Mass Spectrometry Approaches Empowering Neuropeptide Discovery and Therapeutics.

The discovery of insulin in the early 1900s ushered in the era of research related to peptides acting as hormones and neuromodulators, among other regulatory roles. These essential gene products are found in all organisms, from the most primitive to the most evolved, and carry important biologic information that coordinates complex physiology and behavior; their misregulation has been implicated in a variety of diseases. The evolutionary origins of at least 30 neuropeptide signaling systems have been traced to the common ancestor of protostomes and deuterostomes. With the use of relevant animal models and modern technologies, we can gain mechanistic insight into orthologous and paralogous endogenous peptides and translate that knowledge into medically relevant insights and new treatments. Groundbreaking advances in medicine and basic science influence how signaling peptides are defined today. The precise mechanistic pathways for over 100 endogenous peptides in mammals are now known and have laid the foundation for multiple drug development pipelines. Peptide biologics have become valuable drugs due to their unique specificity and biologic activity, lack of toxic metabolites, and minimal undesirable interactions. This review outlines modern technologies that enable neuropeptide discovery and characterization, and highlights lessons from nature made possible by neuropeptide research in relevant animal models that is being adopted by the pharmaceutical industry. We conclude with a brief overview of approaches/strategies for effective development of peptides as drugs. SIGNIFICANCE STATEMENT: Neuropeptides, an important class of cell-cell signaling molecules, are involved in maintaining a range of physiological functions. Since the discovery of insulin's activity, over 100 bioactive peptides and peptide analogs have been used as therapeutics. Because these are complex molecules not easily predicted from a genome and their activity can change with subtle chemical modifications, mass spectrometry (MS) has significantly empowered peptide discovery and characterization. This review highlights contributions of MS-based research towards the development of therapeutic peptides.

Assessment and Comparison of Database Search Engines for Peptidomic Applications.

Protein database search engines are an integral component of mass spectrometry-based peptidomic analyses. Given the unique computational challenges of peptidomics, many factors must be taken into consideration when optimizing search engine selection, as each platform has different algorithms by which tandem mass spectra are scored for subsequent peptide identifications. In this study, four different database search engines, PEAKS, MS-GF+, OMSSA, and X! Tandem, were compared with Aplysia californica and Rattus norvegicus peptidomics data sets, and various metrics were assessed such as the number of unique peptide and neuropeptide identifications, and peptide length distributions. Given the tested conditions, PEAKS was found to have the highest number of peptide and neuropeptide identifications out of the four search engines in both data sets. Furthermore, principal component analysis and multivariate logistic regression were employed to determine whether specific spectral features contribute to false C-terminal amidation assignments by each search engine. From this analysis, it was found that the primary features influencing incorrect peptide assignments were the precursor and fragment ion m/z errors. Finally, an assessment employing a mixed species protein database was performed to evaluate search engine precision and sensitivity when searched against an enlarged search space containing human proteins.

Environmentally Ultrasensitive Fluorine Probe to Resolve Protein Conformational Ensembles by 19F NMR and Cryo-EM.

Limited chemical shift dispersion represents a significant barrier to studying multistate equilibria of large membrane proteins by 19F NMR. We describe a novel monofluoroethyl 19F probe that dramatically increases the chemical shift dispersion. The improved conformational sensitivity and line shape enable the detection of previously unresolved states in one-dimensional (1D) 19F NMR spectra of a 134 kDa membrane transporter. Changes in the populations of these states in response to ligand binding, mutations, and temperature correlate with population changes of distinct conformations in structural ensembles determined by single-particle cryo-electron microscopy (cryo-EM). Thus, 19F NMR can guide sample preparation to discover and visualize novel conformational states and facilitate image analysis and three-dimensional (3D) classification.

Methamphetamine-associated catatonia: Case series and systematic review of the literature from 1943-2020.

BACKGROUND: Catatonia due to a general medical condition may result from a variety of causes, including substance intoxication and withdrawal. Stimulants are occasionally associated with catatonia, though there has been little investigation of methamphetamine's relationship to catatonia. Here we present 5 cases of catatonia associated with methamphetamine use and a systematic review of the associated literature from 1943 to 2020. METHODS: We performed a systematic review of the literature and present 5 cases of catatonia evaluated using the Bush-Francis Catatonia Rating Scale and KANNER catatonia rating scale. RESULTS: Methamphetamine use was associated with catatonia in a small number of cases in the literature. However, some of these reports included other possible etiologies. The patients in our case series met DSM-5 criteria for catatonia due to a general medical condition, with all reporting recent methamphetamine use and testing positive for amphetamines on urine drug screen. CONCLUSIONS: Given the ongoing rise in methamphetamine use in the United States, it is important that clinicians understand that methamphetamine use can be associated with catatonia. Patients with methamphetamine-associated catatonia may respond favorably to lorazepam and require shorter hospital stays than other catatonic patients. Lastly, methamphetamine-associated catatonia highlights how alteration in dopamine function and projections may be a critical neural mechanism underlying catatonia in general.

Is there an association between serum soluble interleukin-2 receptor levels and syndrome severity in persistent Complex Regional Pain Syndrome?

OBJECTIVE: A potentially useful biomarker for Complex Regional Pain Syndrome (CRPS) is the serum soluble interleukin-2 receptor (sIL-2R) level, which is a marker for T-cell activation. Elevated serum sIL-2R levels have been described in CRPS patients compared to healthy controls. In T-cell mediated inflammatory diseases such as sarcoidosis and rheumatoid arthritis, the serum sIL-2R levels correlate with disease severity. In this study, we investigate whether an association exists between serum sIL-2R levels in CRPS patients and CRPS severity. METHODS: A cross-sectional cohort study was conducted in a tertiary pain referral center in the Netherlands. Adult CRPS patients diagnosed by the IASP criteria were included between October 2018 until October 2022. The main study parameters were serum sIL-2R levels and the CRPS severity score. RESULTS: Fifty-three CRPS patients were included with a mean syndrome duration of 84 months (Q3 - Q1:180 - 48). The majority had persistent CRPS with a syndrome duration >1 year (n = 52, 98%). The median pain Numerical Rating Score (NRS) was 7 (Q3 - Q1: 8 - 5) and the mean CRPS severity score was 11 (SD ± 2.3). The median serum sIL-2R level was 330 U/mL (Q3 - Q1:451 - 256). No statistically significant correlation was observed between serum sIL-2R levels and the CRPS severity score (rs = 0.15, P = .28). CONCLUSIONS: Our findings suggest that serum sIL-2R levels cannot be used as a biomarker for syndrome severity in persistent CRPS (syndrome duration >1 year). Serial measurements of serum sIL-2R from early CRPS to persistent CRPS are needed to investigate whether serum sIL-2R levels can be used to monitor T-cell mediated inflammatory syndrome activity.

Intermittent versus continuous esketamine infusions for long-term pain modulation in complex regional pain syndrome: protocol of a randomized controlled non-inferiority study (KetCRPS-2).

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. METHODS: In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patient. DISCUSSION: If our study reveals non-inferiority between intermittent and continuous esketamine infusions, these findings can be beneficial to increase the availability and flexibility of esketamine infusions through outpatient treatments. Furthermore, the costs of outpatient esketamine infusions could be lower than inpatient esketamine infusions. In addition, secondary parameters may predict response to esketamine treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT05212571 , date of registration 01-28-2022. PROTOCOL VERSION: Version 3, February 2022.

Systemic Colonization of Potato Plants by Verticillium dahliae Leads to Infection of Tubers and Sprouting Buds.

A green fluorescent protein (GFP)-tagged isolate of Verticillium dahliae was used to study its colonization in potato plants and tubers. Three-week-old potato plants of the highly susceptible cultivar 'Shepody' were inoculated with a conidial suspension of a GFP-tagged isolate of V. dahliae using a wound inoculation method. Colonization was studied using confocal microscopy combined with tissue sections. Conidia germinated and hyphae grew along the root hairs, elongation zones, and root caps between 24 and 96 h postinoculation (HPI). At 7 days postinoculation (DPI), the pathogen advanced to cortical tissues and grew into the root vascular bundles. At 8 weeks postinoculation (WPI), the stem epidermal cells, cortical tissues, vascular elements, and petioles were fully colonized by the mycelium of V. dahliae. At 11 WPI, the pathogen was detected in the stolon and progeny tubers, as confirmed by both GFP signals in tissues and reisolation of the pathogen on the semiselective NP-10 medium. Progeny potato tubers were harvested from the inoculated potato plants, and the GFP-signal was observed in the epidermal cells and vascular elements of sprouting buds that emerged from the harvested tubers. The infection rate of progeny tubers detected on semiselective NP-10 medium ranged from 34.55 to 55.56%, with an average of 45.31%. In conclusion, we report, for the first time, the entire progression of colonization by V. dahliae in potato plant tissues, progeny tubers, as well as of the sprouting buds that emerged from progeny tubers.

ADVANCEMENTS IN MINIMALLY INVASIVE SURGERY: A COMPREHENSIVE ANALYSIS OF ROBOTIC SURGERY, ENDOSCOPIC TECHNIQUES, AND NATURAL ORIFICE TRANSLUMENAL ENDOSCOPIC SURGERY.

The term "Natural Orifice Transluminal Endoscopic Surgery" (NOTES) defines a surgical approach that leverages the body's natural orifices to access the abdominal cavity, presenting a patient-centric perspective by highlighting its potential to eliminate abdominal wall aggression, mitigate postoperative discomfort, and offer benefits comparable to laparoscopic surgery. This comprehensive paper aims to not only review the existing landscape of NOTES techniques but also to propose advancements in flexible tools augmenting established endoscopic platforms, while also exploring the revolutionary concept of robotic structures grounded in micromechatronics and communication technologies. The thorough analysis encompasses the assessment of advantages and limitations associated with flexible devices and robotic platforms, coupled with an in-depth evaluation of the current array of devices used in NOTES, informed by pertinent literature. The authors' comprehensive approach entails scrutinizing technological breakthroughs and offering viable solutions, fostering a comprehensive understanding. Furthermore, the study encompasses an exhaustive evaluation and juxtaposition of state-of-the-art NOTES devices, supplemented by a nuanced discourse on the merits and demerits of flexible devices and robotic platforms, with a focused emphasis on their inherent strengths and weaknesses. Within this context, the discourse extends to strategic suggestions aimed at refining extant designs and cultivating robust, dependable autonomous robotic platforms purpose-built for NOTES. This narrative encapsulates the multifaceted exploration of benefits, challenges, and potential remedies directed towards enhancing prevailing designs and forging a dependable foundation for the future of NOTES.

THE ROLE OF GENETICS IN DISEASE DIAGNOSIS AND TREATMENT MITOCHONDRIAL RESPIRATORY CHAIN DYSREGULATION IN GENOMIC MEDICINE.

Although mitochondrial DNA respiration circuit abnormalities are among the most common metabolic diseases to manifest in children, identification can be difficult due to their medical variability. Given the multisystem nature of the condition and its diverse and generalized manifestations, making a final diagnosis often takes a long time. Within this summary, they give an in-depth account of the physical signs of adolescent Mitochondrial Respiratory Chain Disorders (MRCDs),analyze the available diagnostics and treatment possibilities, and emphasize current developments in this field of study. During the discovery of fresh biomarkers and the development of next generation sequencing (NGS) technology, extensive research over the years has considerably enhanced the regularity that precise diagnoses are produced. Given the intricate nature of mitochondrial DNA biology and its double genomic investments, Sequencing has made significant progress in identifying the genetic basis of Mitochondrial Respiratory Chain Disorders (MRCDs). Research studies have been created employing a variety of various methods of therapy in an effort to shift the goal on therapy that is mainly curative to possibly having a positive impact on the natural course of the trouble. That's because there is gained a greater awareness of the underlying causes of this category of ailments.

Krankheitsreste: The residual signs of catatonia. A case series.

BACKGROUND: Catatonic signs were first described by 19th- and 20th-century researchers. An important concept known as "Krankheitsreste," or the residual signs of catatonia, was described by Kraepelin in 1896. Modern researchers describe patients who demonstrate "partial response to the treatment of catatonia with residual signs." Kraepelin observed that these signs occurred between catatonic episodes as part of the natural course of illness. Modern psychiatrists see residual signs after intervention or treatment. The determination of residual signs of catatonia is necessary to evaluate the most effective treatment approach to the patient. METHODS: In this case series, we describe 3 patients whose catatonia improved with treatment, but each exhibited continued residual signs of the syndrome. Appropriate consent was obtained from the patients and we identified the varying levels of catatonic signs using the Bush-Francis Catatonia Rating Scale (BFCRS) and the KANNER scale. RESULTS: Scores on both the BFCRS and KANNER scale decreased on followup in all 3 patients, with varying levels of success. The BFCRS score for the patient in Case 1 dropped 4 points upon follow-up, and their score on Part 2 of the KANNER scale decreased 12 points. The patient in Case 2 experienced a 5-point drop in their BFCRS score at follow-up and their score on Part 2 of the KANNER scale decreased 4 points. In Case 3, the patient's BFCRS score dropped 10 points at follow-up and their score on Part 2 of the KANNER scale decreased 20 points. CONCLUSIONS: These 3 patients demonstrate Krankheitsreste, or "partial response to the treatment of catatonia with residual signs." Each patient had a developmental disorder and 2 had autism spectrum disorder. They exhibited improved self-care and greater independence and required less restrictive living environments.

Incontinence as a catatonic sign.

BACKGROUND: Incontinence (urinary or fecal) is not included in DSM-5 criteria for catatonia or in most catatonia rating scales. However, there is a historical basis for the inclusion or consideration of incontinence as a catatonic sign. METHODS: We performed a review of the literature and found references to urinary disturbances and fecal incontinence in 19th- and 20th-century literature. We did a computerized literature review using the terms "catatonia," "catatonic," and "incontinence." RESULTS: We highlight 2 cases in which urinary or fecal incontinence was a presenting or predominant feature of catatonia. Clinical improvement was associated with improvement in incontinence. CONCLUSIONS: These preliminary findings suggest that urinary and fecal incontinence may be an uncommon presentation of catatonia. Furthermore, incontinence may improve at the same time catatonia improves with treatment. The neural circuitry that controls micturition and the sphincter involves neural pathways and multiple neurotransmitters. Catatonia can cause a reemergence of involuntary or reflex maturation, leading to urinary incontinence. This may lead to the need for additional custodial care for patients. Thus, the detection and monitoring of urinary and fecal incontinence may help us better understand the pathophysiology and impairment associated with catatonia.

Exit strategies from lockdowns due to COVID-19: a scoping review.

INTRODUCTION: In response to the ongoing COVID-19 pandemic, countries have adopted various degrees of restrictive measures on people to reduce COVID-19 transmission. These measures have had significant social and economic costs. In the absence of therapeutics, and low vaccination coverage, strategies for a safe exit plan from a lockdown are required to mitigate the transmission and simultaneously re-open societies. Most countries have outlined or have implemented lockdown exit plans. The objective of this scoping review is to (a) identify and map the different strategies for exit from lockdowns, (b) document the effects of these exit strategies, and (c) discuss features of successful exit strategies based on the evidence. METHODS: A five-step approach was used in this scoping review: (a) identifying the research question and inclusion/exclusion criteria; (b) searching the literature using keywords within PubMed and WHO databases; (c) study selection; (d) data extraction; (e) collating results and qualitative synthesis of findings. RESULTS: Of the 406 unique studies found, 107 were kept for full-text review. Studies suggest the post-peak period as optimal timing for an exit, supplemented by other triggers such as sufficient health system capacity, and increased testing rate. A controlled and step-wise exit plan which is flexible and guided by information from surveillance systems is optimal. Studies recommend continued use of non-pharmaceutical interventions such as physical distancing, use of facemasks, and hygiene measures, in different combinations when exiting from a lockdown, even after optimal vaccination coverage has been attained. CONCLUSION: Reviewed studies have suggested adopting a multi-pronged strategy consisting of different approaches depending on the context. Among the different exit strategies reviewed (phase-wise exit, hard exit, and constant cyclic patterns of lockdown), phase-wise exit appears to be the optimal exit strategy.

Evidence for an expanded hypertension care cascade in low- and middle-income countries: a scoping review.

BACKGROUND: With nearly 90% of annual hypertension-related deaths occurring in low- and middle-income countries (LMICs), there is an urgent need to measure the coverage of health services that effectively manage hypertension. However, there is little agreement on how to define effective coverage and the existing hypertension care cascade (hypertension prevalence, percent aware, percent treated, and percent controlled) does not account for the quality of care received by patients. This study reviews definitions of effective coverage and service quality for hypertension management services and proposes an expanded hypertension care cascade to improve measurement of health systems performance. METHODS: A systematic scoping review of literature published in six electronic databases between January 2000 and October 2020 identified studies that defined effective coverage of hypertension management services or integrated dimensions of service quality into population-based estimates of hypertension management in LMICs. Findings informed an expanded hypertension care cascade from which quality-adjusted service coverage can be calculated to approximate effective coverage. RESULTS: The review identified 18 relevant studies, including 6 that defined effective coverage for hypertension management services and 12 that reported a measure of service quality in a population-based study. Based on commonly reported barriers to hypertension management, new steps on the proposed expanded care cascade include (i) population screened, (ii) population linked to quality care, and (iii) population adhering to prescribed treatment. CONCLUSION: There is little consensus on the definition of effective coverage of hypertension management services, and most studies do not describe the quality of hypertension management services provided to populations. Incorporating aspects of service quality to the hypertension care cascade allows for the calculation of quality-adjusted coverage of relevant services, enabling an appropriate measurement of health systems performance through effective coverage.

Dynamics of Verticillium dahliae race 1 population under managed agricultural ecosystems.

BACKGROUND: Plant pathogens and their hosts undergo adaptive changes in managed agricultural ecosystems, by overcoming host resistance, but the underlying genetic adaptations are difficult to determine in natural settings. Verticillium dahliae is a fungal pathogen that causes Verticillium wilt on many economically important crops including lettuce. We assessed the dynamics of changes in the V. dahliae genome under selection in a long-term field experiment. RESULTS: In this study, a field was fumigated before the Verticillium dahliae race 1 strain (VdLs.16) was introduced. A derivative 145-strain population was collected over a 6-year period from this field in which a seggregating population of lettuce derived from Vr1/vr1 parents were evaluated. We de novo sequenced the parental genome of VdLs.16 strain and resequenced the derivative strains to analyze the genetic variations that accumulate over time in the field cropped with lettuce. Population genomics analyses identified 2769 single-nucleotide polymorphisms (SNPs) and 750 insertion/deletions (In-Dels) in the 145 isolates compared with the parental genome. Sequence divergence was identified in the coding sequence regions of 378 genes and in the putative promoter regions of 604 genes. Five-hundred and nine SNPs/In-Dels were identified as fixed. The SNPs and In-Dels were significantly enriched in the transposon-rich, gene-sparse regions, and in those genes with functional roles in signaling and transcriptional regulation. CONCLUSIONS: Under the managed ecosystem continuously cropped to lettuce, the local adaptation of V. dahliae evolves at a whole genome scale to accumulate SNPs/In-Dels nonrandomly in hypervariable regions that encode components of signal transduction and transcriptional regulation.

Building the health-economic case for scaling up the WHO-HEARTS hypertension control package in low- and middle-income countries.

Generally, hypertension control programs are cost-effective, including in low- and middle-income countries, but country governments and civil society are not likely to support hypertension control programs unless value is demonstrated in terms of public health benefits, budget impact, and value-for-investment for the individual country context. The World Health Organization (WHO) and the Pan American Health Organization (PAHO) established a standard, simplified Global HEARTS approach to hypertension control, including preferred antihypertensive medicines and blood pressure measurement devices. The objective of this study is to report on health economic studies of HEARTS hypertension control package cost (especially medication costs), cost-effectiveness, and budget impact and describe mathematical models designed to translate hypertension control program data into the optimal approach to hypertension care service delivery and financing, especially in low- and middle-income countries. Early results suggest that HEARTS hypertension control interventions are either cost-saving or cost-effective, that the HEARTS package is affordable at between US$ 18-44 per person treated per year, and that antihypertensive medicines could be priced low enough to reach a global standard of an average

En general, los programas de control de la hipertensión son costo-eficaces, incluso en los países de ingresos bajos y medios. Aun así, es poco probable que los gobiernos nacionales y la sociedad civil apoyen los programas de control de la hipertensión a menos que se demuestre su valor en términos de beneficios para la salud pública, impacto presupuestario y valor de la inversión para el contexto individual del país. La Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS) implementaron la iniciativa HEARTS, un enfoque mundial estandarizado y simplificado para el control de la hipertensión, que incluye los medicamentos antihipertensivos y los dispositivos de medición de la presión arterial de preferencia. El objetivo de este estudio es informar sobre los estudios en el ámbito de la economía de la salud relativos al costo de las medidas de control de la hipertensión previstas en HEARTS (especialmente, de los medicamentos), la costo-efectividad y el impacto presupuestario, así como describir los modelos matemáticos diseñados para traducir los datos de este programa en un enfoque óptimo para la prestación y el financiamiento de los servicios de atención de la hipertensión, especialmente en países de ingresos medianos y bajos. Los primeros resultados indican que las intervenciones de HEARTS para el control de la hipertensión son de bajo costo o costo-eficaces, que el conjunto de medidas HEARTS es asequible, a un precio que oscila entre US$ 18 y US$ 44 al año por paciente tratado, y que los medicamentos antihipertensivos podrían tener un precio lo suficientemente bajo como para alcanzar un estándar medio mundial de

Geralmente, os programas de controle de hipertensão são custo-efetivos, inclusive em países de baixa e média renda, mas os governos dos países e a sociedade civil provavelmente não apoiarão tais programas a menos que demonstrem valor em termos de benefícios à saúde pública, impacto orçamentário e retorno sobre o investimento no contexto individual do país. A Organização Mundial da Saúde (OMS) e a Organização Pan-Americana da Saúde (OPAS) criaram a Global HEARTS, uma abordagem padrão e simplificada ao controle da hipertensão arterial, que inclui medicamentos anti-hipertensivos preferidos e dispositivos para aferição da pressão arterial preferidos. O objetivo deste estudo é relatar os estudos de economia em saúde que analisaram o custo (especialmente custos de medicamentos), custo-benefício e impacto orçamentário do pacote HEARTS para controle da hipertensão e descrever modelos matemáticos elaborados para traduzir os dados do programa de controle de hipertensão em uma abordagem ideal para a prestação e financiamento de serviços de atenção às pessoas com hipertensão, especialmente em países de baixa e média renda. Os primeiros resultados sugerem que as intervenções HEARTS para controle da hipertensão são de baixo custo ou custo-efetivas, que o pacote HEARTS é acessível (custando de US$ 18 a 44 por pessoa tratada por ano) e que o preço dos medicamentos anti-hipertensivos poderia ser baixo o suficiente para atingir uma média global de

PACAP and Other Neuropeptide Targets Link Chronic Migraine and Opioid-induced Hyperalgesia in Mouse Models.

Chronic use of opioids can produce opioid-induced hyperalgesia (OIH), and when used to treat migraine, these drugs can result in increased pain and headache chronicity. We hypothesized that overlapping mechanisms between OIH and chronic migraine occur through neuropeptide dysregulation. Using label-free, non-biased liquid chromatography-mass spectrometry to identify and measure changes in more than 1500 neuropeptides under these two conditions, we observed only 16 neuropeptides that were altered between the two conditions. The known pro-migraine molecule, calcitonin-gene related peptide, was among seven peptides associated with chronic migraine, with several pain-processing neuropeptides among the nine other peptides affected in OIH. Further, composite peptide complements Pituitary adenylate cyclase-activating polypeptide (PACAP), Vasoactive intestinal peptide (VIP) and Secretogranin (SCG) showed significant changes in both chronic migraine and OIH. In a follow-up pharmacological study, we confirmed the role of PACAP in models of these two disorders, validating the effectiveness of our peptidomic approach, and identifying PACAP as a mechanistic link between chronic migraine and OIH. Data are available via ProteomeXchange with identifier PXD013362.

Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study.

OBJECTIVE: The objective of this study was to assess the effectiveness of a low-dose intravenous S-ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS). METHODS: In this retrospective study, patients with CRPS who received intravenous S-ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S-ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful. RESULTS: Forty-eight patients were included. Mean disease duration was 5 years (interquartile range [IQR] = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03). CONCLUSION: In a group of patients with CRPS with refractory pain, low-dose intravenous S-ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow-up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S-ketamine infusions and to ascertain possible predictors of response to the treatment.

Quantitative Characterization of the Neuropeptide Level Changes in Dorsal Horn and Dorsal Root Ganglia Regions of the Murine Itch Models.

Chronic itch can be extremely devastating and, in many cases, difficult to treat. One challenge in treating itch disorders is the limited understanding of the multitude of chemical players involved in the communication of itch sensation from the peripheral to the central nervous system. Neuropeptides are intercellular signaling molecules that are known to be involved in the transmission of itch signals from primary afferent neurons, which detect itch in the skin, to higher-order circuits in the spinal cord and brain. To investigate the role of neuropeptides in transmitting itch signals, we generated two mouse models of chronic itch-Acetone-Ether-Water (AEW, dry skin) and calcipotriol (MC903, atopic dermatitis). For peptide identification and quantitation, we analyzed the peptide content of dorsal root ganglia (DRG) and dorsal horn (DH) tissues from chronically itchy mice using liquid chromatography coupled to tandem mass spectrometry. De novo-assisted database searching facilitated the identification and quantitation of 335 peptides for DH MC903, 318 for DH AEW, 266 for DRG MC903, and 271 for DRG AEW. Of these quantifiable peptides, we detected 30 that were differentially regulated in the tested models, after accounting for multiple testing correction (q ≤ 0.1). These include several peptide candidates derived from neuropeptide precursors, such as proSAAS, protachykinin-1, proenkephalin, and calcitonin gene-related peptide, some of them previously linked to itch. The peptides identified in this study may help elucidate our understanding about these debilitating disorders. Data are available via ProteomeXchange with identifier PXD015949.

Genome Sequence of Verticillium dahliae Race 1 Isolate VdLs.16 From Lettuce.

Verticillium dahliae is a widespread fungal pathogen that causes Verticillium wilt on many economically important crops and ornamentals worldwide. Populations of V. dahliae have been divided into two distinct races based upon differential host responses in tomato and lettuce. Recently, the contemporary race 2 isolates were further divided into an additional race in tomato. Herein, we provide a high-quality reference genome for the race 1 strain VdLs.16 isolated from lettuce in California, U.S.A. This resource will contribute to ongoing research that aims to elucidate the genetic basis of V. dahliae pathogenicity and population genomic diversity.

Health equity and COVID-19: global perspectives.

The COVID-19 is disproportionally affecting the poor, minorities and a broad range of vulnerable populations, due to its inequitable spread in areas of dense population and limited mitigation capacity due to high prevalence of chronic conditions or poor access to high quality public health and medical care. Moreover, the collateral effects of the pandemic due to the global economic downturn, and social isolation and movement restriction measures, are unequally affecting those in the lowest power strata of societies. To address the challenges to health equity and describe some of the approaches taken by governments and local organizations, we have compiled 13 country case studies from various regions around the world: China, Brazil, Thailand, Sub Saharan Africa, Nicaragua, Armenia, India, Guatemala, United States of America (USA), Israel, Australia, Colombia, and Belgium. This compilation is by no-means representative or all inclusive, and we encourage researchers to continue advancing global knowledge on COVID-19 health equity related issues, through rigorous research and generation of a strong evidence base of new empirical studies in this field.