type constitutes a valuable paleo-environmental archive due to the presence of numerous and well-preserved floral and faunal fossils. The study of the fossil Yedoma inventory allows for qualitative and quantitative reconstructions of past ecosystem and climate conditions and variations over time. Here, we present the results of combined paleo-proxy studies including pollen, chironomid, diatom and mammal fossil analyses from a prominent Yedoma cliff on Sobo-Sise Island in the eastern Lena Delta, NE Siberia to complement previous and ongoing paleo-ecological research in western Beringia. The Yedoma Ice Complex (IC) cliff on Sobo-Sise Island (up to 28 m high, 1.7 km long) was continuously sampled at 0.5 m resolution. The entire sequence covers the last about 52 cal kyr BP, but is not continuous as it shows substantial hiatuses at 36–29 cal kyr BP, at 20–17 cal kyr BP and at 15–7 cal kyr BP. The Marine Isotope Stage (MIS) 3 Yedoma IC (52–28 cal kyr BP) pollen spectra show typical features of tundra–steppe vegetation. Green algae remains indicate freshwater conditions. The chironomid assemblages vary considerably in abundance and diversity. Chironomid-based TJuly reconstructions during MIS 3 reveal warmer-than-today TJuly at about 51 cal kyr BP, 46-44 and 41 cal kyr BP. The MIS 2 Yedoma IC (28–15 cal kyr BP) pollen spectra represent tundra-steppe vegetation as during MIS 3, but higher abundance of Artemisia and lower abundances of algae remains indicate drier summer conditions. The chironomid records are poor. The MIS 1 (7–0 cal kyr BP) pollen spectra indicate shrub-tundra vegetation. The chironomid fauna is sparse and not diverse. The chironomid-based TJuly reconstruction supports similar-as-today temperatures at 6.4–4.4 cal kyr BP. Diatoms were recorded only after about 6.4 cal kyr BP. The Sobo-Sise Yedoma record preserves traces of the West Beringian tundra-steppe that maintained the Mammoth fauna including rare evidence for woolly rhinoceros’ presence. Chironomid-based TJuly reconstructions complement previous plant-macrofossil based TJuly of regional MIS 3 records. Our study from the eastern Lena Delta fits into and extends previous paleo-ecological Yedoma studies to characterize Beringian paleo-environments in the Laptev Sea coastal region.

BackgroundTesticular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumor heterogeneity to unravel tumor progression from initiation till metastasis.MethodsIn total 42 purified samples of four treatment-resistant nonseminomatous TGCC (NS) were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole genome- and targeted sequencing. Their evolution was reconstructed.ResultsIntratumor molecular heterogeneity did not correspond to the supposed primary tumor histological evolution. Metastases after systemic treatment could be derived from cancer stem cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement ofBRCA1andBRCA2genes.ConclusionsOur data strongly support the hypothesis that NS is initiated by whole genome duplication, followed by chromosome copy number alterations in the cancer stem cell population, and accumulation of low numbers of somatic mutations. These observations of heterogeneity at all stages of tumorigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.

Human germ cell tumours (GCTs) are derived from stem cells of the early embryo and the germ line. They occur in the gonads (ovaries and testes) and also in extragonadal sites, where migrating primordial germ cells are located during embryogenesis. This group of heterogeneous neoplasms is unique in that their developmental potential is in effect determined by the latent potency state of their cells of origin, which are reprogrammed to omnipotent, totipotent or pluripotent stem cells. Seven GCT types, defined according to their developmental potential, have been identified, each with distinct epidemiological and (epi)genomic features. Heritable predisposition factors affecting the cells of origin and their niches likely explain bilateral, multiple and familial occurrences of the different types of GCTs. Unlike most other tumour types, GCTs are rarely caused by somatic driver mutations, but arise through failure to control the latent developmental potential of their cells of origin, resulting in their reprogramming. Consistent with their non-mutational origin, even the malignant tumours of the group are characterized by wild-type TP53 and high sensitivity for DNA damage. However, tumour progression and the rare occurrence of treatment resistance are driven by embryonic epigenetic state, specific (sub)chromosomal imbalances and somatic mutations. Thus, recent progress in understanding GCT biology supports a comprehensive developmental pathogenetic model for the origin of all GCTs, and provides new biomarkers, as well as potential targets for treatment of resistant disease. Human germ cell tumours are a heterogeneous group of neoplasms that occur in the gonads and extragonadal sites along the midline of the body. This Review outlines a developmental pathogenetic model for the origin of all germ cell tumours, which is based on the unscheduled reprogramming of cells of the early embryo and germ line.

Antimicrobials can impact bacterial physiology and host immunity with negative treatment outcomes. Extensive exposure to antifolate antibiotics promotes thymidine-dependent Staphylococcus aureus small colony variants (TD-SCVs), commonly associated with worse clinical outcomes. We show that antibiotic-mediated disruption of thymidine synthesis promotes elevated levels of the bacterial second messenger cyclic di-AMP (c-di-AMP), consequently inducing host STING activation and inflammation. An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis. Additionally, TD-SCVs exhibited excessive c-di-AMP production and STING activation in a thymidine-dependent manner. Murine lung infection with TD-SCVs revealed STING-dependent elevation of proinflammatory cytokines, causing higher airway neutrophil infiltration and activation compared with normal-colony S. aureus and hemin-dependent SCVs. Collectively, our results suggest that thymidine metabolism disruption in Firmicutes leads to elevated c-di-AMP-mediated STING-dependent inflammation, with potential impacts on antibiotic usage and infection outcomes.

38th European Photovoltaic Solar Energy Conference and Exhibition; 154-157, Polysilicon-on-oxide (POLO) passivating contacts and interdigitated back-contact (IBC) cell technologies have recently attracted a lot of interest as candidates for the implementation in the next generation of solar cells. An IBC cell with POLO junctions for both polarities – a POLO²-IBC cell – has to electrically isolate the highly defective p+ and n+ poly-Si regions on the rear side of the cell to avoid parasitic recombination. Inserting an initially undoped, intrinsic (i) region between the p+ and n+ poly-Si regions was demonstrated to successfully prevent the parasitic recombination in the transition region of ISFH’s 26.1%- efficient POLO²-IBC cell. In order to further improve the conversion efficiency towards 27%, we apply hydrogen-donating dielectric layer stacks to the p+-(i)-n+ POLO interdigitating rear side to enhance the passivation quality of the POLO junctions. We indeed show a significant improvement of POLO junctions on symmetrical full-area homogenously doped reference samples, but when we apply a hydrogen-donating layer stack on the p+-(i)-n+ POLO interdigitating rear side, we observe a strong degradation in the performance of the POLO²-IBC cell. We attribute this to the formation of a conductive channel between the p+ and n+ poly-Si regions due to the strong negative charge density of the hydrogen-donating layer stack.