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This hypothesis-testing study evaluated the relationship between fetal alcohol syndrome (FAS) and neurodevelopmental disorder (ND) diagnoses within the Independent Healthcare Research Database (IHRD).De-identified eligibility and claim healthcare records prospectively generated from the 1990-2012 Florida Medicaid system were analyzed using SAS software. There were 89,766 children continuously eligible with ≥10 outpatient office visits during the 120 month period following birth in the cohort examined. A total of 321 children were diagnosed with FAS. Autism spectrum disorder (ASD) (n = 922), tics (n = 551), attention deficit disorder/attention deficit-hyperactivity disorder (ADD/ADHD) (n = 20,260), mental retardation (MR) (n = 915), and specific delays in development (SDD) (n = 24,630) incidence rates were examined using frequency risk ratio (RR) and logistic regression models.The incidence rate of tics (RR = 5.68), ADD/ADHD (RR = 2.30), MR (RR = 7.83), SDD (RR = 2.88), and ASD (RR = 6.74) were significantly increased among FAS diagnosed children as compared to undiagnosed children. Adjusted (for gender, race, residency, and date of birth) odds ratios (ORs) were significantly increased for tics (OR = 4.87), ADD/ADHD (OR = 3.40), MR (OR = 7.91), SDD (OR = 9.56), and ASD (OR = 6.87) when comparing the FAS diagnosed children to undiagnosed children.Tens of thousands of American children with lifetime costs in the billions of US dollars were estimated to be impacted by FAS-associated NDs. These impacts are particularly tragic because FAS is dependent upon lifestyle.

Although the use of nondrug rewards (e.g., money) to facilitate smoking cessation is widespread, recent research has found that such rewards may be least effective when people who smoke cigarettes are tempted to do so. Specifically, among people who smoke, the neural response to nondrug rewards appears blunted when access to cigarettes is anticipated, and this blunting is linked to a decrease in willingness to refrain from smoking to earn a monetary incentive. Accordingly, methods to enhance the value of nondrug rewards may be theoretically and clinically important. The current proof-of-concept study tested if real-time fMRI neurofeedback training augments the ability to upregulate responses in reward-related brain areas relative to a no-feedback control condition in people who smoke. Adults (n = 44, age range = 20 – 44) who reported smoking >5 cigarettes per day completed the study. Those in the intervention group (n = 22, 5 female) were trained to upregulate brain responses using feedback of ongoing brain activity (i.e., a dynamic “thermometer” that reflected ongoing changes in reward-related fMRI signal intensity) in a single neurofeedback session with three training runs. The control group (n = 22, 5 female) underwent a nearly identical procedure but received no neurofeedback. Those who received neurofeedback training demonstrated significantly greater increases in striatal BOLD activation compared to controls, but this effect was present only during the first training run. The potential implications of these findings for smoking cessation strategies, as well as directions for neurofeedback research in this population, are discussed.

Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell-targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell-suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.

Positioning of the implant components and tibial insert thickness constitute critical aspects of total knee replacement (TKR) that influence the postoperative knee joint dynamics. This study aimed to investigate the impact of implant component positioning (anterior-posterior and medio-lateral shift) and varying tibial insert thickness on the tibio-femoral (TF) and patello-femoral (PF) joint kinematics and contact forces after cruciate-retaining (CR)-TKR.A validated musculoskeletal multibody simulation (MMBS) model with a fixed-bearing CR-TKR during a squat motion up to 90° knee flexion was deployed to calculate PF and TF joint dynamics for varied implant component positions and tibial insert thicknesses. Evaluation was performed consecutively by comparing the respective knee joint parameters (e.g. contact force, quadriceps muscle force, joint kinematics) to a reference implant position.The PF contact forces were mostly affected by the anterior-posterior as well as medio-lateral positioning of the femoral component (by 3 mm anterior up to 31 % and by 6 mm lateral up to 14 %). TF contact forces were considerably altered by tibial insert thickness (24 % in case of + 4 mm increase) and by the anterior-posterior position of the femoral component (by 3 mm posterior up to 16 %). Concerning PF kinematics, a medialised femoral component by 6 mm increased the lateral patellar tilt by more than 5°.Our results indicate that regarding PF kinematics and contact forces the positioning of the femoral component was more critical than the tibial component. The positioning of the femoral component in anterior-posterior direction on and PF contact force was evident. Orthopaedic surgeons should strictly monitor the anterior-posterior as well as the medio-lateral position of the femoral component and the insert thickness.

Background Non-alcoholic fatty liver disease (NAFLD) affects more than 18 million individuals in Germany. Real-world data help to better characterize the natural history of disease and standard of care. Methods The German NAFLD-Registry is a prospective non-interventional study initiated by the German Liver Foundation and aims to describe clinical characteristics and observe outcomes in patients with NAFLD recruited in secondary and tertiary care. Results From this ongoing study, baseline data of the first 501 patients (mean age 54 years, 48% women) were analysed. 13 % of the study population had a high risk for advanced fibrosis (FIB-4 ≥2.67), approximately one-third had a liver stiffness value ≥9.6kPa measured by transient elastography, and the clinical diagnosis of liver cirrhosis was present in 10%. Typical comorbidities were more prevalent in high risk as compared to low risk patients (FIB-4 Conclusion First data of the German NAFLD registry show that approximately every 10th patient has advanced NAFLD, highlights T2DM patients as a high-risk group and gives insights in the use of comedication and life-style interventions in secondary and tertiary care.

Growing e-commerce leads to more traffic, congestion and emissions in cities due to the increasing parcel volumes. Parcel stations can represent a sustainable form of parcel delivery to private households. This paper addresses the research question under which conditions the use of parcel stations can make a relevant contribution to climate-friendly urban logistics. First, the sustainability of parcel stations is evaluated; then, the usage behavior and the acceptance of the recipients is analyzed in order to identify fields of action for increasing acceptance and the need for further research. The data source for this work is a systematic search of current literature and research projects.

Hexanucleotide repeat expansion (HRE) withinC9orf72is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, includingC9orf72HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheralC9orf72expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects ofC9orf72HRE and clinical diagnosis (n= 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheralC9orf72expression, TE activation, thalamic atrophy, and clinical severity (n= 114 individuals, male and female). We confirmed global thalamic atrophy and reducedC9orf72expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed thatC9orf72expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 elementL1HS.L1HSlevels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated thatC9orf72levels relate to clinical severity, and identified marked derepression of TEs, includingL1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENTPathogenic repeat expansion inC9orf72is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction ofC9orf72in blood and found broad dysregulation of transposable elements—genetic elements typically repressed in the human genome—in symptomaticC9orf72expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD.C9orf72expression was also associated with clinical severity, suggesting that peripheralC9orf72levels capture disease-relevant information.

Immunotherapy has become the standard of care in advanced HCC but is only approved in first- or second-line treatment. We report a patient with HCC refractory to several lines of tyrosine kinase inhibitors, who was treated with Ipilimumab and Nivolumab (Ipi/Nivo) as the fourth line. The tumor responded profoundly to Ipi/Nivo. Established biomarker-predicting responses to immunotherapy, such as a high PD-L1 staining, a high combined-positive score, microsatellite instability or a high tumor mutational burden, were not detected. Potential negative predictive markers for response to immunotherapy such as CTNNB1 and TERT were present. This constellation puts the spotlight on two mutations observed here in the SET domain-containing 2 (SETD2) and low-density lipoprotein receptor-related protein 1b (LRP1B) genes, which may explain the outstanding response. Our case demonstrates that immunotherapy can be efficient in a late-line scenario, resulting in long-term survival. Further studies should prospectively evaluate the value of SETD2 and LRP1B alterations as predictors for the success of immunotherapy in HCC.Die Immuntherapie wurde der Therapiestandard für die Behandlung des fortgeschrittenen HCC, ist allerdings nur in der Erst- oder Zweitlinie zugelassen. Wir berichten hier über einen Patienten mit HCC, der in einer TKI-refraktären Situation mit Ipi/Nivo in der Viertlinie therapiert wurde. Der Tumor sprach profunde auf die Therapie mit Ipi/Nivo an. Etablierte Biomarker, die ein Ansprechen auf eine Immuntherapie voraussagen können, wie eine hohe PD-L1-Expression, ein hoher

This paper presents the findings from a series of participatory design workshops with LGBTQ people living in the rural Midwestern United States. Using future workshops as a method, we seek to understand contemporary problems facing rural LGBTQ people and leverage design exercises to facilitate community members to come up with creative solutions. What we find are people grappling with the complexities of visibility, safety, and resource access in their rural communities; people who wanted to be able to use and create sociotechnical solutions that could help them navigate these complexities. Drawing on these findings, we argue for further exploration of design that experiments with the tension between visibility and safety for LGBTQ people. Further, we argue that future workshops and participatory design are well-positioned for continued work with marginalized communities, but that we need to maintain political orientations towards liberation and justice.?

Massage therapists are particularly exposed to constituents of massage preparations, wet work and mechanical strain and therefore, at high risk to develop occupational dermatitis (OD).To describe the sensitization spectrum of massage therapists with OD.In a retrospective study, patch test data of patients with OD (128 massage therapists and 24 374 patients working in other professions) collected by the Network of Departments of Dermatology (IVDK, 2008-2020) were analysed.Hand dermatitis (91.4%) and allergic contact dermatitis (34.4%) were common in massage therapists with OD. Most frequent were sensitizations to fragrances/essential oils which were found in 54 (42.2%) massage therapists and thus, more often than in other patients with OD. Concomitant positivity to several fragrances/essential oils was frequent. In 8 (14.8%) of the 54 massage therapists, sensitizations to fragrances/essential oils were not detected with the baseline series, but only with special fragrance series.Allergic contact dermatitis is common in massage therapists with OD and is mainly caused by fragrances and essential oils. Hence, massage therapists should be aware of this risk. When OD is suspected, not only the baseline series, but also special fragrance series should be patch tested in this occupational group.

Zusammenfassung Hintergrund Obwohl allergologische Erkrankungen zu den wichtigen Gesundheitsstörungen laut ärztlicher Approbationsordnung zählen, ist die Allergologie in Deutschland nicht als selbstständiges Fach im Studium der Humanmedizin verankert. Ziel der Arbeit Da sämtliche Universitäts- und Hochschulstandorte mit dieser Herausforderung umgehen müssen, war es Ziel unseres Lehrprojekts, eine exemplarische und mit allen beteiligten Kliniken und Instituten abgestimmte Koordination und Verzahnung der allergologischen Lehre an einem Standort zu etablieren. Insbesondere Comprehensive Allergy Centers (CAC) bieten eine bereits vorhandene Infrastruktur, in der diese Neukonzeption der allergologischen Lehre auf andere Standorte übertragen werden könnte. Material und Methoden Nach umfangreicher Bestandsaufnahme der aktuellen allergologischen Lehre an der Universitätsmedizin Göttingen wurde im interdisziplinären Konsens ein neues Lehrkonzept entwickelt, durch die Bereitstellung zusätzlicher digitaler Lehr- und Lernanteile ergänzt („blended learning“) und schließlich evaluiert. Ergebnisse Die allergologische Lehre im klinischen Studienabschnitt zeigte eine starke Fragmentierung, die ohne Koordination der zwölf beteiligten Kliniken/Institute und ohne Abstimmung der jeweiligen Lerninhalte stattfand. In der etablierten Struktur des interdisziplinären CAC erfolgte eine Neukonzeption, Koordination und Schwerpunktsetzung der studentischen Lehre zur klinischen Allergologie. Die Bereitstellung von neuen interaktiven Lerneinheiten sowie ergänzender Materialien zum Selbststudium wurden von den Studierenden positiv bewertet. Eine vergleichende Evaluation von Studierenden nach Absolvieren der unterschiedlichen Curricula zeigte signifikante Verbesserungen im Erreichen der gewünschten Lernziele.

Systems consolidation of new experiences into lasting episodic memories involves hippocampal–neocortical interactions. Evidence of this process is already observed during early post-encoding rest periods, both as increased hippocampal coupling with task-relevant perceptual regions and reactivation of stimulus-specific patterns following intensive encoding tasks. We investigate the spatial and temporal characteristics of these hippocampally anchored post-encoding neocortical modulations. Eighty-nine adults participated in an experiment consisting of interleaved memory task- and resting-state periods. We observed increased post-encoding functional connectivity between hippocampus and individually localized neocortical regions responsive to stimuli encountered during memory encoding. Post-encoding modulations were manifested as a nearly system-wide upregulation in hippocampal coupling with all major functional networks. The configuration of these extensive modulations resembled hippocampal–neocortical interaction patterns estimated from active encoding operations, suggesting hippocampal post-encoding involvement exceeds perceptual aspects. Reinstatement of encoding patterns was not observed in resting-state scans collected 12 h later, nor when using other candidate seed regions. The similarity in hippocampal functional coupling between online memory encoding and offline post-encoding rest suggests reactivation in humans involves a spectrum of cognitive processes engaged during the experience of an event. There were no age effects, suggesting that upregulation of hippocampal–neocortical connectivity represents a general phenomenon seen across the adult lifespan.

ImportanceThe common use of isothiazolinones as preservatives is a global cause of allergic contact dermatitis. Differences in allowable concentrations of methylisothiazolinone (MI) exist in Europe, Canada, and the US.ObjectiveTo compare the prevalence of positive patch test reactions to the methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) combination and MI alone in North America and Europe from 2009 to 2018.Design, Setting, and ParticipantsThis retrospective analysis of North American Contact Dermatitis Group, European Surveillance System on Contact Allergies (ESSCA), and the Information Network of Departments of Dermatology (IVDK) databases included data from patients presenting for patch testing at referral patch test clinics in North America and Europe.ExposuresPatch tests to MCI/MI and MI.Main Outcomes and MeasuresPrevalence of allergic contact dermatitis to MCI/MI and MI.ResultsFrom 2009 to 2018, participating sites in North America and Europe patch tested a total of 226 161 individuals to MCI/MI and 118 779 to MI. In Europe, positivity to MCI/MI peaked during 2013 and 2014 at 7.6% (ESSCA) and 5.4% (IVDK) before decreasing to 4.4% (ESSCA) and 3.2% (IVDK) during 2017 and 2018. Positive reactions to MI were 5.5% (ESSCA) and 3.4% (IVDK) during 2017 and 2018. In North America, the frequency of positivity to MCI/MI increased steadily through the study period, reaching 10.8% for MCI/MI during 2017 and 2018. Positive reactions to MI were 15.0% during 2017 and 2018.Conclusions and RelevanceThe study results suggest that in contrast to the continued increase in North America, isothiazolinone allergy is decreasing in Europe. This trend may coincide with earlier and more stringent government regulation of MI in Europe.

Background: Occupational skin diseases have led the occupational disease statistics in Europe for many years. Especially occupational allergic contact dermatitis is associated with a poor prognosis and low healing rates leading to an enormous burden for the affected individual and for society. Objectives: To present the sensitization frequencies to the most relevant allergens of the European baseline series in patients with occupational contact dermatitis (OCD) and to compare sensitization profiles of different occupations. Methods: The data of 16 022 patients considered having OCD after patch testing within the European Surveillance System on Contact Allergies (ESSCA) network between January 2011 and December 2020 were evaluated. Patients (n = 46 652) in whom an occupational causation was refuted served as comparison group. Results: The highest percentages of OCD were found among patients working in agriculture, fishery and related workers, metal industry, chemical industry, followed by building and construction industry, health care, food and service industry. Sensitizations to rubber chemicals (thiurams, carbamates, benzothiazoles) and epoxy resins were associated with at least a doubled risk of OCD. After a decline from 2014 onwards, the risks to acquire an occupation-related sensitization to methyl(chloro)isothiazolinone (MCI/MI) and especially to methylisothiazolinone (MI) seem to increase again. Sensitization rates to formaldehyde were stable, and to methyldibromo glutaronitrile (MDBGN) slightly decreasing over time. Conclusions: Among allergens in the European Baseline Series, occupational relevance is most frequently attributed to rubber accelerators, epoxy resins and preservatives.

Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350g/week and 210 to 420g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.

Basalt fibre-reinforced polymer (BFRP) composites probably tend to replace some carbon fibre-reinforced polymer (CFRP) applications due to their excellent specific strengths and sustainability. Despite the published early promising results concerning the material properties of BFRP, their application is not widespread, and their machinability is not supported widely by published experiences. The main aim of the present study is to experimentally investigate the drilling-induced geometrical damages of BFRP and CFRP composites. Drilling experiments were conducted at various feed and cutting speed levels using a solid carbide twist drill. The drilling-induced burr was analysed by a Mitutoyo 361–804 digital microscope, a Mitutoyo SJ400 surface tester recorded the surface roughness, and the microstructure was analysed by a Zeiss Evo MA 10 scanning electron microscope. The measured data were evaluated through digital image processing (DIP), response surface methodology (RSM), and analysis of variances (ANOVA). The experimental results show that drilling-induced burr is more severe and surface roughness is worse in BFRP than in CFRP. The composite type influenced the geometrical damages primarily, followed by the feed in the case of burrs and by the cutting speed in the case of surface roughness. The present experimental study suggests that the drilling of BFRP is even more challenging than drilling CFRP from the point of view of burr formation and micro geometrical properties.

Background and Aims: Non-alcoholic steatohepatitis (NASH) is acknowledged as a severe disease that is associated with a significant burden on patients, payers, and society. However, limited evidence exists on the cost associated with NASH across different countries. This analysis aims to describe the cost associated with the routine care of patients with NASH in France, Germany, and the United States. Methods: Data was sourced from the Gesellschaft für Konsumforschung (now Ipsos) Disease Atlas Real- World Evidence program collected from July through November 2017 in France, Germany, and the United States. Country-level unit cost was estimated from national databases for diagnostic tests and procedures, prescription drugs, hospital stays, and outpatient visits in respective local currency based on 2017 values. These were combined to provide an estimate of the cost of management of confirmed NASH in this specific patient population and are presented as mean cost per patient per year for each country in local currency and as USD adjusted for purchasing power parity for comparison. Results: Annual mean ± standard deviation cost of non-alcoholic steatohepatitis ranged from purchasing power parity USD 1,049±2,461 in Germany to USD 1,723±2,988 in the United States. In all markets, the predominant contributor to cost is healthcare resource use represented by hospitalisation and outpatient visits. Conclusions: This study reveals that costs associated with NASH treatment and management vary across the three countries studied, in part due to differences in healthcare systems but also due to different approaches in managing this disease. Our analysis represents the costs for a specific cohort of patients and further studies are warranted to better understand the progressive impact of NASH on healthcare systems and society.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Laser Guide Star Adaptive Optics (LGS-AO) is becoming routine in several astronomical observatories. The use of powerful lasers generates sensible Raman emissions on the uplink laser beam path, plus secondary Rayleigh scattering from atmospheric molecules and Mie scattering from aerosols. This paper reports the results of a campaign done with the 10.4m Gran Telescopio CANARIAS (GTC); this campaign was undertaken to assess the spectral and photometric contamination coming from a 589 nm laser uplink beam scattering and Raman emission induced on the GTC spectro-imager OSIRIS by laser launched about 1 km off-axis. The photometric contamination is due to primary and secondary scattering of the uplink photons, as well by the Raman inelastic scattering. We have propagated the laser beam creating a mesospheric LGS, then pointed and focused the GTC telescope toward the uplink laser beam, at different heights and up to the LGS, taking into account the observing geometry. In our observations, the Raman emissions for O2 and N2 vibrational lines are visible at 20 km, weakening with altitude and becoming undetectable above 30 km. The scattering of the focused uplink beam is detectable at less than +/-0.2 arcmin from the center of the beam, while for the focused LGS the scattering is narrower, being detectable at less than +/-0.1 arcmin around the plume. Recommendations for Laser Traffic Control Systems (LTCS) are given accordingly., Comment: Accepted for publication in MNRAS. 12 pages, 13 Figures, 5 Tables

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact ofRAG1/RAG2on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an ‘experiment of nature’ to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal aRAG-dependent ‘domino effect’ that impacts stringency of tolerance and B cell fate in the periphery.

Complement deficiencies have been considered to be rare for many decades, but this assumption is changing year by year. Recognition of these conditions significantly increases thanks to the availability of different testing approaches and due to clinical awareness. Furthermore, sequencing technologies (including Sanger sequencing, targeted gene panels, and whole exome/genome sequencing) may facilitate the identification of the underlying disease-causing genetic background. On the other hand, functional characterization of the identified possibly pathogenic variations and performing family studies, as illustrated by some of our cases, remain similarly important to establish a precise clinical diagnosis facilitating the most appropriate management. Here, we present 4 illustrative cases with complement deficiencies of diverse etiologies and also provide an educative, step-by-step description on how to identify the underlying cause of complement deficiency based on the results of complement laboratory testing.

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose This is the second article in a 2-part series reviewing the pathophysiology and treatment considerations for arrhythmia. Part 1 of the series discussed aspects related to treating atrial arrhythmias. Here in part 2, the pathophysiology of ventricular arrhythmias and bradyarrhythmias and current evidence on treatment approaches are reviewed. Summary Ventricular arrhythmias can arise suddenly and are a common cause of sudden cardiac death. Several antiarrhythmics may be effective in management of ventricular arrhythmias, but there is robust evidence to support the use of only a few of these agents, and that evidence was largely derived from trials involving patients with out-of-hospital cardiac arrest. Bradyarrhythmias range from asymptomatic mild prolongation of nodal conduction to severe conduction delays and impending cardiac arrest. Vasopressors, chronotropes, and pacing strategies require careful attention and titration to minimize adverse effects and patient harm. Conclusion Ventricular arrhythmias and bradyarrhythmias can be consequential and require acute intervention. As experts in pharmacotherapy, acute care pharmacists can participate in providing high-level intervention by aiding in diagnostic workup and medication selection.

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose This article, the first in a 2-part review, aims to reinforce current literature on the pathophysiology of cardiac arrhythmias and various evidence-based treatment approaches and clinical considerations in the acute care setting. Part 1 of this series focuses on atrial arrhythmias. Summary Arrhythmias are prevalent throughout the world and a common presenting condition in the emergency department (ED) setting. Atrial fibrillation (AF) is the most common arrhythmia worldwide and expected to increase in prevalence. Treatment approaches have evolved over time with advances in catheter-directed ablation. Based on historic trials, heart rate control has been the long-standing accepted outpatient treatment modality for AF, but the use of antiarrhythmics is often still indicated for AF in the acute setting, and ED pharmacists should be prepared and poised to help manage. Other atrial arrhythmias include atrial flutter (AFL), atrioventricular nodal reentry tachycardia (AVNRT), and atrioventricular reentrant tachycardia (AVRT), which warrant distinction due to their unique pathophysiology and because each requires a different approach to utilization of antiarrhythmics. Atrial arrhythmias are typically associated with greater hemodynamic stability than ventricular arrhythmias but still require nuanced management according to patient subset and risk factors. Since antiarrhythmics can also be proarrhythmic, they may destabilize the patient due to adverse effects, many of which are the focus of black-box label warnings that can be overreaching and limit treatment options. Electrical cardioversion for atrial arrhythmias is generally successful and, depending on the setting and/or hemodynamics, often indicated. Conclusion Atrial arrhythmias arise from a variety of mechanisms, and appropriate treatment depends on various factors. A firm understanding of physiological and pharmacological concepts serves as a foundation for exploring evidence supporting agents, indications, and adverse effects in order to provide appropriate care for patients.

Currently, the use of sustainable products and technologies is growing; consequently, mineral-origin basalt fibre-reinforced polymer (BFRP) composites are becoming more popular in industries. Although BFRP parts require mechanical drilling operations for manufacturing holes for assembly, many challenges make the drilling process difficult. Considering that the cutting force is one of the main parameters characterising the drilling process, this study aims to analyse the influence of feed (mm/rev) and cutting speed (m/min) on the thrust force and model the thrust force in the drilling of BFRP composites through response surface methodology (RSM) and advanced statistical modelling methods. In order to determine main and interaction effects and to calculate the regression coefficients and model parameters, mechanical drilling experiments were performed, and the thrust force was recorded. The raw force data were processed using fast Fourier transformation-based low-pass filtering, and then the calculated thrust force parameters were evaluated relative to various feeds and cutting speeds. In addition, results were compared with those of carbon fibre-reinforced polymer composites. The results of the validation experiments show that both RSM and advanced statistical models accurately predict the thrust force in BFRPs of 96.74% and 95.01%, respectively. However, the advanced statistical model can describe not only the maximum values of the force but also its characteristics at a coefficient of determination of 0.68.

A variety of yeast applications in the food and beverage industry require individual and reproducible yeast propagation at high yields and consistent quality. One quality-determining parameter for yeast propagation is effective aeration to avoid oxygen depletion. Therefore, this work investigated three important aeration parameters: airflow, pulse time, and oxygen concentration, for their influence on yeast propagation. The aeration of a propagator involves phase transitions which are gradient-driven processes and can be accelerated with higher gradients between the liquid medium and the gas bubbles. In this study, oxygen-enriched air generated with membrane filters was used to aerate the system in an easy and cost-efficient way without the need for expensive technical gas usage. Propagation experiments were carried out in a pilot-scale reactor equipped with a membrane filter system for enhanced oxygen concentrations in ingas and online sensors for representative monitoring of the process. The membrane filter system is based on the separation of nitrogen in compressed air, leading to oxygen enrichment. Using oxygen-enriched air for propagation aeration showed higher oxygen transfer into the medium and the anaerobic process time caused by oxygen depletion due to high cell numbers was reduced by an average of 7.4% for pulsed aeration. Additionally, we conducted experiments with controlled measures of dissolved oxygen using different oxygen concentrations for aeration. The main objective of this study is to present a new and affordable optimization of propagation aeration using membrane filtration to enrich process air. The results showed increased cell counts for higher ingas oxygen concentrations and no negative impact on cell vitality was observed. Hence, our investigations showed that using oxygen-enriched air reduced the frequency of pulsed aeration, thus hindering foam formation, a limiting factor of the yeast propagation process.

Traditionally, in numerical weather prediction, the computational cost of performing floating-point operations (flops) has been the primary concern. However, in the past couple of decades throughput to storage has become a significant bottleneck – a phenomenon often referred to as the input/output (I/O) performance gap. ECMWF runs time-critical operational weather forecasts four times a day, where the entire workflow of each run must complete within one hour. A single run currently produces around 30TiB of data, and it is expected to increase to hundreds of TiB within the next five-to-ten years. This is impossible on existing infrastructure without re-organising how model data is handled and processed. The proposed solution to this problem in the field of weather and climate numerical models has two elements. One is to decouple data output from numerical computations and dedicate pre-defined processes, called I/O-servers, purely to data output. The other is to move computations of derived (post-processed) data closer to the original “raw” weather data, thus reducing the amount of data to be moved. The challenge then is how to route the combination of raw and post-processed data efficiently to storage without compromising the performance of the running model. We present MultIO, an open-source software library developed at ECMWF for data routing from distributed parallel meteorological and earth-system models. It supports two distinct functionalities. First, it allows the creation of post-processing pipelines to calculate derived meteorological products, such as temporal pointwise statistics, interpolation onto different grids, encoding of data into output formats and output of data storage systems or other consumers. Second, it can act as an I/O-server, creating aggregated horizontal fields from distributed parallel meteorological and earth-system models. MultIO is a key component of the ACROSS project, funded by the EuroHPC JU. It is also partly developed via ECMWF's participation in Destination Earth and is a component of the Digital Twin Engine (DTE).

The Onagraceae or evening-primrose family has a fossil record composed mainly of dispersed pollen that has been discovered in Late Cretaceous to Holocene sediments around the globe. The pollen record suggests the family reached a cosmopolitan distribution during the Eocene. Currently, there is no reliable Onagraceae leaf record, and the meagre mesofossil record is composed of only a few fruits/seeds of Circaea and Ludwigia from the Oligocene to Pliocene of Eurasia. There is also a unique fossil Fuchsia flower that was described from the early Miocene of New Zealand, but other than that, there are no fossil Onagraceae flowers known to date. In addition, Onagraceae pollen has never been found adhering to fossil insects, and as such, there is no direct evidence of which insects visited Onagraceae flowers prior to modern times. Here we present an exceptional finding, an Onagraceae flower bud of Eocene age, from Eckfeld in Germany. Due to the flower’s bud stage the stamens were still packed with pollen. Nevertheless, the in situ pollen enabled us to assign the flower to the genus Ludwigia, based on a combination of unique morphological and ultrastructural traits observed with combined LM, SEM, and TEM, making it one of the earliest records of this genus. More importantly, we also discovered the same Ludwigia-type pollen adhering to the exterior of two different fossil beetles, a Buprestidae and Scarabaeidae, from the same locality. These provide the first-ever direct evidence for paleo-flower-insect visitation in Ludwigia and Onagraceae. Interestingly, we did not discover any Ludwigia-type pollen on the several Hymenoptera fossils investigated during this study, but Hymenoptera are the main flower visitors and pollinators of Ludwigia at present. These findings might suggest that beetles were the main flower visitors and potential pollinators of European Ludwigia during the Eocene and that there has been a shift in primary pollinators through the geological record.

The early to middle Eocene maar lake of Messel is a world-renowned fossil locality. Its oil shale deposits are well-known for their exceptional preservation of vertebrates (e.g., crocodiles, early horses) and invertebrates, especially insects. The makro- and microfossil remains of plants also contributed to providing a more holistic snapshot of this Eocene ecosystem. So far, the palynoflora has mostly been investigated using only conventional LM, and the classic taxonomic qualitative/illustrative work on the palynoflora dates back to the late 1980ies. Here we report on the first results from an ongoing study using combined LM and SEM, and in some cases even TEM, to re-investigate the Messel palynoflora qualitatively. The main goals of our study are to conclude (I) if some of the spores/pollen can be systematically placed with more certainty, (II) if additional spore/pollen types can be discovered, (III) to compare our combined method of investigation with the classic LM-based counting method, and finally (IV) to conclude about the composition and species richness of the palynoflora and how it correlates with the macro- and mesofloras. To accomplish this, we first processed a single sedimentary rock sample without fine-mesh sieving and then extracted and investigated every pollen type encountered using the single-grain method. So far, this sample has produced 30 spore types, 5 gymnosperm pollen types, and about 185 different angiosperm pollen types. The previous LM-based qualitative work identified 173 palynomorphs in an accumulative account from numerous rock samples up-trough the oil shale section. Our study, on a single sample from the lowest part of the oil shale revealed every single pollen type (except for Milfordia (Restionaceae) and Pityosporites microalatus (Cathaya, Pinaceae)) discovered in the accumulative approach using the classic LM counting method. Also, in addition to the c. 140 angiosperm pollen types previously recorded, we can now add at least 45 new pollen types for this locality. Our study shows that when taxonomic resolution and diversity are key, a combined LM and SEM investigation produces higher diversity than relying only on the conventional LM counting method when single samples are compared. In addition, a well-preserved single sample extensively studied using the combined approach is likely to provide the same or even higher number of taxa when compared to conventional LM counting methods analyzing an entire stratigraphic section. The qualitative combined approach will provide a more reliable presence/absence of taxa in the accumulation site hinterland. For quantitative analysis and subtle changes in the surrounding environments conventional counting methods are more appropriate because of the universal availability of light microscopes and difficulties with SEM-counting.