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PurposeCentral serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy.Material and methodsThis is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®).ResultsMean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42–191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22–217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88–218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures.ConclusionSingle or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals’ adaptive skills naturally improve or remain stable, while others’ decrease. To pave the way for ‘precision-medicine’ approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6–30 years), with two assessment time points separated by ~12–24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful “Increasers”, “No-changers”, and “Decreasers” in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup’s neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences’ potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection 1 . Drug targets with genetic support are more likely to be therapeutically valid 2 , 3 , but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging 4 – 6 . Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease. A genetics-led translational approach integrating functional genomic predictors, knowledge of network connectivity and immune ontologies defines the drug target prioritization landscape for 30 immune traits at the gene and pathway level.

The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown. We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1 (E17K) and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing. Overall AKT1 (E17K) mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1 (E17K) mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % (n = 50) and 97.1 % (n = 35) concordance was obtained between tissue and blood samples for the AKT1 (E17K) mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1-mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1 (E17K) as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1 (E17K) could be associated with increased mortality. These findings warrant additional long-term follow-up. The data suggest that AKT1 (E17K) is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer.

Background The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown. Methods We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1 E17K and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing. Results Overall AKT1 E17K mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1 E17K mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % ( n =  50) and 97.1 % ( n =  35) concordance was obtained between tissue and blood samples for the AKT1 E17K mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1 -mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1 E17K as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1 E17K could be associated with increased mortality. These findings warrant additional long-term follow-up. Conclusions The data suggest that AKT1 E17K is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer.

Infants born with a very low birth weight (VLBW, < = 1.500 g) have an increased risk for medical complications and long‐term impairments. Feeding these infants with their mother's own milk (MOM) reduces the risk for adverse outcomes, but many VLBW infants are not fed with MOM for the recommended duration of at least 6 months postpartum. This study examines factors associated with early cessation during the VLBW infants' neonatal intensive care unit (NICU) stay and after discharge. Data were collected from an anonymous, nationwide survey as part of the Neo‐MILK study. Logistic regressions and Cox proportional hazard models were used to identify factors associated with early cessation of MOM feeding. Among the 304 mothers analysed, 19.4% of all mothers ceased MOM feeding during the infants' NICU stay. The total cessation rate before 6 months was 53.9%. An early milk volume of over 500 mL/day compared to less or equal to 500 mL/day was negatively associated with MOM feeding cessation during the infants' NICU stay (Adjusted OR: 0.14). Exclusive pumping was associated with a higher cessation rate after discharge (Adjusted HR: 2.01). Early sufficient milk volume and mixed feeding (pumping and breastfeeding) inform longer MOM feeding duration. Interventions targeting early lactation practices and promoting direct breastfeeding while helping with the transition from pumping to breastfeeding are essential for improving MOM feeding outcomes in VLBW infants. Trial Registration: German Register of Clinical Trials, ID: DRKS00024799, https://drks.de/search/en/trial/DRKS00024799. Early cessation of mother's own milk (MOM) feeding in very low birth weight infants is strongly linked to low milk volume by Day 14 postpartum and exclusive pumping after discharge. Promoting early lactation support and mixed feeding (pumping and breastfeeding) strategies may help extend MOM feeding duration. Summary Professional lactation support is vital during the NICU stay, especially for mothers of VLBW infants who struggle to reach a milk volume of 500 mL/day by Day 14 postpartum. Exclusive pumping is associated with a higher risk of early cessation, highlighting the need to promote a combination of pumping and breastfeeding while supporting the mothers during the transition to direct breastfeeding. Given the unique challenges faced by mothers of VLBW infants, focused interventions are essential to extend MOM feeding durations and thus improve health outcomes for both mother and infant.

Background Pump-dependent mothers of very low birth weight (VLBW, < 1500g) infants experience specific challenges achieving sufficient milk supply in the neonatal intensive care unit (NICU) and are therefore less frequently able to achieve (exclusive) breast milk feeding. Stress due to the limitations on participating in the infant’s care may contribute to this problem. Some explorative studies suggest that pressure to provide milk may be an additional stressor in mothers. However, the type of pressure to provide milk perceived by mothers of VLBW infants has rarely been examined. Methods A retrospective and anonymous questionnaire was conducted with mothers of VLBW infants aged 6 to 24 months at the time of data collection. Quantitative data and written comments were used to examine the mothers’ perceptions. Descriptive and bivariate tests (Spearman´s rho, Pearson’s chi 2 ) were performed to show correlations between pressure to provide breast milk, parental stress (PSS:NICU: role alteration subscale), milk volume, and maternal factors. Pressure to provide milk was measured through two self-developed single items to differentiate between internal and external pressures. Results Data of n  = 533 mothers of VLBW infants was analysed. More than 70% of the mothers agreed that they pressured themselves to provide milk for their infant. In contrast, 34% of the mothers agreed that they felt pressure from outside to provide milk. Higher milk volume 14 days post-partum was significantly correlated with less internal (Spearman´s rho = 0.2017, p  = 0.000) and less external pressure to provide milk (Spearman´s rho = 0.2991; p  = 0.000). Higher PSS:NICU parental role alteration scores were significantly correlated with more internal (Spearman´s rho = -0.2865, p  = 0.000) and more external pressure to provide milk (Spearman´s rho = -0.1478; p  = 0.002). Milk volume 14 days post-partum and the PSS:NICU were not significantly correlated (Spearman´s rho = -0.0190; p  = 0.701). Qualitative analyses highlighted these results and enhanced the bidirectional relationships between maternal pressure to provide milk and milk volume. Conclusions Especially internal pressure to provide milk is perceived by many mothers, being mutually dependent on milk supply and parental stress. Pressure to provide milk may be an important factor to decrease maternal stress in the NICU and, therefore, lead to more positive pumping and breastfeeding experiences. More research and validated instruments are needed to adequately measure pressure to provide milk with its different psychological, social, and environmental dimensions.

Objectives This retrospective study aimed to evaluate the effect of titration-guided focal selective retina therapy (SRT) for chronic central serous chorioretinopathy (cCSCR) and determine the need and effectiveness of re-treatment. Methods SRT was performed in 60 eyes of 57 patients with cCSCR, targeting focal leakage points (FLP) using a Nd:YLF-Laser at 527 nm (R:GEN®, Lutronic, South Korea) titration-guided at 80% threshold, with 140 ms irradiation time, 100 Hz frequency, 1.7 µs pulse duration, 200 µm spot size. Best documented visual acuity (BDVA), peak height of subretinal fluid (SRF), height of SRF at the fovea, central retinal thickness (cRT) and total macular retinal volume (tRV) were measured. Results A significant improvement in BDVA was observed up to 1 year compared to baseline ( p  < 0.02). A limited analysis due to the small sample size showed no significant difference between the BDVA at baseline and 2-year ( n  = 15) and 3-year ( n  = 10) follow-ups. A significant decrease in the height of the SRF at the highest point and fovea and total retinal volume up to the 3-year follow-up was observed compared to the baseline ( p  < 0.03). Thirty (50%) eyes of 30 patients required re-treatment, on average 9.2 ± 9.6 months after the initial SRT. This study found no predictors for the need of re-treatment. Conclusions The study concludes that SRT is safe and shows anatomical and functional benefits for treating cCSCR. We recommend performing regular check-ups every three months and following a zero-fluid tolerance policy for re-treatment. Trial registration German Clinical Trials Register ID: DRKS00031038, registration date: 2023-01-16

The benefits of cytology-based cervical cancer screening programs in reducing morbidity and mortality are well recognized. Especially, overtreatment of human papillomavirus (HPV) high-risk positive early dysplastic lesions may have a negative impact on reproductive outcomes for fertile women. To optimize the clinical management an objective standard is needed to distinguish precancer that requires treatment, from spontaneously resolving HPV infections. In the current study, we examined the prognostic relevance of HPV-L1 capsid protein analysis with Cytoactiv in an international prospective multicenter study including 908 HPV high-risk positive early dysplastic lesions (LSIL/HSIL) during a follow-up period of 54 months. The clinical end points of the study were histologically confirmed CIN3+ as progression, CIN1/2 for stable disease and repeated negative Pap smears as spontaneous clinical remission. The difference of the clinical outcome of HPV-L1-negative and HPV-L1-positive cases was statistically highly significant ( P -value<0.0001) independent of the classification as mild dysplasia (LSIL) and moderate dysplasia (HSIL). Of the HPV-L1-negative HPV high-risk positive mild/moderate dysplasias 84% progressed to CIN3, as compared with only 20% of the HPV-L1-positive cases. The data from our study show that HPV-L1 detection allows to identify transient HPV infections and precancerous lesions within the group of HPV high-risk positive early dysplastic lesions. The high progression rate of HPV-L1-negative mild and moderate dysplasia emphasizes the precancerous nature of these lesions. A close follow-up with colposcopy and histological evaluation is advisable and removal of these lesions should be considered. The low malignant potential of HPV-L1-positive cases, however, indicates transient HPV infection, justifying a watch and wait strategy with cytological follow-up, thus preventing overtreatment especially for women in their reproductive age.