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With health equity growing as a priority within health care, health systems must transform that calling into action within their social, economic, and political environments. The current literature has not compared how different organizations manage the same health disparities intervention. This qualitative study aims to illustrate how different organizations navigated the implementation and sustainability of a hypertension disparities intervention by comparing experiences across Federally Qualified Health Centers (FQHCs), a private health system, and other non-clinical partnering organizations. As a study within a randomized controlled trial designed to reduce disparities in hypertension care, we conducted interviews with health care leaders before and after participation in the trial's multi-level intervention. Before participation, we interviewed five health care leaders representing five health systems. Following the intervention, we interviewed 14 leaders representing the five health systems and two partnering organizations. Discussions focused on intervention implementation and plans for sustainability. The primary considerations in implementation were appropriate staffing and multi-level organizational buy-in. When discussing long-term planning, health systems prioritized the structure of a stepped-care protocol incorporating community health workers (CHWs) and case managers. The sustainability of the CHW intervention at FQHCs was dependent on funding, whereas a private, non-FQHC physician practice network focused on expanding current resources for more patients. These findings serve as anticipatory guidance for organizations aiming to reduce hypertension disparities and provide support for policies that financially assist these interventions. Further investigation is warranted on the organizational factors that may influence the degree of success in eliminating health care disparities., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Personal characteristics may be associated with believing misinformation and not believing in best practices to protect oneself from COVID-19., Objective: To examine the associations of a person's age, race/ethnicity, education, residence, health literacy, medical mistrust level, and sources of health-related information with their COVID-19 health and conspiracy myth beliefs., Design: We surveyed adults with hypertension in Maryland and Pennsylvania between August 2020 and March 2021. Incorrect responses were summed for eight health (mean = 0.68; range 0-5) and two conspiracy (mean = 0.92; range 0-2) COVID-19 questions. Higher scores indicated more incorrect responses. Statistical analyses included two-sample t-tests, Spearman's correlation, and log binomial regression., Participants: In total, 561 primary care patients (mean age = 62.3 years, 60.2% female, 46.0% Black, 10.2% Hispanic, 28.2% with a Bachelor's degree or higher, 42.8% with annual household income less than $60,000) with a diagnosis of hypertension and at least one of five commonly associated conditions., Main Measures: Sociodemographic characteristics, health literacy, medical mistrust level, source of health-related information, and COVID-19 conspiracy and health myth beliefs., Key Results: In multivariable analyses, participants who did not get information from medical professional sources (prevalence ratio (PR) = 1.28; 95% CI = 1.06-1.55), had less than a bachelor's degree (PR = 1.49; 95% CI = 1.12-1.99), were less confident filling out medical forms (PR = 1.24; 95% CI = 1.02-1.50), and had higher medical mistrust (PR = 1.34; 95% CI = 1.05-1.69) were more likely to believe any health myths. Participants who had less than a bachelor's degree (PR = 1.22; 95% CI = 1.02-1.45), were less confident filling out medical forms (PR = 1.21; 95% CI = 1.09-1.34), and had higher medical mistrust (PR = 1.72; 95% CI = 1.43-2.06) were more likely to believe any conspiracy myths., Conclusions: Lower educational attainment and health literacy, greater medical mistrust, and certain sources of health information are associated with misinformed COVID-19 beliefs. Programs addressing misinformation should focus on groups affected by these social determinants of health by encouraging reliance on scientific sources., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Sickle cell disease (SCD) is a painful chronic blood disorder that causes serious complications and comorbidities, often leading to premature death. SCD impacts millions of people worldwide, including an estimated 100 000 in the United States, most of whom are Black or Latino. We analyzed Medicaid enrollment, claims, and encounter data via the Transformed Medicaid Statistical Information System (T-MSIS) to examine the 2021 health care utilization and spending of Medicaid enrollees with SCD. Our analysis found that Medicaid enrollees with SCD have high annual medical and pharmacy expenditures that are not evenly distributed across the population. Among the most severe enrollees with genotypes eligible for clinical trials, those in the top 5% of health care spending incurred, on average, nearly $200 000 per year for this chronic condition., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

The existence of coastal ecosystems depends on their ability to gain sediment and keep pace with sea level rise. Similar to other coastal areas, Northeast Florida (United States) is experiencing rapid population growth, climate change, and shifting wetland communities. Rising seas and more severe storms, coupled with the intensification of human activities, can modify the biophysical environment, thereby increasing coastal exposure to storm-induced erosion and inundation. Using the Guana Tolomato Matanzas National Estuarine Research Reserve as a case study, we analyzed the distribution of coastal protection services-expressly, wave attenuation and sediment control-provided by estuarine habitats inside a dynamic Intracoastal waterway. We explored six coastal variables that contribute to coastal flooding and erosion-(a) relief, (b) geomorphology, (c) estuarine habitats, (d) wind exposure, (e) boat wake energy, and (f) storm surge potential-to assess physical exposure to coastal hazards. The highest levels of coastal exposure were found in the north and south sections of the Reserve (9% and 14%, respectively) compared to only 4% in the central, with exposure in the south driven by low wetland elevation, high surge potential, and shorelines composed of less stable sandy and muddy substrate. The most vulnerable areas of the central Reserve and main channel of the Intracoastal waterway were exposed to boat wakes from larger vessels frequently traveling at medium speeds (10-20 knots) and had shoreline segments oriented towards the prevailing winds (north-northeast). To guide management for the recently expanded Reserve into vulnerable areas near the City of Saint Augustine, we evaluated six sites of concern where the current distribution of estuarine habitats (mangroves, salt marshes, and oyster beds) likely play the greatest role in natural protection. Spatially explicit outputs also identified potential elevation maintenance strategies such as living shorelines, landform modification, and mangrove establishment for providing coastal risk-reduction and other ecosystem-service co-benefits. Salt marshes and mangroves in two sites of the central section (N-312 and S-312) were found to protect more than a one-quarter of their cross-shore length (27% and 73%, respectively) from transitioning to the highest exposure category. Proposed interventions for mangrove establishment and living shorelines could help maintain elevation in these sites of concern. This work sets the stage for additional research, education, and outreach about where mangroves, salt marshes, and oyster beds are most likely to reduce risk to wetland communities in the region., Competing Interests: Gregory M. Verutes is an Academic Editor for PeerJ and employed by Blue Forest Conservation., (© 2024 Verutes et al.)

Purpose: Infants with perceived feeding problems are frequently referred for assessment of their feeding abilities. However, little is known regarding how healthy nondysphagic infants perform on commonly used assessments, making determination of impairment difficult. The aim of this investigation was to elucidate the characteristics of healthy term infant feeding performance using three commonly employed clinical assessments: Neonatal Eating Assessment Tool-Mixed (NeoEat-Mixed), Oral Feeding Scale, and Early Feeding Skills (EFS)., Method: In this prospective case-control study, we recruited 30 infants without feeding impairments to undergo video-monitored bottle feeds under their normal feeding conditions. Caregiver perception of infant feeding was evaluated using the NeoEat-Mixed. Milk ingestion was monitored real time using the Oral Feeding Scale for rate of milk transfer and modified proficiency as characterized by the total volume consumed out of the total volume the caregiver provided. Videos were analyzed by two speech pathologists using the EFS assessment. Descriptive statistics were used to characterize performance., Results: Participants underwent feeding monitoring at an average chronological age of 4 ± 2 months. Caregivers primarily reported normal, nonconcerning feeding patterns across all of the NeoEAT-Mixed outcomes. Infants consumed milk at an average rate of transfer of 7 ± 3 ml/min, a modified proficiency of 50 ± 21%, and achieved the highest OFS score of 4 (93%, n = 28). The majority of infants scored the best EFS score (mature-3) as it related to the absence of color changes during the feed (97%, n = 29), although commonly scored in the worst EFS score (immature-1) in their presentation of one or more compelling stress cues (63%, n = 19)., Conclusion: Establishing healthy term infant normative values for commonly used feeding assessments is critical in accurately distinguishing infants with feeding impairments from those with normal developmental variants.

Introduction: Cutaneous squamous cell carcinoma (cSCC) is a common tumor of elderly Caucasian patients., Methods: Competing multivariable risk models to analyze different types of cSCC associated death (local infiltration [LI], locoregional [LR], and distant metastases [DM]) in terms of prognostic factors., Results and Discussion: 1400 patients were analyzed. In the adjusted multivariable subdistribution hazard approach for tumor volume, the best model for death of cSCC overall revealed the presence of desmoplasia (HR 4.52; p < 0.001), bone invasion (HR 10.06; p < 0.01), and immunosuppression (HR 3.19; p = 0.003) as significant factors. Death due to LI indicated desmoplasia (HR 15.39; p < 0.01) and bone invasion (HR 16.9; p < 0.001) as significant factors. For death by LM, immunosuppression with a HR of 3.27; p = 0.004 was the only significant prognostic factors as well as in death by DM with a HR of 4.54; p = 0.02., Conclusions: The three types of death caused by cSCC can be distinguished based on risk factors with different weights. Patients with these factors should be monitored closely., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The use of nurse care managers (CMs) and community health workers (CHWs) has demonstrated effectiveness in supporting improved blood pressure management among racially, ethnically, and socioeconomically minoritized populations. We partnered with a community advisory board (CAB) to develop a CM and CHW training curriculum and team-based collaborative care intervention to address uncontrolled hypertension. The objective of this study was to train CMs and CHWs to implement patient-centered techniques and address social determinants of health related to hypertension control. In partnership with a CAB, we developed and implemented a training curriculum for the CM/CHW collaborative care team. The training improved CM and CHW confidence in their ability to address medical and nonmedical issues that contribute to uncontrolled hypertension in their patients; however, preexisting norms and beliefs among CMs and CHWs created challenges with teamwork. The training curriculum was feasible and well-received. Additionally, the CMs' and CHWs' reactions provided insights to improve future collaborative care training and teamwork., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We examined measles mortality in the European past in an outbreak in an isolated German village, Hagelloch, in 1861., Methods: Pfeilsticker's contemporary thesis was used to describe the measles case fatality ratio (CFR) and complications. Data on onset of prodromes and rash was used to determine index cases and secondary cases of measles within the household. The church register provided information on survival in 1862., Results: The epidemic affected nearly all children under 14 years of age. The overall CFR was 6.4%(12/187), and 10%(7/70) for children under five years of age; 44% of children were secondary cases (82/187). Secondary cases had higher CFR than index cases (RR = 3.03 (95% CI: 0.91-10.07). Boys had higher CFR than girls (RR = 4.46 (1.03-19.22)). Boys infected by a girl had higher CFR than boys infected by other boys (RR = 6.30 (1.18-85.64)). Children who survived measles virus infection in 1861, did not have higher mortality in the following year compared with those who had not had measles in 1861 (RR = 0.24 (0.07-0.82))., Conclusions: Severe measles in the European past had determinants similar to those observed more recently in low-income countries., Brief Summary: The measles case fatality was 6% in rural Germany in 1861. Mortality was highest for boys infected in the household by a girl. There was no excess mortality after the acute phase of measles infection., Competing Interests: Declaration of Competing Interest Nothing to declare, (Copyright © 2022. Published by Elsevier Ltd.)

Background: Inserting a chest drain for a left-sided neonatal pneumothorax carries a risk of penetrating the pericardium. We identified reference ranges for the chest wall thickness (CWT) and distance between the pericardium and parietal pleura to improve safety of chest tube insertion., Method: We prospectively measured the CWT using ultrasound in 20 neonates (body weight [BW] 640-2,700 g, age <10 days) at the usual site of puncture in the 4th and 5th intercostal space (ICS). Furthermore, we measured the minimal distance between the parietal pleura and the cardiac silhouette in 131 neonatal chest X-rays (birth weight, 420-4,930 g [divided into 11 weight groups]; age <10 days). Both data sets were transformed into weight-dependent percentiles (Ps). We considered the difference between the sum of P 2.5 for the CWT plus P 2.5 for pleura-heart distance minus P 97.5 for the CWT as a safe corridor for placing the tip of the needle., Results: At both ICSs, curves for the above metrics did not cross, indicating a narrow but safe corridor for each BW with at least 97.5% probability. This safety corridor was 4.6-5.2 mm wide for the 4th and 2.8-3.4 mm for the 5th ICS., Conclusion: These data offer a reference for left-sided chest drain insertion for BW <2,700 g, which may help to improve safety of the procedure., (© 2021 S. Karger AG, Basel.)

Formed at the confluence of marine and fresh waters, estuaries experience both the seaside pressures of rising sea levels and increasing storm severity, and watershed and precipitation changes that are shifting the quality and quantity of freshwater and sediments delivered from upstream sources. Boating, shoreline hardening, harvesting pressure, and other signatures of human activity are also increasing as populations swell in coastal regions. Given this shifting landscape of pressures, the factors most threatening to estuary health and stability are often uncertain. To identify the greatest contemporary threats to coastal wetlands and oyster reefs across the southeastern United States (Mississippi to North Carolina), we summarized recent population growth and land-cover change and surveyed estuarine management and science experts. From 1996 to 2019, human population growth in the region varied from a 17% decrease to a 171% increase (mean = +43%) with only 5 of the 72 SE US counties losing population, and nearly half growing by more than 40%. Individual counties experienced between 999 and 19,253 km 2 of new development (mean: 5725 km 2 ), with 1-5% (mean: 2.6%) of undeveloped lands undergoing development over this period across the region. Correspondingly, our survey of 169 coastal experts highlighted development, shoreline hardening, and upstream modifications to freshwater flow as the most important local threats facing coastal wetlands. Similarly, experts identified development, upstream modifications to freshwater flow, and overharvesting as the most important local threats to oyster reefs. With regards to global threats, experts categorized sea level rise as the most pressing to wetlands, and acidification and precipitation changes as the most pressing to oyster reefs. Survey respondents further identified that more research, driven by collaboration among scientists, engineers, industry professionals, and managers, is needed to assess how precipitation changes, shoreline hardening, and sea level rise are affecting coastal ecosystem stability and function. Due to the profound role of humans in shaping estuarine health, this work highlights that engaging property owners, recreators, and municipalities to implement strategies to improve estuarine health will be vital for sustaining coastal systems in the face of global change., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: AUTHOR DISCLOSUREDrs Hane, Howard, Dietz, and Maroushek have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

Whole-genome sequencing (WGS) has changed our understanding of bacterial pathogens, aiding outbreak investigations and advancing our knowledge of their genetic features. However, there has been limited use of genomics to understand antimicrobial resistance of veterinary pathogens, which would help identify emerging resistance mechanisms and track their spread. The objectives of this study were to evaluate the correlation between resistance genotypes and phenotypes for Staphylococcus pseudintermedius, a major pathogen of companion animals, by comparing broth microdilution antimicrobial susceptibility testing and WGS. From 2017-2019, we conducted antimicrobial susceptibility testing and WGS on S. pseudintermedius isolates collected from dogs in the United States as a part of the Veterinary Laboratory Investigation and Response Network (Vet-LIRN) antimicrobial resistance monitoring program. Across thirteen antimicrobials in nine classes, resistance genotypes correlated with clinical resistance phenotypes 98.4 % of the time among a collection of 592 isolates. Our findings represent isolates from diverse lineages based on phylogenetic analyses, and these strong correlations are comparable to those from studies of several human pathogens such as Staphylococcus aureus and Salmonella enterica. We uncovered some important findings, including that 32.3 % of isolates had the mecA gene, which correlated with oxacillin resistance 97.0 % of the time. We also identified a novel rpoB mutation likely encoding rifampin resistance. These results show the value in using WGS to assess antimicrobial resistance in veterinary pathogens and to reveal putative new mechanisms of resistance., (Published by Elsevier B.V.)

Aim: Oximetry values are influenced by the averaging time (AT) used. We aimed to evaluate the effect of different ATs on number, duration, mean single event and total integral of desaturations in preterm infants and children to convert between parameters obtained with different ATs., Methods: In a prospective observational study, 49 children underwent sleep laboratory-based polysomnography and 15 preterm infants were studied in the intensive care unit. Their raw red-to-infrared-saturation-data were reprocessed using seven different ATs (3-16 seconds). Desaturation thresholds were <80% (infants) and <90% (children), conversion formulas and their median percentage errors were calculated., Results: We found a linear relationship between the logarithms of the ATs and those of the desaturation parameters, leading to a conversion formula with different exponents. Based on this relationship, the number of desaturations decreased from AT = 3s to AT = 16s by factor 0.28 (children) and 0.18 (infants); total oxygen saturation integral decreased by factor 0.72 (children) and 0.48 (infants). The desaturation duration increased by factor 1.89 (children) and 3.34 (infants)., Conclusion: The number and total integral decreased, but the duration and mean single event integral increased with increasing AT. These changes were stronger in infants. Conversion formulas may facilitate comparisons between studies using different averaging times., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

MEST of the kidney are a benign group of tumors with very rare incidence of malignant transformation. First described in 1998, this tumor has never been reported in a transplanted organ before. We present a unique case of de novo MEST in a donor kidney 4 years after transplant into a pediatric patient. Although removal of the lesions is curative without risking malignant transformation, in this case, surgical removal was not attempted to prevent reduction in transplant longevity. In this unique report of MEST in a transplanted kidney, we describe the patient/transplant outcomes without MEST resection., (© 2019 Wiley Periodicals, Inc.)

Exposure to stress increases the risk of developing mood disorders. While a subset of individuals displays vulnerability to stress, others remain resilient, but the molecular basis for these behavioral differences is not well understood. Using a model of chronic social defeat stress, we identified region-specific differences in myelination between mice that displayed social avoidance behavior ('susceptible') and those who escaped the deleterious effect to stress ('resilient'). Myelin protein content in the nucleus accumbens was reduced in all mice exposed to stress, whereas decreased myelin thickness and internodal length were detected only in the medial prefrontal cortex (mPFC) of susceptible mice, with fewer mature oligodendrocytes and decreased heterochromatic histone marks. Focal demyelination in the mPFC was sufficient to decrease social preference, which was restored following new myelin formation. Together these data highlight the functional role of mPFC myelination as critical determinant of the avoidance response to traumatic social experiences., Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., Competing Interests: VB, KD, MA, MW, AA, JD, GT, HP, NB, PC, JL No competing interests declared, (© 2019, Bonnefil et al.)

Background: Postnatally acquired cytomegalovirus (pCMV) infection through breast milk (BM) may cause severe illness and even death, yet BM is advantageous for preterm infants. Therefore, effective methods to prevent CMV transmission are needed., Methods: To assess the effectiveness of short-term pasteurization (62°C for 5 seconds) in preventing CMV transmission via BM in preterm infants. Design: Prospective interventional bicentric cohort study with infant enrollment between 6/2010 and 1/2012. A cohort from the Tuebingen neonatal intensive care unit (NICU) from 1995-1998 served as historical controls. Differences in CMV transmission were compared with reference to the cumulative time at risk for CMV transmission. Setting: Two German level-3 NICUs. Eighty-seven preterm infants of 69 CMV immunoglobulin G-positive mothers with birth weight <1500 g or gestational age <32 weeks and 83 historical controls were included. Intervention: BM samples were short-term pasteurized from postnatal day 4 to discharge. Primary endpoint: CMV status at discharge, evaluated by polymerase chain reaction and short-term microculture from urine., Results: Two of 87 (2.3%) study infants had a pCMV transmission. This compared to 17 of 83 (20.5%) controls. Total time under risk for infection was 9.6 years vs 10.0 years in controls, yielding an incidence of 0.21/year (95% confidence interval [CI], 0.03 to 0.75/year) vs 1.70/year (95% CI, 0.99 to 2.72/year), respectively. The risk ratio controls vs study infants was 8.3 (95% CI, 2.4 to 52.4) according to Cox proportional hazard model (P = .0003)., Conclusions: Short-term pasteurization significantly reduces the incidence of pCMV infection through BM in the NICU., Clinical Trials Registration: NCT01178905., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Transplanted bone marrow mononuclear cells (BMC) support the healing of large bone defects. Neutralization of microRNA (MiR) that negatively affects key processes of the reparative response in BMC might help to further improve the beneficial effect of transplanted BMC in bone healing. Hence, the aim of this study was to evaluate if the neutralization of MiR-92A (vascularization) and MiR-335-5p (osteogenic differentiation) in BMC using specific antiMiRs leads to a further improvement of the BMC-supported therapy of large bone defects. BMC transiently transfected with antiMiR- 92A, antiMiR-335, antiMiR-92A, and antiMiR-355 or control antiMiR were seeded on β-TCP (beta-tricalcium phosphate) and placed in a femoral large bone defect (5 mm) in Sprague-Dawley rats. Ultimate load as well as osseous integration of the β-TCP-scaffolds were significantly improved in the antiMiR-335 group compared to the control group after 8 weeks, whereas neutralization of antiMiR-92A lead to an improvement of early vascularization after 1 week, but not to enhanced bone healing after 8 weeks. We demonstrated that the targeted inhibition of MiRs in transplanted BMC is a new approach that enhances BMC-supported bone healing.

Human oligodendrocyte progenitor cells (hOPCs) persist into adulthood as an abundant precursor population capable of division and differentiation. The transcriptional mechanisms that regulate hOPC homeostasis remain poorly defined. Herein, we identify paired related homeobox protein 1 (PRRX1) in primary PDGFαR + hOPCs. We show that enforced PRRX1 expression results in reversible G 1/0 arrest. While both PRRX1 splice variants reduce hOPC proliferation, only PRRX1a abrogates migration. hOPC engraftment into hypomyelinated shiverer/rag2 mouse brain is severely impaired by PRRX1a, characterized by reduced cell proliferation and migration. PRRX1 induces a gene expression signature characteristic of stem cell quiescence. Both IFN-γ and BMP signaling upregulate PRRX1 and induce quiescence. PRRX1 knockdown modulates IFN-γ-induced quiescence. In mouse brain, PRRX1 mRNA was detected in non-dividing OPCs and is upregulated in OPCs following demyelination. Together, these data identify PRRX1 as a regulator of quiescence in hOPCs and as a potential regulator of pathological quiescence., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Karl-Peter Hadeler is a first-generation pioneer in mathematical biology. His work inspired the contributions to this special issue. In this preface we give a brief biographical sketch of K.P. Hadelers scientific life and highlight his impact to the field.

The most frequently cited articles out of KP Hadeler's 45 papers with epidemiological applications are summarized. Parasitic diseases which increase the death rate of the hosts proportional to the integer number of parasites present were described by integral equations for the generating function of the age- and time-dependent number of parasites. A model was derived for a population structured by the continuous level of parasitic infection. Stimulated by the spread of AIDS a new class of epidemic models was developed which take into account explicitly the formation and separation of pairs. For predator-prey populations with parasitic infections threshold conditions for the persistence of the predator were derived. The interaction of epidemics and demography was analysed. Several epidemiological conditions led to backward bifurcations associated with multiple infective stationary states.

The success rate of extracorporeal shock wave therapy (ESWT) for fracture nonunions in human medicine (i.e. radiographic union at 6 months after ESWT) is only approximately 75%. Detailed knowledge regarding the underlying mechanisms that induce bio-calcification after ESWT is limited. We analyzed the biological response within mineralized tissue of a new invertebrate model organism, the zebra mussel Dreissena polymorpha , after exposure with extracorporeal shock waves (ESWs). Mussels were exposed to ESWs with positive energy density of 0.4 mJ/mm 2 (A) or were sham exposed (B). Detection of newly calcified tissue was performed by exposing the mussels to fluorescent markers. Two weeks later, the A-mussels showed a higher mean fluorescence signal intensity within the shell zone than the B-mussels ( P <0.05). Acoustic measurements revealed that the increased mean fluorescence signal intensity within the shell of the A-mussels was independent of the size and position of the focal point of the ESWs. These data demonstrate that induction of bio-calcification after ESWT may not be restricted to the region of direct energy transfer of ESWs into calcified tissue. The results of the present study are of relevance for better understanding of the molecular and cellular mechanisms that induce formation of new mineralized tissue after ESWT., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Introduction: Complete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes., Patients and Methods: We quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 10 6 lymph node cells, i.e. the disseminated cancer cell density (DCCD)., Results: We uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCD NSN  = DCCD SN c /10 1 - c (c = 0.69; 95% confidence interval [CI]: 0.62-0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCD SN (p = 0.02; HR 1.34, 95% CI: 1.05-1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07-2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCD SN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs., Conclusion: The assessment of DCCD SN renders CLND for staging purposes unnecessary., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of ~0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2, are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets.

Emerging evidence shows that oligodendrogenesis and myelination are highly responsive to behavioral experience, including physical activity and social experience. This form of myelin plasticity is being increasingly appreciated and examined in the prefrontal cortex (PFC), a critical brain region involved in complex emotional and cognitive behavior. However, it remains unclear whether myelination in other brain regions is affected by behavioral experience. Here we report that exposure to 4 weeks of chronic variable stress induced anxiety- and depressive-like behavior in male adult mice. In concert with these behavioral responses, transcriptional analysis of PFC, and nucleus accumbens (NAc)-a brain region critical for reward response-revealed downregulation of transcripts encoding for myelin genes and oligodendrocyte-specific genes. In contrast, upregulation of myelin-related transcripts was observed in the corpus callosum (CC), whereas the amygdala (AMG) did not show significant changes. Shorter exposure to the same stressors induced behavioral changes to a less extent and was followed by a stress habituation period. However, reduced myelin and oligodendrocyte-specific gene transcripts were detected as early as one week following stress exposure in the PFC and NAc. These data indicate that oligodendrocyte and their progenitors in multiple brain regions are responsive to stressful experiences and show distinctive and region-specific patterns of gene expression. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 152-162, 2018., (© 2017 Wiley Periodicals, Inc.)

Background: Airway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations that are mechanistically undefined. The leukotriene (LT) and wingless/integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive., Objective: We sought to study the activation of the LT and Wnt pathways during early- or late-onset allergic airway inflammation and to address regulatory mechanisms and clinical relevance in normal human bronchial epithelial cells (NHBEs) and nasal polyp tissues., Methods: Mice were sensitized with house dust mite (HDM) allergens from days 3, 15, or 60 after birth. Remodeling factors in murine bronchoalveolar lavage fluid, lung tissue, or human nasal polyp tissue were analyzed by means of Western blotting, immunoassays, or histology. Regulatory mechanisms were studied in cytokine/HDM-stimulated NHBEs and macrophages., Results: Bronchoalveolar lavage fluid LT levels were increased in neonatal and adult but reduced in juvenile HDM-sensitized mice. Lungs of neonatally sensitized mice showed increased 5-lipoxygenase levels, whereas adult mice expressed more group 10 secretory phospholipase A 2 , Wnt5a, and transglutaminase 2 (Tgm2). Older mice showed colocalization of Wnt5a and LT enzymes in the epithelium, a pattern also observed in human nasal polyps. IL-4 promoted epithelial Wnt5a secretion, which upregulated macrophage Tgm2 expression, and Tgm2 inhibition in turn reduced LT release. Tgm2, group 10 secretory phospholipase A 2 , and LT enzymes in NHBEs and nasal polyps were refractory to corticosteroids., Conclusion: Our findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, Tgm2, and LTs, which might represent a therapeutic target for airway inflammation and remodeling., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The asymptotically homogeneous SIR model of Thieme (1992) for growing populations, with incidence depending in a general way on total population size, is reconsidered with respect to other parameterizations that give clear insight into epidemiological relevant relations and thresholds. One important feature of the present approach is case fatality as opposed to differential mortality. Although case fatality models and differential mortality models are equivalent via a transformation in parameter space, the underlying ideas and the dynamic behaviors are different, e.g. the basic reproduction number depends on differential mortality but not on case fatality. The persistent distributions and exponents of growth of infected solutions are computed and discussed in terms of the parameters. The notion of asymptotically exponentially growing state (as opposed to stationary state or exponential solution) coined by Thieme is interpreted in terms of stability theory. Of some interest are limiting cases of models without recovery where two infected solutions exist., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We studied whether care management is a pragmatic solution for improving population blood pressure (BP) control and addressing BP disparities between Blacks and Whites in routine clinical environments., Design: Quasi-experimental, observational study., Setting and Participants: 3,964 uncontrolled hypertensive patients receiving primary care within the last year from one of six Baltimore clinics were identified as eligible., Intervention: Three in-person sessions over three months with registered dietitians and pharmacists who addressed medication titration, patient adherence to healthy behaviors and medication, and disparities-related barriers., Main Measures: We assessed the population impact of care management using the RE-AIM framework. To evaluate effectiveness in improving BP, we used unadjusted, adjusted, and propensity-score matched differences-in-differences models to compare those who completed all sessions with partial completers and non-participants., Results: Of all eligible patients, 5% participated in care management. Of 629 patients who entered care management, 245 (39%) completed all three sessions. Those completing all sessions on average reached BP control (mean BP 137/78) and experienced 9 mm Hg systolic blood pressure (P<.001) and 4 mm Hg DBP (P=.004) greater improvement than non-participants; findings did not vary in adjusted or propensity-score matched models. Disparities in systolic and diastolic BP between Blacks and Whites were not detectable at completion., Conclusions: It may be possible to achieve BP control among both Black and White patients who participate in a few sessions of care management. However, the very limited reach and patient challenges with program completion should raise significant caution with relying on care management alone to improve population BP control and eliminate related disparities.

Interferon-γ (IFN-γ) and interleukin-4 (IL-4) are key effector cytokines for the differentiation of T helper type 1 and 2 (Th1 and Th2) cells. Both cytokines induce fate-decisive transcription factors such as GATA3 and TBX21 that antagonize the polarized development of opposite phenotypes by direct regulation of each other's expression along with many other target genes. Although it is well established that mesenchymal cells directly respond to Th1 and Th2 cytokines, the nature of antagonistic differentiation programs in airway epithelial cells is only partially understood. In this study, primary normal human bronchial epithelial cells (NHBEs) were exposed to IL-4, IFN-γ, or both and genome-wide transcriptome analysis was performed. The study uncovers an antagonistic regulation pattern of IL-4 and IFN-γ in NHBEs, translating the Th1/Th2 antagonism directly in epithelial gene regulation. IL-4- and IFN-γ-induced transcription factor hubs form clusters, present in antagonistically and polarized gene regulation networks. Furthermore, the IL-4-dependent induction of IL-24 observed in rhinitis patients was downregulated by IFN-γ, and therefore IL-24 represents a potential biomarker of allergic inflammation and a Th2 polarized condition of the epithelium.

Background: To improve understanding of shockwave therapy mechanisms, in vitro experiments are conducted and the correlation between cell reaction and shockwave parameters like the maximum pressure or energy density is studied. If the shockwave is not measured in the experimental setup used, it is usually assumed that the device's shockwave parameters (=manufacturer's free field measurements) are valid. But this applies only for in vitro setups which do not modify the shockwave, e.g., by reflection or refraction. We hypothesize that most setups used for in vitro shockwave experiments described in the literature influence the sound field significantly so that correlations between the physical parameters and the biological reaction are not valid., Methods: To reveal the components of common shockwave in vitro setups which mainly influence the sound field, 32 publications with 37 setups used for focused shockwave experiments were reviewed and evaluated regarding cavitation, cell container material, focal sound field size relative to cell model size, and distance between treated cells and air. For further evaluation of the severity of those influences, experiments and calculations were conducted., Results: In 37 setups, 17 different combinations of coupling, cell container, and cell model are described. The setup used mainly is a transducer coupled via water to a tube filled with a cell suspension. As changes of the shockwaves' maximum pressure of 11 % can already induce changes of the biological reaction, the sound field and biological reactions are mainly disturbed by use of standard cell containers, use of coupling gel, air within the 5 MPa focal zone, and cell model sizes which are bigger than half the -6 dB focal dimensions., Conclusions: Until now, correct and sufficient information about the shockwave influencing cells in vitro is only provided in 1 of 32 publications. Based on these findings, guidelines for improved in vitro setups are proposed which help minimize the influence of the setup on the sound field.

Background: With the advent of computer-assisted three-dimensional surface imaging and rapid data processing, oral and maxillofacial surgeons and orthodontists are enabled to analyze facial growth three dimensionally. Normative data, however, are still rare and inconsistent. The aim of the present study was to establish a valid reference system and to give normative data for facial growth., Methods: Three-dimensional facial surface images were obtained from 344 healthy Caucasian children (aged 0 to 7 years). The images were put in correspondence by means of six landmarks close to the skull base (exocanthion, endocanthion, otobasion inferius). Growth curves for 21 landmarks were estimated in the three dimensions., Results: Facial regions close to the skull base (orbit and ear) showed a biphasic growth pattern, with accelerated growth during the first year of life that subsided to a decreased and linear velocity thereafter. Landmarks on the nose, lips, and chin demonstrated either a curvilinear or a linear growth pattern., Conclusions: The rapid increase of the orbit and ear region in infancy is a secondary phenomenon to the rapid growth of the neurocranium during the first year of life. Thereafter, maxillary and mandibular growth prevails. The present study gives three-dimensional normative data for an expanded growth span between birth and childhood.

Naive CD4(+) T cells are the common precursors of multiple effector and memory T-cell subsets and possess a high plasticity in terms of differentiation potential. This stem-cell-like character is important for cell therapies aiming at regeneration of specific immunity. Cell surface proteins are crucial for recognition and response to signals mediated by other cells or environmental changes. Knowledge of cell surface proteins of human naive CD4(+) T cells and their changes during the early phase of T-cell activation is urgently needed for a guided differentiation of naive T cells and may support the selection of pluripotent cells for cell therapy. Periodate oxidation and aniline-catalyzed oxime ligation technology was applied with subsequent quantitative liquid chromatography-tandem MS to generate a data set describing the surface proteome of primary human naive CD4(+) T cells and to monitor dynamic changes during the early phase of activation. This led to the identification of 173 N-glycosylated surface proteins. To independently confirm the proteomic data set and to analyze the cell surface by an alternative technique a systematic phenotypic expression analysis of surface antigens via flow cytometry was performed. This screening expanded the previous data set, resulting in 229 surface proteins, which were expressed on naive unstimulated and activated CD4(+) T cells. Furthermore, we generated a surface expression atlas based on transcriptome data, experimental annotation, and predicted subcellular localization, and correlated the proteomics result with this transcriptional data set. This extensive surface atlas provides an overall naive CD4(+) T cell surface resource and will enable future studies aiming at a deeper understanding of mechanisms of T-cell biology allowing the identification of novel immune targets usable for the development of therapeutic treatments., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival., Methods and Findings: We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3-123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61-2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02-2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories., Conclusions: Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically.

Objective: The number of desaturations determined in recordings of pulse oximeter saturation (SpO2) primarily depends on the time over which values are averaged. As the averaging time in pulse oximeters is not standardized, it varies considerably between centers. To make SpO2 data comparable, it is thus desirable to have a formula that allows conversion between desaturation rates obtained using different averaging times for various desaturation levels and minimal durations., Methods: Oxygen saturation was measured for 170 hours in 12 preterm infants with a mean number of 65 desaturations <90% per hour of arbitrary duration by using a pulse oximeter in a 2-4 s averaging mode. Using 7 different averaging times between 3 and 16 seconds, the raw red-to-infrared data were reprocessed to determine the number of desaturations (D). The whole procedure was carried out for 7 different minimal desaturation durations (≥ 1, ≥ 5, ≥ 10, ≥ 15, ≥ 20, ≥ 25, ≥ 30 s) below SpO2 threshold values of 80%, 85% or 90% to finally reach a conversion formula. The formula was validated by splitting the infants into two groups of six children each and using one group each as a training set and the other one as a test set., Results: Based on the linear relationship found between the logarithm of the desaturation rate and the logarithm of the averaging time, the conversion formula is: D2 = D1 (T2/T1)(c), where D2 is the desaturation rate for the desired averaging time T2, and D1 is the desaturation rate for the original averaging time T1, with the exponent c depending on the desaturation threshold and the minimal desaturation duration. The median error when applying this formula was 2.6%., Conclusion: This formula enables the conversion of desaturation rates between different averaging times for various desaturation thresholds and minimal desaturation durations.

Objective: Applying shock waves to the heart has been reported to stimulate the heart and alter cardiac function. We hypothesized that shock waves could be used to diagnose regional viability., Method: We used a Langendorff model to investigate the acute effects of shock waves at different energy levels and times related to systole, cycle duration and myocardial function., Results: We found only a small time window to use shock waves. Myocardial fibrillation or extrasystolic beats will occur if the shock wave is placed more than 15 ms before or 30 ms after the onset of systole. Increased contractility and augmented relaxation were observed after the second beat, and these effects decreased after prolonging the shock wave delay from 15 ms before to 30 ms after the onset of systole. An energy dependency could be found only after short delays (-15 ms). The involved processes might include post-extrasystolic potentiation and simultaneous pacing., Conclusion: In summary, we found that low-energy shock waves can be a useful tool to stimulate the myocardium at a distance and influence function., (Copyright © 2013 Elsevier B.V. All rights reserved.)

High light acclimation implicates mechanisms on various molecular levels and time scales. The recently identified small transcription factor network of APETALA 2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors is triggered upon transfer of Arabidopsis to high light and depends on metabolite export and mitogen activated protein kinase activation. An experimental design was developed consisting of a low light to high light and back to low light illumination. This allowed the determination of the time point of no return post high light transfer which activates transcription of the AP2/ERF network. Within 10 seconds of high light treatment transcript levels of ERF6, ERF104, ERF105 and RRTF were triggered to increase from low to high levels within the next 10 minutes witnessing an ultrafast retrograde pathway with a very early time point of no return. This response differed profoundly from other high light-responsive transcripts such as stromal ascorbate peroxidase (sAPX) which accumulated in a dose-dependent manner or COR47.

Background: The optimal treatment of complex, displaced proximal humeral fractures is controversial. A systematic literature review of the time period from 1970 to 2009 was conducted. The purpose was to evaluate the clinical success and complications of the available treatment modalities to determine specific treatment recommendations for the different fracture patterns., Methods: The databases (PubMed/EMBASE) were searched for the time period (01/1970-09/2009). Study quality, treatment modalities, classification, outcome scores and complications of 200 publications including 9377 patients were analyzed. Interventions were compared by analysis of variance with subsequent Tukey's-test. Complication rates among methods were compared by using Pearson's-chi-square-test and pairwise comparisons using Fisher's-two-tailed-exact-test., Results: Hemiarthroplasty, angle-stable plate and non-operative treatment were used for 63% of the follow-up-patients. For 3- and 4-part fractures, patients with hemiarthroplasty [3-Part: 56.4 (lower/upper 95% confidence interval (CI): 43.3-68.7); 4-Part: 49.4 (CI: 42.2-56.7)] received a lower score than different surgical head-preserving methods such as ORIF [3-Part: 82.4 (CI: 76.6-86.9); 4-Part: 83.0 (CI:78.7-86.6)], intramedullary nailing [3-Part: 79.1 (CI:74.0-83.4)] or angle-stable plates [4-Part: 66.4 (CI: 59.7-72.4)].The overall complication rate was 56%. The most common complications were fracture-displacement, malunion, humeral head necrosis and malreduction. The highest complication rates were documented for conventional plate and hemiarthroplasty and for AO-C, AO-A, for 3- and 4-part fractures. Only 25% of the data were reported with detailed classification results and the corresponding outcome scores., Discussion: Despite the large amount of patients included, it is difficult to determine adequate recommendations for the treatment of proximal humeral fractures because a relevant lack of follow-up data impaired subsequent analysis. For displaced 3- and 4-part fractures head-preserving therapy received better outcome scores than hemiarthroplasty. However, a higher number of complications occurred in more complex fractures and when hemiarthroplasty or conventional plate osteosynthesis was performed. Thus, when informing the patient for consent, both the clinical results and the possibly expected complications with a chosen treatment modality should be addressed.

Hypophosphatasia (HPP) is a heterogeneous rare, inherited disorder of bone and mineral metabolism caused by different mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease. TNAP deficiency, however, may also result in neurological symptoms such as neonatal seizures. The exact biological role of TNAP in the human brain is still not known and the pathophysiology of neurological symptoms due to TNAP deficiency in HPP is not understood in detail. In this report, we describe the clinical features and functional studies of a patient with severe perinatal HPP which presented with rapidly progressive encephalopathy caused by new compound heterozygous mutations in the ALPL gene which result in a functional ALPL "knock out", demonstrated in vitro. In contrast, an in vitro simulation of the genetic status of his currently asymptomatic parents who are both heterozygous for one mutation, showed a residual in vitro AP activity of above 50%. Interestingly, in our patient, the fatal outcome was due to progressive encephalopathy which was refractory to antiepileptic therapy including pyridoxine, rather than hypomineralization and respiratory insufficiency often seen in HPP patients. The patient's cranial MRI showed progressive cystic degradation of the cortex and peripheral white matter with nearly complete destruction of the cerebrum. To our knowledge, this is the first MRI-based report of a deleterious neurological clinical outcome due to a progressive encephalopathy in an infant harboring a functional human ALPL "knock out". This clinical course of disease suggests that TNAP is involved in development and may be responsible for multiple functions of the human brain. According to our data, a certain amount of residual TNAP activity might be mandatory for normal CNS function in newborns and early childhood., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Pulse oximeter saturation values are usually obtained by averaging over preceding measurements. This study investigates the dynamics between the averaging time and desaturation level, duration and extent., Methods and Results: Prospective observational study of 15 preterm infants. Oxygen saturation was recorded for 168 h using a pulse oximeter. The raw red-to-infrared data were reprocessed using seven different averaging times to determine the number of desaturations below four thresholds and for seven different minimal desaturation durations. The total number of desaturations <80% was 339 with an averaging time of 16 s and 1958 with an averaging time of 3 s (minimal event duration >0 s). There was a significantly lower pulse oximeter saturation nadir with the shorter averaging time, while the maximum duration was significantly longer when using a 16 s averaging time., Conclusions: When using pulse oximeters, more attention should be given to averaging time and duration of desaturations.

Rubella in early pregnancy bears a high risk for congenital defects (e.g., cataracts, hearing loss, and heart disease) and for long-term sequelae in the newborn. Despite implementation of vaccination programs in many regions, the threat of devastating consequences from congenital rubella virus infection remains and careful screening of maternal immune status before and during pregnancy helps to reduce the risk. This study compared the performance of the Elecsys Rubella IgG assay with that of other assays routinely used for screening. Samples from 1,090 women undergoing routine antenatal care were tested using the Elecsys and Enzygnost Rubella IgG assays and the hemagglutination inhibition test. Samples with hemagglutination inhibition titers of <32 (n = 148) were additionally tested using the Vidas, AxSYM, Liaison, and Architect Rubella IgG assays. Agreement of qualitative results from the Elecsys, Enzygnost, and hemagglutination inhibition assays was good in all samples. All assays showed 100.0% specificity. In samples with hemagglutination inhibition titers of <32, the Elecsys, AxSYM, and Enzygnost assays showed higher sensitivity (>90.0%) than the other immunoassays (78.6 to 82.4%). The Elecsys assay reported significantly higher rubella virus IgG levels than the other immunoassays across the whole set of 1,090 samples, with the largest bias and deviation from limits of agreement in Bland-Altman analysis. In conclusion, the Elecsys assay is highly sensitive and specific with regard to qualitative results and suitable for routine automated screening. However, given the considerable variation between quantitative results from different immunoassays, testing methods should be documented and the same assay used throughout an individual's antenatal follow-up wherever possible.

Children with cleft lip or cleft lip and alveolus represent a minor group in the cleft population. The aim of this study was to analyze the faces of these children. In a prospective, cross-sectional study, 344 healthy children and 30 children with cleft lip or cleft lip and alveolus were scanned three-dimensionally at the age of 0 to 6 years. Twenty-one standard anthropometric landmarks were identified, and the images were superimposed. Growth curves for normal facial development were calculated. The facial morphology of cleft children was compared with that of unaffected children.Facial morphology and growth in the transverse direction of the examined patients appeared broadened in all levels. Especially the nasal landmarks indicated a widening of the nose. The landmarks ac l, sbal l, sbal r, c l, sn l, and ls l differed significantly from unaffected children. In the sagittal and vertical dimensions, there was no significant difference compared with unaffected children.Our study demonstrates that surgical and orthodontic treatment can restore the vertical and sagittal dimensions of the face in children with cleft lip with and without alveolar clefts; however, the transverse dimension-especially the nose-remains too broad.

Protracted social isolation of adult mice induced behavioral, transcriptional and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC) and impaired adult myelination. Social re-integration was sufficient to normalize behavioral and transcriptional changes. Short periods of isolation affected chromatin and myelin, but did not induce behavioral changes. Thus, myelinating oligodendrocytes in the adult PFC respond to social interaction with chromatin changes, suggesting that myelination acts as a form of adult plasticity.

Objective: To examine the impact of rapidly changing environmental factors on the incidence of type 1 diabetes mellitus (T1D)., Method: We compared the frequency of T1D in children before and after the reunification of Germany by means of the registries of the German Democratic Republic (GDR, 1960-1989) and of Baden-Wuerttemberg (BW, 1987-2006). The number of cases of diabetes onset in East Germany after the reunification was predicted by a mathematical model. The observed incidence rate in the Eastern part of Germany after the reunification was taken from the literature 1., Results: In Germany, the incidence rate of T1D in children aged 0-14 was 7.2/100 000/year (95%-CI 6.9-7.5, GDR, 1980-1987), and 10.4/100 000/year (95%-CI 9.5-11.4, BW, 1987-1994). For the whole observation period (1960-2006), the observed incidence rates y could be described by the square of a linear function [GDR: y=(1.86 + 0.040 * (year - 1960))²; r²=0.85; BW: y=(3.03 + 0.085 * (year - 1987))², r²=0.89]. The mean rise in incidence before the reunification was less than half the mean rise after the reunification (mean slope: BW 0.085, 95%-CI 0.080-0.090 vs. GDR 0.040, 95% CI 0.036-0.044). The observed incidence for East Germany after 1989 was higher than the prediction on the basis of the GDR -registry (GDR 12.3/100 000/year vs. Saxony 15.7/100 000/year, 95%-CI 14.2-17.3, n=412; 1999-2003)., Conclusion: We conclude that the basis for the disease progress is a genetic predisposition. Environmental factors may modify changes in incidence of type 1 diabetes but do not determine the overall risk., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: There is a need for standardized texts to assess reading performance, for multiple equivalent texts for repeated measurements, and for texts equated across languages for multi-language studies. Paragraphs are preferable to single sentences for accurate speed measurement. We developed such texts previously in 6 languages. The aim of our current study was to develop texts in more languages for a wide range of countries and users, and to assess the reading speeds of normally-sighted readers., Methods: Ten texts were designed for 17 languages each by a linguist who matched content, length, difficulty, and linguistic complexity. The texts then were used to assess reading speeds of 436 normally-sighted native speakers (age 18-35 years, 25 per language, 36 in Japanese), presented at a distance of 40 cm and size 1 M, that is 10-point Times New Roman font. Reading time (aloud) was measured by stopwatch., Results: For all 17 languages, average mean reading speed was 1.42 ± 0.13 texts/min (±SD), 184 ± 29 words/min, 370 ± 80 syllables/min, and 863 ± 234 characters/min. For 14 languages, mean reading time was 68 ms/character (95% confidence interval [CI] 65-71 ms). Our analysis focussed on words per minute. The variability of reading speed within subjects accounts only for an average of 11.5%, between subjects for 88.5%., Conclusions: The low within-subject variability shows the equivalence of the texts. The IReST (second edition) can now be provided in 17 languages allowing standardized assessment of reading speed, as well as comparability of results before and after interventions, and is a useful tool for multi-language studies (for further information see www.amd-read.net).

Purpose: The aim of this study was to assess the brain regions associated with impaired performance in a virtual, dynamic collision avoidance task, in a group of patients with homonymous visual field defects (HVFDs) because of unilateral vascular brain lesions., Methods: Overall task performance was quantitatively assessed as the number of collisions while crossing an intersection at two levels of traffic density. Twenty-six patients were divided into two subgroups using the median split method: patients with 'performance above average' (HVFD(A), i.e. lower number of collisions) and patients with 'performance below average' (HVFD(B), i.e. higher number of collisions). In order to identify the anatomical structures that might be specifically affected in HVFD(B) patients but spared in HVFD(A) patients, overlap, subtraction and voxel-based lesion-symptom mapping analyses were performed using the MRIcron software., Results: No significant difference in collision avoidance between patients with left- and right-hemispheric lesions was revealed. Separate lesion analysis in 12 patients with right- and 14 patients with left-hemispheric lesions showed that the cortical structures associated with impaired collision avoidance were the parieto-occipital region and posterior cingulate gyrus in the right hemisphere and the inferior occipital cortex and parts of the fusiform (occipito-temporal) gyrus in the left hemisphere., Conclusion: In the present collision avoidance paradigm, impaired performance of patients with right-hemispheric lesions is associated with damage in the dorsal processing stream and potential impact on the visual spatial working memory (WM), while impaired performance of patients with left-hemispheric lesions is associated with damage in the ventral stream and potential impact on the visual object WM., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To identify the variable with the strongest association between the magnitude of the relative afferent pupillary defect (RAPD) and visual field indices in patients with glaucomatous optic neuropathy., Methods: Seventy-nine consecutive subjects with manifest glaucomatous optic neuropathy at least in one eye were enrolled in this retrospective study. RAPD was assessed with the swinging flashlight test and quantified with a neutral density filter. Perimetry was performed using the fast thresholding strategy German Adaptive Threshold Estimation. The values of the central differential luminance sensitivity (DLS), of the MD (mean defect) and of the 'loss volume' (LVOL) based on the individually modelled 3D hill of vision-the latter two within the eccentricities of 10°, 20° and 30°, respectively-were entered into a linear regression model without intercept as a function of RAPD., Results: An absolute value of RAPD of 0.3 log(10) units or more was present in 20 out of 79 glaucoma subjects (25%). The magnitude of RAPD was most closely associated with LVOL-30° (R(2)=0.77), followed by MD-30° (R(2)=0.73), MD-20° (R(2)=0.71), LVOL-20° (R(2)=0.67), MD-10° (R(2)=0.58), LVOL-10° (R(2)=0.54) and central DLS (R(2)=0.04)., Conclusions: The prevalence of RAPD in glaucoma patients is comparatively small (25%). The magnitude of RAPD in glaucoma subjects is associated most closely with the LVOL within 30° eccentricity (which is the maximum visual field region tested in this study) and most loosely with central DLS, underscoring the impact of the entire (30°) visual field area on the afferent pupillary system.

Aims: We aimed to demonstrate that Hypericin, a component of St. Johns Wort, selectively visualizes malignant gliomas. Hypericin is known as one of the most powerful photosensitizers in nature with excellent fluorescent properties., Methods: In five patients with a recurrence of a malignant glioma a newly developed water soluble formulation of hypericin was given intravenously (0.1 mg/kg body weight) 6 h before the surgical procedure. Tumor resection was performed under white light and fluorescence mode. The intensity grade of the tissue fluorescence was categorisized by the surgeon in three grades, highly fluorescent, weakly fluorescent and not fluorescent. In these areas tissue samples were taken and investigated by two blinded independent neuropathologists. Tissue samples were histologically classified differentiating between tumor tissue, tumor necrosis, tissue with scattered tumor cells and normal brain tissue., Results: In all patients tumor tissue was clearly distinguishable by its typically red fluorescence color from normal brain tissue which was colored blue under a special fluorescent filter. Histological evaluation of the 110 tissue samples showed a specificity of 100% and sensitivity of 91% for one of the two neuropathologists, whereas specificity for second pathologist was 90% and sensitivity 94%. The i.v. application of Hypericin proofed to be safe in all cases and there were no side effects observed., Conclusion: Hypericin in its water soluble form is a well tolerated drug. In addition to its high photosensitizing properties hypericin will open up interesting new therapeutic possibilities especially when used in combination with fluorescence detection and simultaneously photodynamic therapy., (© 2011 Elsevier Ltd. All rights reserved.)

Objective: To provide data on type 1 diabetes (T1D) epidemiology in childhood over a period of 20 years and to predict prevalence and cohort-age-specific incidence rates (IRs) for the next two decades in Germany., Methods: The Baden-Wuerttemberg Diabetes Incidence Registry (DIARY) includes children and adolescents below 15 years of age with new onset of T1D (period 1987-2006, n = 5108 cases)., Results: The mean age- and sex-standardized IR was 15.3/100 000/year (95% CI 14.8-15.7) and the average increase in the IR was 4.4% per year (95% CI 3.9-4.9). Within the next 20 years (2007-2026), the risk for developing diabetes will increase like the square of a linear function with calendar year for all age ranges. There is a strong correlation between the predicted IRs of the cohorts and the observed IRs (n = 300; root mean square error = 0.56; r(2) = 0.71) and a negative correlation between mean age at onset and T1D IR (p = 0.02). On 31 December 2006, the prevalence of T1D was 0.126% (95% CI 0.121-0.132). The predicted prevalence (end of 2026) is estimated to be 0.265% (95% CI 0.25-0.28; predicted cases: n = 2950; 95% CI 2900-3000)., Conclusions: In comparison to observations made in the past, the risk of disease rises even faster than expected: The younger the child, the quicker the increase of the cohort-age-specific IR and the higher the risk for T1D during lifetime., (© 2011 John Wiley & Sons A/S.)

Background: Hypericin (HYP) is a naturally occurring photosensitizer. Cellular uptake and photodynamic inactivation after incubation with this photosensitizer have neither been examined in medulloblastoma cells in vitro, nor compared with 5-aminolevulinic acid-derived protoporphyrin IX (5-ALA-derived PpIX)., Methods: In 3 medulloblastoma cell lines (D283 Med, Daoy, and D341 Med) the time- and concentration-dependent intracellular accumulation of HYP and 5-ALA-derived PpIX was analyzed by fluorescence microscopy (FM) and FACS. Photocytotoxicity was measured after illumination at 595 nm (HYP) and 635 nm (5-ALA-derived PpIX) in D283 Med cells and compared to U373 MG glioma cells., Results: All medulloblastoma cell lines exhibited concentration- and time-dependent uptake of HYP. Incubation with HYP up to 10 µM resulted in a rapid increase in fluorescence intensity, which peaked between 2 and 4 hours. 5-ALA-derived PpIX accumulation increased in D283 Med cells by 22% over baseline after 5-ALA incubation up to 1.2 mM. Photocytotoxicity of 5-ALA-derived PpIX was higher in D283 Med medulloblastoma compared to U373MG glioma. The LD50 [lethal dose (light dose that is required to reduce cell survival to 50% of control)] of 5-ALA-derived PpIX was 3.8 J/cm(2) in D283 Med cells versus 5.7 J/cm2 in U373MG glioma cells. Photocytotoxicity of HYP in D283 Med cells was determined at 2.5 µM after an incubation time of 2 h and an illumination wavelength of 595 nm. The [Formula: see text] value was 0.47 J/cm(2)., Conclusion: By its 5-fold increase in fluorescence over autofluorescence levels HYP has excellent properties for tumor visualization in medulloblastomas. The high photocytotoxicity of HYP, compared to 5-ALA-derived PpIX, is convincingly demonstrated by its 8- to 13-fold lower LD50. Therefore HYP might be a promising molecule for intraoperative visualization and photodynamic treatment of medulloblastomas.