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Silicon waveguides can be functionalized with an organic χ(2)-nonlinear cladding. This complements silicon photonics with the electro-optic (EO) effect originating from the cladding and enables functionalities such as pure phase modulation, parametric amplification, or THz-wave generation. Claddings based on a polymer matrix containing chromophores have been introduced, and their strong χ(2) nonlinearity has already been used to demonstrate ultralow power consuming modulators. However, these silicon-organic hybrid (SOH) devices inherit not only the advantageous properties; these polymer claddings require an alignment procedure called poling and must be operated well below their glass transition temperature. This excludes some applications. In contrast, claddings made from organic crystals come with a different set of properties. In particular, there is no need for poling. This new class of claddings also promises stronger resilience to high temperatures, better long-term stability, and photo-chemical stability. We report on the deposition of an organic crystal cladding of N-benzyl-2-methyl-4-nitroaniline (BNA) on silicon-on-insulator (SOI) waveguides, which have a CMOS-like metal stack on top. Adhering to such an architecture, which preserves the principal advantage of using CMOS-based silicon photonic fabrication processes, permits the first demonstration of high-speed modulation at 12.5 Gbit/s in this material class, which proves the availability of the EO effect from BNA on SOI also for other applications.

Objective: Assess implementation feasibility and outcomes for an Osteoarthritis Management Program (OAMP) at an academic center. Design: This open study assessed an OAMP designed to deliver care in 1–5 individual or group visits across ≤12 months. Eligibility included adults with knee or hip osteoarthritis with ≥1 visit from 7/1/2017–1/15/2021. A multidisciplinary care team provided: education on osteoarthritis, self-management, exercise, weight loss; pharmacologic management; assessments of mood, sleep, quality of life, and diet. Clinic utilization and growth are reported through 2022. Patient outcomes of body mass index (BMI), pain, and function were analyzed using multivariable general linear models. OAMP outcomes were feasibility and sustainability. Results: Most patients were locally referred by primary care. 953 patients attended 2531 visits (average visits 2.16, treatment duration 187.9 days). Most were female (72.6%), older (62.1), white (91.1%), and had medical insurance (95.4%). Obesity was prevalent (84.7% BMI ≥30, average BMI 40.9), mean Charlson Comorbidity Index was 1.89, and functional testing was below average. Longitudinal modeling revealed statistically but not clinically significant pain reduction (4.4–3.9 on 0–10 scale, p ​= ​0.002). BMI did not significantly change (p ​= ​0.87). Higher baseline pain and BMI correlated with greater reductions in each posttreatment. Uninsured patients had shorter treatment duration. Increasing clinic hours (4–24 ​h weekly) and serving 953 patients over four years demonstrated OAMP sustainability. Conclusions: OAMP implementation was feasible and sustainable. Patients with high baseline pain and BMI were more likely to improve. Noninsurance was a barrier. These results contribute to understanding OAMP outcomes in U.S. healthcare.

The stable isotope composition of lacustrine sediments is routinely used to infer Late Holocene changes in precipitation over Scandinavia and, ultimately, atmospheric circulation dynamics in the North Atlantic realm. However, such archives only provide a low temporal resolution (ca. 15 years), precluding the ability to identify changes on inter-annual and quasi-decadal timescales. Here, we present a new, high-resolution reconstruction using shells of freshwater pearl mussels, Margaritifera margaritifera, from three streams in northern Sweden. We present seasonally to annually resolved, calendar-aligned stable oxygen and carbon isotope data from 10 specimens, covering the time interval from 1819 to 1998. The bivalves studied formed their shells near equilibrium with the oxygen isotope signature of ambient water and, thus, reflect hydrological processes in the catchment as well as changes, albeit damped, in the isotope signature of local atmospheric precipitation. The shell oxygen isotopes were significantly correlated with the North Atlantic Oscillation index (up to 56 % explained variability), suggesting that the moisture that winter precipitation formed from originated predominantly in the North Atlantic during NAO+ years but in the Arctic during NAO− years. The isotope signature of winter precipitation was attenuated in the stream water, and this damping effect was eventually recorded by the shells. Shell stable carbon isotope values did not show consistent ontogenetic trends, but rather oscillated around an average that ranged from ca. −12.00 to −13.00 ‰ among the streams studied. Results of this study contribute to an improved understanding of climate dynamics in Scandinavia and the North Atlantic sector and can help to constrain eco-hydrological changes in riverine ecosystems. Moreover, long isotope records of precipitation and streamflow are pivotal to improve our understanding and modeling of hydrological, ecological, biogeochemical and atmospheric processes. Our new approach offers a much higher temporal resolution and superior dating control than data from existing archives.

BackgroundSo far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population.ObjectiveThe aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator.MethodsA systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared.ResultsOf 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately.ConclusionOptimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

24 h cold exposure (4°C) is sufficient to reduce pathogen susceptibility in Arabidopsis thaliana against the virulent Pseudomonas syringae pv. tomato ( Pst ) strain even when the infection occurs five days later. This priming effect is independent of the immune regulator Enhanced Disease Susceptibility 1 (EDS1) and can be observed in the immune-compromised eds1-2 null mutant. In contrast, cold priming-reduced Pst susceptibility is strongly impaired in knock-out lines of the stromal and thylakoid ascorbate peroxidases (sAPX/tAPX) highlighting their relevance for abiotic stress-related increased immune resilience. Here, we extended our analysis by generating an eds1 sapx double mutant. eds1 sapx showed eds1 -like resistance and susceptibility phenotypes against Pst strains containing the effectors avrRPM1 and avrRPS4. In comparison to eds1-2 , susceptibility against the wildtype Pst strain was constitutively enhanced in eds1 sapx . Although a prior cold priming exposure resulted in reduced Pst titers in eds1-2 , it did not alter Pst resistance in eds1 sapx . This demonstrates that the genetic sAPX requirement for cold priming of basal plant immunity applies also to an eds1 null mutant background.

Background: The Co-FriSero study describes a COVID-19 outbreak at the Friedrichroda hospital in Thuringia, Germany, with 185 beds and 404 employees, at the onset of the pandemic between March 30th, 2020, and April 13th, 2020. This study aimed to analyze potential sources of SARS-CoV-2 transmission amongst hospital employees., Methods: After the outbreak, a comprehensive follow-up was conducted through a questionnaire and a seroprevalence study using two different immunoassays for IgG detection and a third for discordant results., Results: PCR screenings confirmed SARS-CoV-2 infection in 25 of 229 employees, with an additional 7 detected through serology. Statistical analysis indicated that direct patient contact, exposure to high flow ventilation in non-isolated rooms, direct contact with colleagues, shared use of recreational rooms, and carpooling were associated with an increased infection risk. Conversely, contact with family and friends, public transportation, public events, and use of locker rooms were not associated with infection. Male gender showed a lower infection likelihood, independent of age and other risk factors., Conclusion: This study highlights the role of direct patient care and internal staff interactions in the spread of SARS-CoV-2 in the hospital setting. It suggests that non-traditional transmission routes like carpooling require consideration in pandemic preparedness., (© 2024. The Author(s).)

For my senior high school capstone project, I focused on pediatric oncology, which included shadowing two physicians. I realized that although physicians do incredible work, the nurses I encountered were so hands on and appea.

Virologic failure of long-acting rilpivirine/cabotegravir is rare but may result in severely limited treatment options. Known risk factors cannot predict all cases. Therapeutic drug monitoring (TDM) may help identify patients at risk, but reliable thresholds are missing. We report retrospective TDM in a cohort of 5 patients, including 1 virological failure., Competing Interests: Potential conflicts of interest. J.G.: received financial support from Mitteldeutscher Arbeitskreis HIV e.V.; H.K.: advisory committee/review panel (AbbVie, Gilead, Hexal, Janssen, MSD, Shionogi, ViiV), grant/research support (Arrowhead, BMS, Hectorstiftung, MSD), speaking/teaching (AbbVie, BMS, Janssen, MSD, Pfizer); U.S.: received speaker fees, advisory board honoraria, or travel grants to scientific conferences from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, Amgen, AstraZeneca, GSK, Seqirus, Sanofi-Aventis; C.S.: received speaker fees, advisory board honoraria, or travel grants to scientific conferences from Gilead, MSD, Janssen-Cilag, AbbVie, ViiV Healthcare, and TAD; B.T.S.: received fees and financial support from Mitteldeutscher Arbeitskreis HIV e.V., Gilead, MSD, Janssen-Cilag, Pfizer, ViiV, AstraZeneca, AIDS-Hilfe Potsdam, AIDS-Hilfe Dresden, and Merck. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Polyphosphates, chains of polymerized phosphate subunits, are used as food additives for various applications such as conservation, water retention, and pH buffering. Currently, the value chain of phosphates is linear, based on mining fossil phosphate rock, which is anticipated to be depleted in a few hundred years. With no replacement available, a transition to a circular phosphate economy, to which biological systems can contribute, is required. Baker's yeast can hyperaccumulate phosphate from various phosphate-rich waste streams and form polyphosphates, which can be used directly or as polyphosphate-rich yeast extract with enhanced properties in the food industry. By maturing the technology to an industrial level and allowing upcycled waste streams for food applications, substantial contributions to a sustainable phosphate economy can be achieved., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest. LMB filed two patent applications: “Zusammensetzung, enthaltend getrocknetes Polyphosphat und Verfahren zur Gewinnung von Polyphosphat aus polyphosphat-haltigen Hefezellen dazu” (DE 10 2019 131 561.1) and “Polyphosphatreiche Hefeextrakte und Herstellverfahren dazu” (DE 10 2018 130 081.6, PCT/EP2019/082709)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: State mental health systems are retraining their workforces to deliver services supported by research. Knowledge about evidence-based therapies (EBTs) for child and adolescent disorders is robust, but the feasibility of their statewide scaling has not been examined. The authors reviewed implementation feasibility for 12 commonly used EBTs, defining feasibility for statewide scaling as an EBT having at least one study documenting acceptability, facilitators and barriers, or fidelity; at least one study with a racially and ethnically diverse sample; an entity for training, certification, or licensing; and fiscal data reflecting the costs of implementation., Methods: The authors reviewed materials for 12 EBTs being scaled in New York State and conducted a literature review with search terms relevant to their implementation. Costs and certification information were supplemented by discussions with treatment developers and implementers., Results: All 12 EBTs had been examined for implementation feasibility, but only three had been examined for statewide scaling. Eleven had been studied in populations reflecting racial-ethnic diversity, but few had sufficient power for subgroup analyses to demonstrate effectiveness with these samples. All had certifying or licensing entities. The per-clinician costs of implementation ranged from $500 to $3,500, with overall ongoing costs ranging from $100 to $6,000. A fiscal analysis of three EBTs revealed hidden costs ranging from $5,000 to $24,000 per clinician, potentially limiting sustainability., Conclusions: The evidence necessary for embedding EBTs in state systems has notable gaps that may hinder sustainability. Research-funding agencies should prioritize studies that focus on the practical aspects of scaling to assist states as they retrain their workforces., Competing Interests: Dr. Horwitz reports receiving royalties from American Psychiatric Association Publishing. The other authors report no financial relationships with commercial interests.

Background: Quality control (QC), quality assurance, and standardization are crucial for modern diagnostic testing in the field of medical microbiology. The need for efficient QC to ensure accurate laboratory results, treatment, and infection prevention has led to significant efforts in standardizing assay reagents and workflows. External quality assessment (EQA) schemes, like those offered by INSTAND, play a vital role in evaluating in-house and commercial routine diagnostic assays, regarded as mandatory by national and global guidelines. The recent impact of polymerase chain reaction/nucleic acid amplification technology (PCR/NAAT) assays in medical microbiology requires that high-performing assays be distinguished from inadequately performing ones, especially those made by inexperienced suppliers., Objectives: The study assesses the evolving diagnostic performance trends over 2 decades for the detection of EHEC/STEC, Borrelia ( B.) burgdorferi , and MRSA/cMRSA. It explores the historical context of assay utilization, participant engagement, and rates of correct results in EQA schemes. The research seeks to identify patterns in assay preferences, participant proficiency, and the challenges encountered in detecting emerging variants or clinical strains., Results: The study highlights the decline in in-house PCR assay usage, the emergence of new diagnostic challenges, and educational aspects within EQA schemes. Specific examples, such as the inclusion, in certain EQA surveys, of EHEC strains carrying stx -2f or B. miyamotoi , highlight the role of EQAs in increasing awareness and diagnostic capabilities. Advancements in MRSA detection, especially through the adoption of commercial assays, demonstrate the impact that technology evolution has had on diagnostic performance., Conclusion: Achieving excellence in diagnostic molecular microbiology involves a multifaceted approach, including well-evaluated assays, careful instrumentation selection, and structured training programs. EQA schemes contribute significantly to this pursuit by providing insights into the evolving diagnostic landscape and identifying areas for improvement in the diagnostic workflow as well as in PCR/NAAT assay design., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kremser, Weiss, Kaufmann-Stoeck, Vierbaum, Kappler, Schellenberg, Hiergeist, Fingerle, Baier and Reischl.)

Lysosomal accumulation of the glycosphingolipid globotriaosylceramide Gb3 is linked to the deficient activity of the α-galactosidase A in the Anderson-Fabry disease and an elevated level of deacylated Gb3 is a hallmark of this condition. Localization of Gb3 in the plasma membrane is critical for studying how the membrane organization and its dynamics are affected in this genetic disorder. Gb3 analogs containing a terminal 6-azido-functionalized galactose in its head group globotriose (αGal1, 4βGal1, and 4Glc) are attractive chemical reporters for bioimaging, as the azido-group may act as a chemical tag for bio-orthogonal click chemistry. We report here the production of azido-Gb3 analogs employing mutants of galactokinase, UTP-glucose-1-phosphate uridylyltransferase, and α-1,4-galactosyltransferase LgtC, which participate in the synthesis of the sugar motif globotriose. Variants of enzymes galactokinase/UTP-glucose-1-phosphate uridylyltransferase generate UDP-6-azido-6-deoxy-d-galactose, which is the galactosyl-donor used by LgtC for transferring the terminal galactose moiety to lactosyl-acceptors. Residues at the galactose-binding site of the 3 enzymes were modified to facilitate the accommodation of azido-functionalized substrates and variants outperforming the wild-type enzymes were characterized. Synthesis of 6-azido-6-deoxy-d-galactose-1-phosphate, UDP-6-azido-6-deoxy-d-galactose, and azido-Gb3 analogs by variants GalK-E37S, GalU-D133V, and LgtC-Q187S, respectively, is 3-6-fold that of their wild-type counterparts. Coupled reactions with these variants permit the production of the pricy, unnatural galactosyl-donor UDP-6-azido-6-deoxy-d-galactose with ~90% conversion yields, and products azido-globotriose and lyso-AzGb3 with substrate conversion of up to 70%. AzGb3 analogs could serve as precursors for the synthesis of other tagged glycosphingolipids of the globo-series., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The Co-HCW study is a prospective, longitudinal, single-center observational study that aims to assess the SARS-CoV-2 seroprevalence and infection status in staff members of Jena University Hospital (JUH) in Jena, Germany., Methods: This follow-up study covers the observation period from 19th May 2020 to 22nd June 2021. At each of the three voluntary study visits, participants filled out a questionnaire regarding their SARS-CoV-2 exposure and provided serum samples to detect specific SARS-CoV-2 antibodies. Participants who were tested positive for antibodies against nucleocapsid and/or spike protein without previous vaccination and/or reported a positive SARS-CoV-2 PCR test were regarded to have been infected with SARS-CoV-2. Multivariable logistic regression modeling was applied to identify potential risk factors for infected compared to non-infected participants., Results: Out of 660 participants that were included during the first study visit, 406 participants (61.5%) were eligible for the final analysis as their COVID-19 risk area (high-risk n = 76; intermediate-risk n = 198; low-risk n = 132) did not change during the study. Forty-four participants [10.8%, 95% confidence interval (95%CI) 8.0-14.3%] had evidence of a current or past SARS-CoV-2 infection detected by serology (n = 40) and/or PCR (n = 28). No association between SARS-CoV-2 infection and the COVID-19 risk group according to working place was detected. However, exposure to a SARS-CoV-2 positive household member [adjusted OR (AOR) 4.46, 95% CI 2.06-9.65] or colleague (AOR 2.30, 95%CI 1.10-4.79) was found to significantly increase the risk of a SARS-CoV-2 infection., Conclusion: Our results demonstrate that non-patient-related SARS-CoV-2 exposure posed the highest infection risk for hospital staff members of JUH., (© 2023. The Author(s).)

Rapid testing for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) of patients presenting to emergency departments (EDs) facilitates the decision for isolation on admission to hospital wards. Differences in the sensitivity of molecular assays have implications for diagnostic workflows. This study evaluated the performance of the cobas ® Liat ® RT-PCR, which is routinely used as the initial test for ED patients in our hospitals, compared with the eazyplex ® RT-LAMP. A total of 378 oropharyngeal and nasal swabs with positive Liat ® results were analysed. Residual sample aliquots were tested using NeuMoDx™, cobas ® RT-PCR, and the eazyplex ® assay. Patients were divided into asymptomatic (n = 157) and symptomatic (n = 221) groups according to the WHO case definition. Overall, 14% of positive Liat ® results were not confirmed by RT-PCR. These samples were mainly attributed to 26.8% of asymptomatic patients, compared to 3.8% of the symptomatic group. Therefore, positive Liat ® results were used to provisionally isolate patients in the ED until RT-PCR results were available. The eazyplex ® assay identified 62% and 90.6% of RT-PCR-confirmed cases in asymptomatic and symptomatic patients, respectively. False-negative eazyplex ® results were associated with RT-PCR Ct values > 30, and were more frequent in the asymptomatic group than in the symptomatic group (38.1% vs. 5.1%, respectively). Both the Liat ® and eazyplex ® assays are suitable for testing symptomatic patients. Their use in screening asymptomatic patients depends on the need to exclude any infection or identify those at high risk of transmission.

Understanding persistent cellular and humoral immune responses to SARS-CoV-2 will be of major importance to terminate the ongoing pandemic. Here, we assessed long-term immunity in individuals with mild COVID-19 up to 1 year after a localized SARS-CoV-2 outbreak. CoNAN was a longitudinal population-based cohort study performed 1.5 months, 6 months, and 12 months after a SARS-CoV-2 outbreak in a rural German community. We performed a time series of five different IgG immunoassays assessing SARS-CoV-2 antibody responses on serum samples from individuals that had been tested positive after a SARS-CoV-2 outbreak and in control individuals who had a negative PCR result. These analyses were complemented with the determination of spike-antigen specific TH cell responses in the same individuals. All infected participants were presented as asymptomatic or mild cases. Participants initially tested positive for SARS-CoV-2 infection either with PCR, antibody testing, or both had a rapid initial decline in the serum antibody levels in all serological tests but showed a persisting T H cell immunity as assessed by the detection of SARS-CoV-2 specificity of T H cells for up to 1 year after infection. Our data support the notion of a persistent T-cell immunity in mild and asymptomatic cases of SARS-CoV-2 up to 1 year after infection. We show that antibody titers decline over 1 year, but considering several test results, complete seroreversion is rare., Trial Registration: German Clinical Trials Register DRKS00022416., Competing Interests: SW received speaker fees from MSD and Infectopharm. SH received speaker fees from Pfizer, MSD and Astra Zeneca. TK received speaker fees from Roche. MP has participated in international advisory boards from Pfizer, Novartis, Basilea and Cubist and received speaker fees from the same companies. CB has participated in advisory boards from GSK and received speaking fees from Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schnizer, Andreas, Vivas, Kamradt, Baier, Kiehntopf, Glöckner, Scherag, Löffler, Kolanos, Guerra, Pletz and Weis.)

For wireless networks beyond 5G, directivity and reconfigurability of antennas are highly relevant. Therefore, we propose a linear antenna array based on photodiodes operating at 300 GHz, and an optical phased array based on polymer waveguides to orchestrate the antennas. Due to its low thermal conductivity and high thermo-optical coefficient, the polymer chip enables highly efficient and crosstalk-free phase shifting. With these, we demonstrate purely photonic-controlled beam steering across 20°. Compared to a single emitter, the 3-dB beam width is reduced by 8.5° to 22.5° and the output power is >10 dB higher. Employing Snell's law for coupling into air, we can precisely predict the radiation patterns.

Background: In cystic fibrosis (CF), acute respiratory exacerbations critically enhance pulmonary destruction. Since these mainly occur outside regular appointments, they remain unexplored. We previously elaborated a protocol for home-based upper airway (UAW) sampling obtaining nasal-lavage fluid (NLF), which, in contrast to sputum, does not require immediate processing. The aim of this study was to compare UAW inflammation and pathogen colonization during stable phases and exacerbations in CF patients and healthy controls., Methods: Initially, we obtained NLF by rinsing 10 ml of isotonic saline/nostril during stable phases. During exacerbations, subjects regularly collected NLF at home. CF patients directly submitted one aliquot for microbiological cultures. The remaining samples were immediately frozen until transfer on ice to our clinic, where PCR analyses were performed and interleukin (IL)-1β/IL-6/IL-8, neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were assessed., Results: Altogether, 49 CF patients and 38 healthy controls (HCs) completed the study, and 214 NLF samples were analyzed. Of the 49 CF patients, 20 were at least intermittently colonized with P. aeruginosa and received azithromycin and/or inhaled antibiotics as standard therapy. At baseline, IL-6 and IL-8 tended to be elevated in CF compared to controls. During infection, inflammatory mediators increased in both cohorts, reaching significance only for IL-6 in controls (p=0.047). Inflammatory responses tended to be higher in controls [1.6-fold (NE) to 4.4-fold (MMP-9)], while in CF, mediators increased only moderately [1.2-1.5-fold (IL-6/IL-8/NE/TIMP-1/MMP-9)]. Patients receiving inhalative antibiotics or azithromycin (n=20 and n=15, respectively) revealed lower levels of IL-1β/IL-6/IL-8 and NE during exacerbation compared to CF patients not receiving those antibiotics. In addition, CF patients receiving azithromycin showed MMP-9 levels significantly lower than CF patients not receiving azithromycin at stable phase and exacerbation. Altogether, rhinoviruses were the most frequently detected virus, detected at least once in n=24 (49.0%) of the 49 included pwCF and in n=26 (68.4%) of the 38 healthy controls over the 13-month duration of the study. Remarkably, during exacerbation, rhinovirus detection rates were significantly higher in the HC group compared to those in CF patients (65.8% vs. 22.4%; p<0.0001)., Conclusion: Non-invasive and partially home-based UAW sampling opens new windows for the assessment of inflammation and pathogen colonization in the unified airway system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Erdmann, Schilling, Hentschel, Lehmann, von Bismarck, Ankermann, Duckstein, Baier, Zagoya and Mainz.)

Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR ( p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation ( p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.

Exposure of Arabidopsis (Arabidopsis thaliana) to 4°C imprints a cold memory that modulates gene expression in response to a second (triggering) stress stimulus applied several days later. Comparison of plastid transcriptomes of cold-primed and control plants directly before they were exposed to the triggering stimulus showed downregulation of several subunits of chloroplast NADPH dehydrogenase (NDH) and regulatory subunits of ATP synthase. NDH is, like proton gradient 5 (PGR5)-PGR5-like1 (PGRL1), a thylakoid-embedded, ferredoxin-dependent plastoquinone reductase that protects photosystem I and stabilizes ATP synthesis by cyclic electron transport (CET). Like PGRL1A and PGRL1B transcript levels, ndhA and ndhD transcript levels decreased during the 24-h long priming cold treatment. PGRL1 transcript levels were quickly reset in the postcold phase, but expression of ndhA remained low. The transcript abundances of other ndh genes decreased within the next days. Comparison of thylakoid-bound ascorbate peroxidase (tAPX)-free and transiently tAPX-overexpressing or tAPX-downregulating Arabidopsis lines demonstrated that ndh expression is suppressed by postcold induction of tAPX. Four days after cold priming, when tAPX protein accumulation was maximal, NDH activity was almost fully lost. Lack of the NdhH-folding chaperonin Crr27 (Cpn60β4), but not lack of the NDH activity modulating subunits NdhM, NdhO, or photosynthetic NDH subcomplex B2 (PnsB2), strengthened priming regulation of zinc finger of A. thaliana 10, which is a nuclear-localized target gene of the tAPX-dependent cold-priming pathway. We conclude that cold-priming modifies chloroplast-to-nucleus stress signaling by tAPX-mediated suppression of NDH-dependent CET and that plastid-encoded NdhH, which controls subcomplex A assembly, is of special importance for memory stabilization., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chloroplasts serve as cold priming hubs modulating the transcriptional response of Arabidopsis thaliana to a second cold stimulus for several days by postcold accumulation of thylakoid ascorbate peroxidases (tAPX). In an attempt to investigate cross-priming effects of cold on plant pathogen protection, we show here that such a single 24-h cold treatment at 4°C decreased the susceptibility of Arabidopsis to virulent Pseudomonas syringae pv. tomato DC3000 but did not alter resistance against the avirulent P. syringae pv. tomato avRPM1 and P. syringae pv. tomato avrRPS4 strains or the effector-deficient P. syringae pv. tomato strain hrcC - . The effect of cold priming against P. syringae pv. tomato was active immediately after cold exposure and memorized for at least 5 days. The priming benefit was established independent of the immune regulator Enhanced Disease Susceptibility 1 (EDS1) or activation of the immune-related genes NHL10 , FRK1 , ICS1 and PR1 but required thylakoid-bound as well as stromal ascorbate peroxidase activities because the effect was absent or weak in corresponding knock-out-lines. Suppression of tAPX postcold regulation in a conditional-inducible tAPX-RNAi line led to increased bacterial growth numbers. This highlights that the plant immune system benefits from postcold regeneration of the protective chloroplast peroxidase system.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

We demonstrate a monolithically integrated photonic integrated circuit (PIC) for terahertz spectroscopy with wide spectral bandwidth. The PIC includes two widely tunable sampled grating DBR (SG DBR) lasers, semiconductor optical amplifiers (SOAs), and passive components to combine signals. The SG DBR lasers cover 22 nm and 24 nm tuning range, respectively, with 4 nm overlap in the C band. The side mode suppression ratio (SMSR) exceeds 37 dB with a linewidth below 4.3 MHz. We used the PIC to generate THz radiation with a state-of-the-art photodiode emitter. The measured THz power spectrum between 0.03 and 1 THz compares well with the spectrum generated with commercial tunable laser sources. This demonstrates the suitability of our PIC for future miniaturized continuous wave (cw) THz systems.

Background: In Germany, the first case of coronavirus disease 2019 (COVID-19) was registered on 28 January 2020. By February 2021, the third wave of the pandemic began. So far, only few data are available on the SARS-CoV-2 prevalence and the clinical impact of an infection in patients with cystic fibrosis (CF)., Methods: From February 2020 until March 2021, we screened 156 CF patients for anti-SARS-CoV-2 IgG antibodies (serology) and the presence of SARS-CoV-2 in deep throat saliva or nasopharyngeal swabs (molecular testing). From patients with confirmed SARS-CoV-2 infection, we recorded symptoms and collected clinical data., Results: In total, 13 patients (8.3%) were tested positive for SARS-CoV-2 infection, most of them during the second and the beginning third wave of the pandemic. Ten positive tested patients described symptoms linked to COVID-19. The most common symptom was cough followed by fatigue and headache. SARS-CoV-2 infection did not impair lung function. No positive tested patient needed to be hospitalized., Conclusions: SARS-CoV-2 infections in patients with CF are not as rare as initially anticipated, as frequent testing revealed. However, infected patients did not experience more severe clinical courses or worse clinical outcome. Our observation is in line with published reports indicating that individuals with CF are not at higher risk for severe COVID-19., (© 2022. The Author(s).)

Objective: Respiratory illnesses, including coronavirus disease 2019 (COVID-19), have resulted in millions of deaths globally. Guidance on mask-wearing in community settings has been inconsistent. This review examined the effectiveness of mask-wearing on respiratory virus transmission in community settings., Methods: A search was conducted for English language reports of randomized controlled trials of mask-wearing in the community and effect on laboratory-confirmed respiratory infections or influenza-like illness. Investigators abstracted study characteristics and assessed bias. Meta-analysis was conducted to calculate pooled risk estimates., Results: Eleven studies were included. In 7 studies that evaluated influenza-like illness symptoms as an outcome (3029 participants), this study found mask-wearing associated with a decreased risk of influenza-like illness (overall risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.96). Studies examining laboratory-confirmed respiratory infections as an outcome (10,531 participants) showed no statistically significant association between mask-wearing and infections (RR, 1.04; 95% CI, 0.60-1.80). However, masking combined with enhanced hand hygiene was associated with a decreased risk for both influenza-like illness symptoms (RR, 0.88; 95% CI, 0.51-1.51) and laboratory-confirmed respiratory infection (RR, 0.79; 95% CI, 0.52-1.18)., Conclusions: Masking in community settings decreases transmission of influenza-like illness. Mask-wearing combined with enhanced hand hygiene reduces transmission of influenza-like illness and laboratory-confirmed respiratory infection.

The Co-HCW study is a prospective cohort study among hospital staff, including healthcare workers (HCWs) and administration staff, at the Jena University Hospital (JUH), Germany. The objectives of this study were to assess SARS-CoV-2 IgG seroprevalence, individual exposure risk factors and compliance of HCWs to wear personal protective equipment (PPE). After the first nosocomial COVID-19 outbreak at JUH, mandatory masking was implemented on 20th March 2020. We evaluated point seroprevalence using two IgG detecting immunoassays and issued a questionnaire to assess COVID-19 exposure, clinical symptoms and compliance to wear PPE. Antibody retesting was offered to participants with a divergent result of both immunoassays 5-10 weeks after the first test. Between 19th May and 19th June 2020, we analysed 660 participants [out of 3,228; 20.4%]. Among them, 212 participants (32.1%) had received a previous COVID-19 test. Four of them (1.9%) reported a positive test result. After recruitment, 18 participants (2.7%) had SARS-CoV-2 antibodies in at least one immunoassay. Overall, 21 participants (3.2%) had any evidence of a past or current SARS-CoV-2 infection. Among them, 13 (61.9%) were not aware of direct COVID-19 exposure and 9 (42.9%) did not report any clinical symptoms. COVID-19 exposure at home (adjusted OR (aOR) with 95% CI: 47.82 (5.49, 416.62)) was associated with SARS-CoV-2 seroprevalence. We observed no evidence for an association between seroprevalence and exposure at work (aOR 0.48 (0.13, 1.70)) or with COVID-19 risk area according to the working place (aOR for intermediate-risk vs. high-risk: 1.97 (0.42, 9.22), aOR for low-risk versus high-risk: 2.10 (0.40, 11.06); p = .655). Reported compliance of HCWs to wear PPE differed (p < .001) between working in high-risk (98.3%) and in intermediate-risk areas (69.8%). In conclusion, compared to administration staff, we observed no additional risk to acquire SARS-CoV-2 infections by patient care, probably due to high compliance to wear PPE., (© 2021 The Authors. Transboundary and Emerging Diseases published by Wiley-VCH GmbH.)

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community have been linked to its pathogenesis. Randomized controlled trials in UC and relapsing Clostridioides difficile infection (CDI) have established fecal microbiota (FM) transfer (FMT) as an effective therapy. In this context, preliminary results indicated that the transfer of sterile fecal microbiota filtrates (<0.2 μm; FMF, FMFT) of donor stool also drives gastrointestinal microbiota changes and eliminates symptoms in CDI patients. However, along with the success of FMT, regulatory agencies issued safety alerts following reports of serious adverse events due to transmission of enteric pathogens through FMT. To reduce this risk, we established an extensive test protocol for our donors and quarantine regulations for the produced capsules, but alternative concepts are desirable., Methods: Our project is a randomized, controlled, longitudinal, prospective, three-arm, multicenter, double-blind study to determine the safety and efficacy of repeated long-term, multi-donor FM or FMF transfers compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical remission at week 12., Discussion: This proposal aims to examine (a) the efficacy of encapsulated transfer of FM and FMF as a therapy for mild to moderate UC, (b) the short- and long-term safety of FMT and FMFT in patients with UC, and (c) the microbial and immunologic changes that occur after FMT and FMFT to help understand how and why it affects inflammatory bowel disease., Trial Registration: ClinicalTrials.gov NCT03843385 . DRKS (Deutsches Register für Klinische Studien) DRKS00020471., (© 2022. The Author(s).)

Cutaneous leishmaniasis (CL) frequently entails chronic skin lesions that heal only slowly. Until now, the available therapeutic options are very limited. Here, we present a case of a 5½-year-old Syrian refugee with two progressive lower-leg skin ulcers caused by Leishmania tropica. The patient received topical treatment with LeiProtect®, a newly developed, hydroxypropylcellulose-based, filmogenic gel containing nontoxic concentrations of pharmaceutical sodium chlorite. The skin lesions completely healed within 8 weeks and did not relapse during 1 year of follow-up, underlining the efficacy of this novel local therapy of CL.

Background: Infections, as well as adverse birth outcomes, may be more frequent in migrant women. Schistosomiasis, echinococcosis, and hepatitis E virus (HEV) seropositivity are associated with the adverse pregnancy outcomes of fetal growth restriction and premature delivery., Methods: A cohort study of 82 pregnant women with a history of migration and corresponding delivery of newborns in Germany was conducted., Results: Overall, 9% of sera tested positive for anti-HEV IgG. None of the patients tested positive for anti-HEV IgM, schistosomiasis, or echinococcus serology. Birth weights were below the 10th percentile for gestational age in 8.5% of the neonates. No association between HEV serology and fetal growth restriction (FGR) frequency was found., Conclusions: In comparison to German baseline data, no increased risk for HEV exposure or serological signs of exposure against schistosomiasis or echinococcosis could be observed in pregnant migrants. An influence of the anti-HEV serology status on fetal growth restriction could not be found.

Rapid vaccination may be of benefit in long-term care facilities (LTCF) that are affected by an ongoing COVID-19 outbreak. However, there are concerns regarding the safety and effectiveness of such an approach, particularly regarding the vaccination of pre-symptomatic patients. Here, we report the effectiveness of vaccination in a German LTCF hit by an outbreak that was detected 5 days after the first vaccine doses were administered. In detail, 66.7% of the unvaccinated patients experienced an unfavorable course; this proportion was much lower (33.3%) among the vaccinated patients. Even though this study is limited by a small number of patients, the observation and the comparison with related published data shows that vaccination (i) is safe and (ii) may still be of benefit when given shortly before an infection or even in pre-symptomatic LTCF-patients.

Purpose: To explore associations of nutritional, infectious, and lifestyle factors with esophageal cancer (EC) occurrence in a high-risk area of Malawi., Methods: This case-control study was performed with 227 patients undergoing endoscopy for dysphagia or other upper gastrointestinal complaints. Data on clinicopathological characteristics and risk factors were collected using a questionnaire developed for this study specifically. Ninety-eight blood samples were collected and the prevalence of antibodies against human immunodeficiency virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, and Helicobacter pylori were determined serologically., Results: The tumor and control groups comprised 157 (69.2%) and 70 (31.8%) patients, respectively. Patients with tumors were significantly older than controls (55.5 vs. 43.5 years, p < 0.001). The male/female ratio did not differ between groups (59% and 54% male, respectively; p = 0.469). EC was associated with smoking (p < 0.001), and alcohol consumption (p = 0.020), but 43% of patients with tumors did not smoke or drink. EC was associated with the consumption of hot food and tea (p = 0.003) and smoked fish (p = 0.011). EC was not associated with any serologically investigated infectious agents. In an age adjusted binary logistic regression analysis of all nutritive factors, only locally made alcohol was significant [odds ratio (OR), 9.252; 95% confidence interval (CI), 1.455-58.822; p = 0.018]., Conclusions: Apart from alcohol consumption and smoking, the consumption of hot food or tea and smoked fish are associated with EC. Locally distilled alcohol consumption increases the EC risk in Malawi., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objectives: Vaccine induced thrombotic thrombocytopenia (VITT) may occur after COVID-19 vaccination with recombinant adenoviral vector-based vaccines. VITT can present as cerebral sinus and venous thrombosis (CSVT), often complicated by intracranial hemorrhage. Today it is unclear, how long symptomatic VITT can persist. Here, we report the complicated long-term course of a VITT patient with extremely high titers of pathogenic anti-platelet factor 4 (PF4)-IgG antibodies., Methods: Clinical and laboratory findings are presented, including the course of platelet counts, D-Dimer levels, clinical presentation, imaging, SARS-CoV-2-serological and immunological, platelet activating anti-PF4-IgG, as well as autopsy findings., Results: The patient presented with extended superior sagittal sinus thrombosis with accompanying bifrontal intracerebral hemorrhage. Repeated treatment with intravenous immune globuline (IVIG) resolved recurrent episodes of thrombocytopenia. Moreover, the patient's serum remained strongly positive for platelet-activating anti-PF4-IgG over three months. After a period of clinical stabilization, the patient suffered a recurrent and fatal intracranial hemorrhage., Conclusions: Complicated VITT with extremely high anti-PF4-IgG titers over three months can induce recurrent thrombocytopenia despite treatment with IVIG and anticoagulation. Plasma exchange, immunoadsorption, and /or immunosuppressive treatment may be considered in complicated VITT to reduce extraordinarily high levels of anti-PF4-IgG. Long-term therapy in such cases must take the individual bleeding risk and CSVT risk into account.

Cold-priming uncouples cold and light regulation of otherwise tightly co-regulated genes. In this study, we focused on the early regulatory processes in Arabidopsis within the first 2 h in cold and in high light after a 5-d lag-phase at 20 °C and 24 h cold-priming at 4 °C. Priming quickly modified gene expression in a trigger-specific manner. In the early stress-response phase during cold and high-light triggering, it reduced the regulatory amplitudes of many up- and down-regulated genes. A third of the priming-regulated genes were jasmonate-sensitive, including the full set of genes required for oxylipin biosynthesis. Analysis of wild-type and mutant plants based on qPCR demonstrated that biosynthesis of the jasmonic acid (JA) precursor 12-oxo phytenoic acid (OPDA) relative to the availability of JA dampened the response of the genes for oxylipin biosynthesis. In oxylipin biosynthetic mutants, cold-priming more strongly affected genes involved in the biosynthesis of OPDA than in its conversion to JA. In addition, priming-dependent dampening of the triggering response was more linked to OPDA than to regulation of the JA concentration. Spray application of OPDA prior to triggering counteracted the priming effect. Regulation of the oxylipin hub was controlled by modulation of the oxylipin-sensitivity of the genes for OPDA biosynthesis, but it was insensitive to priming-induced accumulation of thylakoid ascorbate peroxidase, thus identifying a parallel-acting cold-priming pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Humoral immunity after infection or after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been attributed a key part in mitigating the further transmission of the virus. In this study, we used a commercial anti-Spike immunoglobulin G (S-IgG) assay and developed a cell culture-based neutralization assay to understand the longitudinal course of neutralizing antibodies in both SARS-CoV2 infected or vaccinated individuals. We show that even more than one year after infection, about 78% of observed study participants remained seropositive concerning S-IgG antibodies. In addition, the serum of the individuals had stable neutralization capacity in a neutralization assay against a SARS-CoV-2 patient isolate from March 2020. We also examined volunteers after either homologous BNT162b2 prime-boost vaccination or heterologous AZD1222 prime/mRNA-based booster vaccination. Both the heterologous and the homologous vaccination regimens induced higher levels of neutralizing antibodies in healthy subjects when compared to subjects after a mild infection, showing the high effectiveness of available vaccines. In addition, we could demonstrate the reliability of S-IgG levels in predicting neutralization capacity, with 94.8% of seropositive samples showing a neutralization titer of ≥10, making it a viable yet cheap and easy-to-determine surrogate parameter for neutralization capacity.