[Persecuted and forgotten? The neurologists Kurt Goldstein and Friedrich Heinrich Lewy]. / Verfolgt und vergessen? Die Neurologen Kurt Goldstein und Friedrich Heinrich Lewy.

This paper commemorates the careers and the scientific influence of the clinical neurologists Kurt Goldstein and Friedrich Heinrich Lewy including their forced migration in the mid-1930s. Goldstein (1878-1965) set up independent neurological departments in Frankfurt/Main and Berlin, adopting a decidedly holistic approach in medical care, research and teaching. He is therefore considered a co-founder of modern neuropsychology and neurorehabilitation. Goldstein came into the focus of the National Socialists as a Jew, socialist and adherent of psychotherapeutic methods. After a short incarceration he fled via Switzerland and Holland to the USA. Lewy (1885-1970) for his part specialized in neuropathological examinations and in 1912 quickly discovered the inclusion bodies in the cytoplasm of nerve cells named after him. As head of a neurological institute in Berlin with inpatient beds, he decided to leave Germany as early as 1933 and arrived after a stopover in England in the United States one year later. The biographies of the two highly innovative neurologists illustrate that career opportunities for doctors of Jewish descent were already clearly limited during the Weimar Republic and that they had to face anti-Semitic tendencies even after their arrival in the USA.

Effects of mental health interventions among people hospitalized with COVID-19 infection: A systematic review of randomized controlled trials.

OBJECTIVE: We evaluated the effects of mental health interventions among people hospitalized with COVID-19. METHODS: We conducted a systematic review and searched 9 databases (2 Chinese-language) from December 31, 2019 to June 28, 2021. Eligible randomized controlled trials assessed interventions among hospitalized COVID-19 patients that targeted mental health symptoms. Due to the poor quality of trials, we sought to verify accuracy of trial reports including results. RESULTS: We identified 47 randomized controlled trials from China (N = 42), Iran (N = 4) and Turkey (N = 1) of which 21 tested the efficacy of psychological interventions, 5 physical and breathing exercises, and 21 a combination of interventions. Trial information could only be verified for 3 trials of psychological interventions (cognitive behavioral, guided imagery, multicomponent online), and these were the only trials with low risk of bias on at least 4 of 7 domains. Results could not be pooled or interpreted with confidence due to the degree of poor reporting and trial quality, the frequency of what were deemed implausibly large effects, and heterogeneity. CONCLUSION: Trials of interventions to address mental health in hospitalized COVID-19 patients, collectively, are not of sufficient quality to inform practice. Health care providers should refer to existing expert recommendations and standard hospital-based practices. REGISTRATION: PROSPERO (CRD42020179703); registered on April 17, 2020.

Effects of COVID-19 Mental Health Interventions Among Children, Adolescents, and Adults Not Quarantined or Undergoing Treatment Due to COVID-19 Infection: A Systematic Review of Randomised Controlled Trials.

OBJECTIVES: Our objective was to assess the effects of mental health interventions for children, adolescents, and adults not quarantined or undergoing treatment due to COVID-19 infection. METHODS: We searched 9 databases (2 Chinese-language) from December 31, 2019, to March 22, 2021. We included randomised controlled trials of interventions to address COVID-19 mental health challenges among people not hospitalised or quarantined due to COVID-19 infection. We synthesized results descriptively due to substantial heterogeneity of populations and interventions and risk of bias concerns. RESULTS: We identified 9 eligible trials, including 3 well-conducted, well-reported trials that tested interventions designed specifically for COVID-19 mental health challenges, plus 6 other trials with high risk of bias and reporting concerns, all of which tested standard interventions (e.g., individual or group therapy, expressive writing, mindfulness recordings) minimally adapted or not specifically adapted for COVID-19. Among the 3 well-conducted and reported trials, 1 (N = 670) found that a self-guided, internet-based cognitive-behavioural intervention targeting dysfunctional COVID-19 worry significantly reduced COVID-19 anxiety (standardized mean difference [SMD] 0.74, 95% confidence interval [CI], 0.58 to 0.90) and depression symptoms (SMD 0.38, 95% CI, 0.22 to 0.55) in Swedish general population participants. A lay-delivered telephone intervention for homebound older adults in the United States (N = 240) and a peer-moderated education and support intervention for people with a rare autoimmune condition from 12 countries (N = 172) significantly improved anxiety (SMD 0.35, 95% CI, 0.09 to 0.60; SMD 0.31, 95% CI, 0.03 to 0.58) and depressive symptoms (SMD 0.31, 95% CI, 0.05 to 0.56; SMD 0.31, 95% CI, 0.07 to 0.55) 6-week post-intervention, but these were not significant immediately post-intervention. No trials in children or adolescents were identified. CONCLUSIONS: Interventions that adapt evidence-based strategies for feasible delivery may be effective to address mental health in COVID-19. More well-conducted trials, including for children and adolescents, are needed.

A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution.

The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.

Population genomics of an outbreak of the potato late blight pathogen, Phytophthora infestans, reveals both clonality and high genotypic diversity.

An outbreak of the potato late blight pathogen Phytophthora infestans in Denmark was characterized in order to resolve the population structure and determine to what extent sexual reproduction was occurring. A standard set of microsatellite simple sequence repeats (SSRs) and single nucleotide polymorphism (SNP) markers generated using restriction site-associated DNA sequencing (RAD-seq) were employed in parallel. A total of 83 individuals, isolated from seven different potato fields in 2014, were analysed together with five Danish whole-genome sequenced isolates, as well as two Mexican individuals used as an outgroup. From a filtered dataset of 55 288 SNPs, population genomics analyses revealed no sign of recombination, implying clonality. In spite of this, multilocus genotypes were unique to individual potato fields, with little evidence of gene flow between fields. Ploidy analysis performed on the SNPs dataset indicated that the majority of isolates were diploid. These contradictory results with clonality and high genotypic diversity may suggest that rare sexual events likely still contribute to the population. Comparison of the results generated by SSRs vs SNPs data indicated that large marker sets, generated by RAD-seq, may be advised going forward, as it provides a higher level of genetic discrimination than SSRs.

The Happy Teen programme: a holistic outpatient clinic-based approach to prepare HIV-infected youth for the transition from paediatric to adult medical care services in Thailand.

INTRODUCTION: We developed an 18-month Happy Teen 2 (HT2) programme comprised of a one-day workshop, two half-day sessions, and three individual sessions to prepare HIV-infected youth for the transition from paediatric to adult HIV care services. We describe the programme and evaluate the change in youth's knowledge scores. METHODS: We implemented the HT2 programme among HIV-infected Thai youth aged 14-22 years who were aware of their HIV status and receiving care at two hospitals in Bangkok (Siriraj Hospital, Queen Sirikit National Institute of Child Health [QSNICH]). Staff interviewed youth using a standardized questionnaire to assess HIV and health-related knowledge at baseline and at 12 and 18 months while they participated in the programme. We examined factors associated with a composite knowledge score ≥95% at month 18 using logistic regression. RESULTS: During March 2014-July 2016, 192 of 245 (78%) eligible youth were interviewed at baseline. Of these, 161 (84%) returned for interviews at 12 and 18 months. Among the 161 youth, the median age was 17 years, 74 (46%) were female, and 99% were receiving antiretroviral treatment. The median composite score was 45% at baseline and increased to 82% at 12 months and 95% at 18 months (P < 0.001). The range of median knowledge scores for antiretroviral management, HIV monitoring, HIV services, and family planning significantly increased from baseline (range 0-75%) to (range 67-100%) at 12 months and to 100% at 18 months (P < 0.001). Almost all youth were able to describe education and career goals at 12 and 18 months compared to 75% at baseline. In multivariable analysis, a composite knowledge score at 18 months >95% was associated with education level >high school (aOR: 2.15, 95%CI, 1.03-4.48) and receipt care at QSNICH (aOR: 2.43, 95%CI, 1.18-4.98). Youth whose mother and father had died were less likely to have score ≥95% (aOR: 0.22, 95%CI, 0.07-0.67) than those with living parents. CONCLUSIONS: Knowledge useful for a successful transition from paediatric to adult HIV care increased among youth participating in the HT2 programme. Youth follow-up will continue to assess the impact of improved knowledge on outcomes following the transition to adult care services.

Historic Late Blight Outbreaks Caused by a Widespread Dominant Lineage of Phytophthora infestans (Mont.) de Bary.

Phytophthora infestans (Mont.) de Bary, the causal agent of potato late blight, was responsible for the Irish potato famine of the 1840s. Initial disease outbreaks occurred in the US in 1843, two years prior to European outbreaks. We examined the evolutionary relationships and source of the 19th-century outbreaks using herbarium specimens of P. infestans from historic (1846-1970) and more recent isolates (1992-2014) of the pathogen. The same unique SSR multilocus genotype, named here as FAM-1, caused widespread outbreaks in both US and Europe. The FAM-1 lineage shared allelic diversity and grouped with the oldest specimens collected in Colombia and Central America. The FAM-1 lineage of P. infestans formed a genetic group that was distinct from more recent aggressive lineages found in the US. The US-1 lineage formed a second, mid-20th century group. Recent modern US lineages and the oldest Mexican lineages formed a genetic group with recent Mexican lineages, suggesting a Mexican origin of recent US lineages. A survey of mitochondrial haplotypes in a larger set of global herbarium specimens documented the more frequent occurrence of the HERB-1 (type Ia) mitochondrial haplotype in archival collections from 1866-75 and 1906-1915 and the rise of the Ib mitochondrial lineage (US-1) between 1946-1955. The FAM-1 SSR lineage survived for almost 100 years in the US, was geographically widespread, and was displaced first in the mid-20th century by the US-1 lineage and then by distinct new aggressive lineages that migrated from Mexico.

Biomedical HIV Prevention Including Pre-exposure Prophylaxis and Opiate Agonist Therapy for Women Who Inject Drugs: State of Research and Future Directions.

Women who inject drugs (WWID) are at higher risk of HIV compared with their male counterparts as a result of multiple factors, including biological, behavioral, and sociostructural factors, yet comparatively little effort has been invested in testing and delivering prevention methods that directly target this group. In this article, we discuss the need for expanded prevention interventions for WWID, focusing on 2 safe, effective, and approved, yet underutilized biomedical prevention methods: opiate agonist therapy (OAT) and oral pre-exposure prophylaxis (PrEP). Although both interventions are well researched, they have not been well examined in the context of gender. We discuss the drivers of women injectors' higher HIV risk, review the effectiveness of OAT and PrEP interventions among women, and explain why these new HIV prevention tools should be prioritized for WWID. There is substantial potential for impact of OAT and PrEP programs for WWID in the context of broader gender-responsive HIV prevention initiatives. Although awaiting efficacy data on other biomedical approaches in the HIV prevention research "pipeline," we propose that the scale-up and implementation of these proven, safe, and effective interventions are needed now.

Persistence of the mitochondrial lineage responsible for the Irish potato famine in extant new world phytophthora infestans.

The plant pathogen Phytophthora infestans emerged in Europe in 1845, triggering the Irish potato famine and massive European potato crop losses that continued until effective fungicides were widely employed in the 20th century. Today the pathogen is ubiquitous, with more aggressive and virulent strains surfacing in recent decades. Recently, complete P. infestans mitogenome sequences from 19th-century herbarium specimens were shown to belong to a unique lineage (HERB-1) predicted to be rare or extinct in modern times. We report 44 additional P. infestans mitogenomes: four from 19th-century Europe, three from 1950s UK, and 37 from modern populations across the New World. We use phylogenetic analyses to identify the HERB-1 lineage in modern populations from both Mexico and South America, and to demonstrate distinct mitochondrial haplotypes were present in 19th-century Europe, with this lineage initially diversifying 75 years before the first reports of potato late blight.

Reconstructing genome evolution in historic samples of the Irish potato famine pathogen.

Responsible for the Irish potato famine of 1845-49, the oomycete pathogen Phytophthora infestans caused persistent, devastating outbreaks of potato late blight across Europe in the 19th century. Despite continued interest in the history and spread of the pathogen, the genome of the famine-era strain remains entirely unknown. Here we characterize temporal genomic changes in introduced P. infestans. We shotgun sequence five 19th-century European strains from archival herbarium samples--including the oldest known European specimen, collected in 1845 from the first reported source of introduction. We then compare their genomes to those of extant isolates. We report multiple distinct genotypes in historical Europe and a suite of infection-related genes different from modern strains. At virulence-related loci, several now-ubiquitous genotypes were absent from the historical gene pool. At least one of these genotypes encodes a virulent phenotype in modern strains, which helps explain the 20th century's episodic replacements of European P. infestans lineages.

Rectal cancer.

These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.

A selenium-based click AdoMet analogue for versatile substrate labeling with wild-type protein methyltransferases.

Protein methylation is catalyzed by S-adenosyl-L-methionine-dependent protein methyltransferases (MTases), and this posttranslational modification serves diverse cellular functions. Some MTases seem to exhibit broad substrate specificities and comprehensive methods for target profiling are needed. Here we report the synthesis of a new AdoMet analogue for enzymatic transfer of a small propargyl group and labeling of modified proteins through copper-catalyzed azide-alkyne cycloaddition (CuAAC). Replacement of sulfur by selenium strongly enhanced the stability of the progargylic cofactor, leading, in combination with better activation by the selenonium center, to higher enzymatic reactivity. A broad spectrum of wild-type protein MTases acting on lysine, arginine, and glutamine residues accept this cofactor and modified substrates can be efficiently labeled by CuAAC click chemistry.

Review of over-the-counter treatments for aphthous ulceration and results from use of a dissolving oral patch containing glycyrrhiza complex herbal extract.

AIM: The aim of this article is to present a review of over-the-counter (OTC) treatment strategies used for aphthous ulcerations and to provide results from the use of an herbal extract containing glycyrrhiza. BACKGROUND: Aphthous ulceration, a disease of the intra-oral mucosa, is a common condition of unknown etiology that is often self-managed by OTC (no prescription required) medication. REVIEW: Preparations currently on the market can be divided into several categories: local anesthetic agents, oxygenating agents, mouth rinses, and barriers - further subdivided into paste coverings such as gels or dissolvable or non-dissolvable adhesive patches containing plant extract or synthetic drugs. Other strategies include herbs, hematinic replacement, or off-label OTC drug applications. While many OTC treatments are available and accepted for use with aphthous ulceration, a review of the literature via a number of published research search engines suggests that to date there are no randomized controlled studies to demonstrate OTC preparations do more than manage symptoms. Exceptions include OTC cyanoacrylate products and CankerMelts GX patches which include glycyrrhiza (licorice) extract. The use of CankerMelts has been shown to alter the course of the condition by reducing lesion duration, size, and pain. SUMMARY: The results of the studies reviewed here suggest CankerMelts GX discs may be as effective as amlexanox (which must be prescribed) in reducing pain and speeding healing. In addition it can be applied by the patient without the adverse events associated with cyanoacrylate formulations.

A controlled trial of a dissolving oral patch concerning glycyrrhiza (licorice) herbal extract for the treatment of aphthous ulcers.

Recurrent aphthous ulcers (RAU) are a common and painful condition. This article describes a randomized, double-blind clinical trial of an over-the-counter medicated intraoral adhesive patch for treatment of RAU. Subjects were randomly assigned to either an active drug (patch with extract of glycyrrhiza root) or placebo patch treatment group (both n=23) at onset of a lesion. Lesion size and pain report (unstimulated and stimulated) were assessed at intervals. A no-treatment group (n=23) also was recruited and assessed similarly. By the eighth day, the ulcer size for the active treatment group was significantly lower (p < 0.05), while the By the fourth day, the active treatment group lesions in the no-treatment group increased 13% from baseline.reported significantly less pre-stimulus pain (p < 0.01); at this point, 81% of this group reported no pre-stimulus pain, comp ared with 63% of the placebo patch group and 40% of the no-treatment group

Levels of trace elements in green turtle eggs collected from Hong Kong: Evidence of risks due to selenium and nickel.

Concentrations of 22 trace elements were determined in green turtle (Chelonia mydas) eggs collected from Hong Kong. Concentrations of selenium, lead and nickel in these eggs were generally higher than those reported in other studies. The predicted no effect concentrations (PNEC; ng/g wet weight) of Pb (1000), Se (340 and 6000 for the worst-case and best-case scenarios, respectively) and Ni (17) in the green turtle eggs were estimated. Hazard quotients (HQs) estimate that Se (HQs: 0.2-24.5) and Ni (HQs: 4.0-26.4) may pose some risks to the turtles. Our study also found that concentrations of Ag, Se, Zn, Hg and Pb in the shell of the turtle eggs were significantly correlated with levels in the whole egg contents (yolk+albumen). Once the precise relationships of specific elements are established, egg-shell concentrations may be used as a non-lethal, non-invasive, surrogate for predicting whole egg burden of certain contaminants in marine turtles.

Enterotoxin-based mucosal adjuvants alter antigen trafficking and induce inflammatory responses in the nasal tract.

The safety of nasal vaccines containing enterotoxin-based mucosal adjuvants has not been studied in detail. Previous studies have indicated that native cholera toxin (nCT) can alter antigen trafficking when applied nasally. In this study, we determined the enterotoxin-based variables that alter antigen trafficking. To measure the influence of enterotoxin-based mucosal adjuvants on antigen trafficking in the nasal tract, native and mutant enterotoxins were coadministered with radiolabeled tetanus toxoid (TT). The nCT and heat-labile enterotoxin type 1 (LTh-1) redirected TT into the olfactory neuroepithelium (ON/E). Antigen redirection occurred mainly across the nasal epithelium without subsequent transport along olfactory neurons into the olfactory bulbs (OB). Thus, no significant accumulation of the vaccine antigen TT was observed in the OB when coadministered with nCT. In contrast, neither mutant CT nor mutant LTh-1, which lack ADP-ribosyltransferase activity, redirected TT antigen into the ON/E. Thus, ADP-ribosyltransferase activity was essential for antigen trafficking across the olfactory epithelium. Accumulation of TT in the ON/E was also due to B-subunit binding to GM1 gangliosides, as was demonstrated (i) by redirection of TT by LTh-1 in a dose-dependent manner, (ii) by ganglioside inhibition of the antigen redirection by LTh-1 and nCT, and (iii) by the use of LT-IIb, a toxin that binds to gangliosides other than GM1. Redirection of TT into the ON/E coincided with elevated production of interleukin 6 (IL-6) but not IL-1beta or tumor necrosis factor alpha in the nasal mucosa. Thus, redirection of TT is dependent on ADP-ribosyltransferase activity and GM1 binding and is associated with production of the inflammatory cytokine IL-6.

Effectiveness of the quillaja saponin semi-synthetic analog GPI-0100 in potentiating mucosal and systemic responses to recombinant HagB from Porphyromonas gingivalis.

The gram-negative, anaerobic bacterium Porphyromonas gingivalis, has been implicated in the etiology of adult periodontal disease. Among the potential virulence factors of this bacterium, the non-fimbrial adhesin hemagglutinin B (HagB) appears to be involved in the initial adherence of the bacteria to host tissue and the induction of anti-HagB antibody responses affords some protection from experimental alveolar bone loss. In the present study, we have investigated the ability of the quillaja saponin derivative GPI-0100 to act as an immunostimulant of responses to HagB following subcutaneous (s.c.) or intranasal (i.n.) immunization of mice. We have also compared the immunopotentiating ability of GPI-0100 with that of five other adjuvants. Evidence is provided that GPI-0100 was more effective than monophosphoryl lipid A and alum in inducing serum anti-HagB responses following s.c. immunization. A comparison of the responses induced following i.n. immunization with HagB and adjuvant revealed that the heat-labile toxin of Escherichia coli (LT) and the non-enzymatic mutant LT (E112K), followed by GPI-0100 potentiated higher serum and mucosal anti-HagB antibody responses, which in most cases were higher than those seen with the other adjuvants tested (i.e. monophosphoryl lipid A, alum and the B subunit of cholera toxin). Furthermore, a difference was seen in the nature of the serum IgG anti-HagB response based on the adjuvant used and route of immunization. These results demonstrate the effectiveness of GPI-0100 as both a systemic and mucosal adjuvant and support its potential use in the development of vaccines against periodontal, as well as other pathogens.