bluuebunny/crossref_metadata_2025 huggingface dataset:
The Patient Experienced Symptom State (PESS): a patient-reported global outcome measure that may better reflect disease remission status
Authors: Duarte Cátia , Santos Eduardo , da Silva José A P , Kristianslund Eirik Klami , Kvien Tore K , Dougados Maxime , de Wit Maarten , Gossec Laure , Heiberg Turid
Published: March 2020

Objectives

In RA, Patient Acceptable Symptom State assesses disease from the patient’s perspective, which does not correspond either to disease remission or to full control of disease impact. This study aims to explore the properties of a novel multilevel Patient Experienced Symptom State (PESS).

Methods

This was a cross-sectional analysis of two datasets of patients with RA. PESS was assessed through the question: ‘Consider how your RA has affected you. If you remain in the coming months as you have been the last week, how would you rate your condition?’, with five levels (from ‘very bad’ to ‘very good’). Construct validity of PESS was assessed against validated disease activity [DAS28, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)] and impact measures [RA Impact of Disease (RAID) and modified HAQ]. Multiple pairwise comparisons between groups and receiver-operating characteristic curves with Youden Index were performed.

Results

A total of 1407 patients [74% female, mean (S.d.) age 53.5 (13.4) years, mean disease duration 14.3 (12.0) years and mean DAS28 3.0 (1.5)] were analysed. Overall, 16.3% considered themselves as being in ‘very good’, 21.6% in ‘good’ and 31.9% in ‘acceptable’ state. Disease activity and impact measures differed significantly across the five levels (P < 0.01). Cut-off values corresponding to ‘good’ and ‘very good’ PESS states were in the range of low disease activity/remission (for ‘good’ and ‘very good’: DAS28-ESR-4v ≤2.6/≤2.3; CDAI ≤5.0/≤3.1; SDAI ≤5.1/≤3.8, respectively) and very low disease impact (RAID domains all ≤1).

Conclusion

PESS ‘very good’ status corresponds to currently recommended targets for RA management and reflects full control of disease impact. PESS appears to be an easy-to-use and relevant measure in the evaluation of patients with RA.
VARIATION OF INDOOR RADON CONCENTRATION WITHIN A RESIDENTIAL COMPLEX
Authors: Sferle Teofana , Dobrei Gabriel , Dicu Tiberius , Burghele Bety-Denissa , Brişan Nicoleta , Cucoş (Dinu) Alexandra , Catalina Tiberiu , Istrate Andrei , Lupulescu Alexandru , Moldovan Mircea , Niţă Dan , Papp Botond , Pap Istvan , Szacsvai Kinga , Florică Ştefan , Ţenter Ancuţa , Sainz Carlos
Published: March 2020

A recent challenge in research dedicated to residential exposure to radon comes from the growing number of houses retrofitted to reduce energy consumption. Efficiently insulated buildings and modern architectural solutions can lead to the accumulation of high levels of indoor pollutants. A systematic analysis was conducted in a residential complex (consisting of six houses) in order to assess the annual radon concentration and to evaluate the intensity of the relationships with various factors, such as the indoor-outdoor temperature differences, wind speed and wind direction. Three types of occupational behaviour, influencing the ventilation rate of the dwellings and, implicitly, the indoor radon activity concentration were observed. By calculating the partial correlation coefficient between the radon concentration and the wind direction, with the wind speed as the control variable, for all six houses the correlation coefficient presents negative values.
EMERGENCY EVACUATION SIMULATION FOR A RADIATION DISASTER: A CASE STUDY OF A RESIDENTIAL SCHOOL NEAR NUCLEAR POWER PLANTS IN KOREA
Authors: Kim Juyoul , Rukundo Faith , Musauddin Ashraf , Tseren Batbuyan , Uddin Gazi Muhammad Borhan , Kiplabat Tarus
Published: March 2020

Ensuring evacuation of people from a building in a fast and secure manner is of great significance in the event of emergency situations. This study aimed at evaluating the level of evacuation preparedness and movement of residents at the KEPCO International Nuclear Graduate School (KINGS) in the event of a nuclear emergency. Evacuation times from KINGS after a nuclear disaster at Shin Kori nuclear power plant (NPP) were estimated using Pathfinder. Four scenarios of night and day time by assuming the normal and worst scenarios were simulated. With regard to worst scenarios, the times estimated for residents to gather and leave the assembly point for the night time scenario were estimated to 22~23 min, whereas 38~39 min were calculated for the crowd to leave the assembly point. The results of this study can be used by emergency planners when planning for evacuation from a residential building nearby NPP.
Neural reward related-reactions to monetar gains for self and charity are associated with donating behavior in adolescence
Authors: Spaans Jochem P , Peters Sabine , Crone Eveline A
Published: March 2020

The aim of the current study was to examine neural signatures of gaining money for self and charity in adolescence. Participants (N = 160, aged 11–21) underwent functional magnetic resonance imaging-scanning while performing a zero-sum vicarious reward task in which they could either earn money for themselves at the expense of charity, for a self-chosen charity at the expense of themselves, or for both parties. Afterwards, they could donate money to charity, which we used as a behavioral index of giving. Gaining for self and for both parties resulted in activity in the ventral striatum (specifically in the NAcc), but not gaining for charity. Interestingly, striatal activity when gaining for charity was positively related to individual differences in donation behavior and perspective taking. Dorsal anterior cingulate cortex, insula and precentral gyrus were active when gaining only for self, and temporal-parietal junction when gaining only for charity, relative to gaining for both parties (i.e. under equity deviation). Taken together, these findings show that striatal activity during vicarious gaining for charity depends on levels of perspective taking and predicts future acts of giving to charity. These findings provide insight in the individual differences in the subjective value of prosocial outcomes.
Stuck between a rock and a hard place: firewall and forum clauses—what protection is available when foreign courts seek to intervene‡
Authors: Reynolds Rachael , Barker Roye Deborah
Published: March 2020

Trustees can all too easily find themselves caught up in litigation in another jurisdiction given the increasingly international nature of offshore trusts. The firewall regime and forum for administration clauses within deeds, when robustly applied and upheld by the Courts, are the key to ensuring questions concerning a trust are dealt with by the courts of its home jurisdiction. Being joined to foreign proceedings can result in trustees being caught up in a clash of laws and processes and potentially facing conflicting orders and obligations, but in a recent Cayman Islands decision, where a trustee had found itself in such an invidious position, the Grand Court of the Cayman Islands confirmed that all questions concerning a Cayman trust are to be determined in accordance with Cayman law and further held, importantly, that the forum for administration clause in question, together with the firewall, bestowed upon the Cayman Court exclusive jurisdiction to determine questions concerning the administration of a Cayman trust. The Cayman Court was also prepared, by way of a novel and practical approach in comity, to facilitate a mechanism whereby questions concerning a Cayman trust arising in the foreign proceedings be dealt with by the Cayman Court: by offering to act as an auxiliary court.
Exogenous Application of Harpin Protein Hpa1 ontoPinellia ternataInduces Systemic Resistance Against Tobacco Mosaic Virus
Authors: Wang Defu , Wang Baoxia , Wang Jiangran , Wang Shuting , Wang Weiyu , Niu Yanbing
Published: March 2020

The harpin protein Hpa1 has various beneficial effects in plants, such as promoting plant growth and inducing pathogen resistance. Our previous study found that Hpa1 could significantly alleviate the mosaic symptoms of tobacco mosaic virus (TMV) in Pinellia ternata, indicating that Hpa1 can effectively stimulate resistance. Here, the potential mechanism of disease resistance and field applicability of Hpa1 against TMV in P. ternata were further investigated. The results showed that 15 µg ml−1Hpa1 had stronger antiviral activity than the control, and its protective effect was better than its curative effect. Furthermore, Hpa1 could significantly induce an increase in defense-related enzyme activity, including polyphenol oxidase, peroxidase, catalase, and superoxide dismutase, as well as increase the expression of disease resistance-related genes (PR1, PR3, PR5, and PDF1.2). Concurrently, Hpa1 significantly increased the content of some disease resistance-related substances, including hydrogen peroxide, phenolics, and callose, whereas the content of malondialdehyde was reduced. In addition, field application analysis demonstrated that Hpa1 could effectively elicit a defense response against TMV in P. ternata. Our findings propose a mechanism by which Hpa1 can prevent TMV infection in Pinellia by inducing systemic resistance, thereby providing an environmentally friendly approach for the use of Hpa1 in large-scale applications to improve TMV resistance in Pinellia.
Case Study: Naltrexone for the Treatment of Nitrous Oxide Use
Authors: Ickowicz Sarah , Brar Rupinder , Nolan Seonaid
Published: March 2020

Background:

Using a clinical case example, we describe and discuss the use of oral naltrexone as a novel treatment strategy for nitrous oxide use. Nitrous oxide is an inhalant drug that is readily available and legally obtained. Though frequency of reported cases of substance use disorder for nitrous oxide is low, previous case reports have described severe neurological and psychiatric harms associated with chronic use. Despite this, evidence for pharmacotherapy is currently lacking. Clinical studies have shown variable efficacy for naltrexone across a number of substances including alcohol, nicotine, and stimulants.

Case:

We present here a case of a 41-year-old man with a substance use disorder for nitrous oxide who was reportedly using of up to four hundred 8 g canisters of nitrous oxide per day. Oral naltrexone was initiated at 50 mg daily in an attempt to decrease cravings. The dose was subsequently titrated to 100 mg daily, resulting in a decrease in nitrous oxide use to less than sixty 8 g canisters per week over a 1-month timeframe.

Discussion:

Previous literature surrounding naltrexone provides both a plausible mechanism of action for craving reduction as well as a precedent for its use across a number of substances. To our knowledge, use of naltrexone for nitrous oxide use has not been previously described. While clinical studies are currently lacking, this case highlights naltrexone as a possible treatment strategy for nitrous oxide use, with potential to reduce significant harms associated with chronic use.
An Acute Care Contingency Management Program for the Treatment of Stimulant Use Disorder: A Case Report
Authors: Bach Paxton , Garrod Emma , Robinson Kaye , Fairbairn Nadia
Published: March 2020

Background:

Illicit stimulants such as crystal methamphetamine and cocaine are a rising cause of morbidity and mortality in North America. Unfortunately, there are few evidence-based approaches for the management of stimulant use disorder. Contingency management programs are currently the best evidenced treatment strategy, designed to reward behavior change and offer competing reinforcers toward the goal of reducing substance use, but these programs are often difficult to access. Given that it is well understood that hospitalization presents a valuable opportunity for the initiation of treatment for a variety of substance use disorders, the adaptation of contingency management programs to an acute medicine inpatient setting is a potentially viable option to improve care, and to increase access to effective treatment for stimulant use disorders.

Case Summary:

We present a case outlining the clinical care of a complex medical patient admitted with osteomyelitis, whose course in hospital changed significantly upon enrollment in a pilot contingency management program in an urban hospital in Canada.

Discussion:

This case illustrates how effective treatment programs can be adapted as needed for use in novel settings, especially where current options are inaccessible, inadequate, or ineffective.
Treatment of cutaneous lupus erythematosus: current approaches and future strategies
Authors: Shi Hong , Gudjonsson Johann E. , Kahlenberg J. Michelle
Published: March 2020

Purpose of review

Cutaneous lupus erythematosus (CLE) is a highly heterogeneous autoimmune disease. No specific Federal Drug Administration-approved therapies for CLE-alone are available, and resistance to conventional treatments is common. This review will summarize current treatment approaches and pending treatment strategies.

Recent findings

Research into the pathogenesis of CLE is accelerating. A skewed type I interferon production and response contribute to CLE lesions. The pathophysiology of lesions may be similar among the lesional subtypes, and patients with a more TLR9-driven disease mechanism may have more benefit from hydroxychloroquine. Case reports continue to support the use of dapsone for CLE, especially bullous lupus erythematosus. Rituximab and Belimumab have efficacy in patients with systemic lupus erythematosus and severe active CLE. The significant role for type I interferons in CLE and encouraging clinical data suggest anifrolumab as a very promising agent for CLE. Dapirolizumab, BIIB059, Ustekinumab and Janus kinase inhibitors also have supportive early data as promising new strategies for CLE treatment.

Continued research to understand the mechanisms driving CLE will facilitate the development and approval of new targets. The pipeline for new treatments is rich.
Screening for Opioid and Stimulant Exposure In Utero Through Targeted and Untargeted Metabolomics Analysis of Umbilical Cords
Authors: Mamillapalli Srivalli Swathi , Smith-Joyner Annalisa , Forbes Lauren , McIntyre Kadesha , Poppenfuse Samantha , Rushing Blake , Strom Cody , Danell Allison S. , May Linda , Kuehn Devon , Kew Kimberly , Ravisankar Srikanth
Published: March 2020

Background:

Neonatal abstinence syndrome is an array of signs and symptoms experienced by a newborn due to abrupt discontinuation of intrauterine exposure to certain drugs, primarily opioids. In the United States, the incidence of neonatal abstinence syndrome has tripled over the past decade. The current standard of care for drug testing includes the analysis of infant urine and meconium. Sample collection is associated with several limitations, including diaper media interferences, limited sample amount, sample heterogeneity, and the need for professional staff for collection. Umbilical cord tissue has emerged as a convenient sample matrix for testing owing to its universal availability. The purpose of this study was to examine umbilical cords using an untargeted metabolomics approach to determine the detected drugs and validate an analytical method to confirm and quantify the identified drugs.

Methods:

A metabolomics analysis was performed with 21 umbilical cords to screen for drugs and drug metabolites by liquid chromatography–mass spectrometry. Drugs were identified using the National Institute of Standards and Technology database, and an analytical method was developed and validated using secondary liquid chromatography–mass spectrometry instrument for positive confirmation and quantitative analysis.

Results:

Twenty-one random umbilical cords from women were tested: 4 were positive for cocaine and the primary and secondary metabolites; one was positive for methadone, the primary metabolite; 3 were positive for cotinine, the metabolite of nicotine; and 5 were positive for acetyl norfentanyl.

Conclusions:

Our research is a prospective method development study using untargeted and targeted approaches to characterize steady-state drug metabolite levels in the umbilical cord matrix at the time of delivery. By characterizing drug type and concentration, this methodology can be used to develop a reliable complementary testing method for meconium toxicology screens.
Associations of social, physical, and financial factors with diet quality among older, community-dwelling women
Authors: Shikany James M. , Manson JoAnn E. , Shadyab Aladdin H. , Garcia Lorena , Lewis Cora E. , Neuhouser Marian L. , Tinker Lesley F. , Beasley Jeannette M. , Beresford Shirley A.A. , Zaslavsky Oleg , Vitolins Mara Z. , Sealy-Jefferson Shawnita , Bae Sejong
Published: March 2020

Objective:

This analysis examined whether specific social, physical, and financial factors were associated with diet quality among older, community-dwelling women.

Methods:

This cross-sectional analysis was conducted in a subset of 6,094 community-dwelling Women's Health Initiative participants who completed a food frequency questionnaire, administered from 2012 to 2013, and a self-administered supplemental questionnaire, administered approximately 1 year later. The supplemental questionnaire included five questions assessing social, physical, and financial factors related to eating. Diet quality was assessed with the Healthy Eating Index-2010 (HEI-2010; range of 0-100; higher score indicates a higher quality diet). The total HEI-2010 score was calculated by summing individual scores representing the intake of nine adequacy components (beneficial food groups) and three moderation components (food groups to limit). Associations of responses to the five questions on the supplemental questionnaire with HEI-2010 scores were examined with multiple linear regression, adjusting for relevant covariates.

Results:

Mean ± standard deviation age of participants was 78.8 ± 6.7 years. Reporting eating fewer than two meals per day, having dental or other mouth problems causing problems with eating, and not always being able to shop, cook, or feed oneself were associated with statistically significantly lower HEI-2010 scores, compared with those not reporting these issues, after multivariable adjustment: 5.37, 2.98, and 2.39 lower scores, respectively (all P values <0.0001). Reporting eating alone most of the time and not always having enough money to buy food were not associated with HEI-2010 scores.

Conclusions:

Among older, community-dwelling women, eating fewer than two meals per day, dental and other mouth problems, and diminished ability to shop for food, prepare meals, and feed oneself were associated with lower diet quality. These are potential targets for interventions to improve diet quality in older women.

Video Summary:

http://links.lww.com/MENO/A561.
Androgen Suppresses Hyperosmolarity-Induced Inflammatory Mediators in Human Corneal Epithelial Cells
Authors: Zibandeh Noushin , Yıldız Erdost , Özer Berna , Taş Ayşe Yıldız , Sahin Afsun
Published: March 2020

Purpose:

To investigative the effects of sex steroids on hyperosmolar stress-induced proinflammatory cytokine expression of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, and IL-6, and on the mitogen-activated protein kinase pathway in immortalized human corneal epithelial cells (hCECs).

Methods:

Immortalized hCECs were cultured with keratinocyte-free medium until reaching 80% confluency with either 10−8 M dihidrotestosteron (DHT) or 10−8 M 17-β-estradiol, and then, the medium was changed to hyperosmolar for various time points. After hyperosmolar treatment, a real-time polymerase chain reaction was performed to show the TNF-α, IL-8, and IL-6 gene expression levels in hCECs. In addition, the treated cells were lysed, and Western blot analysis was applied for phosphorylated and nonphosphorylated forms of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 kinase, and c-Jun N-terminal kinase 1/2 (JNK1/2). hCECs viability was measured with Annexin V/propidium iodide.

Results:

Pretreatment with 10−8 M DHT or 17-β-estradiol inhibited the high osmolarity-induced expression of TNF-α, IL-8, and IL-6. The upregulation of p-ERK, p-JNK, and p-p38 with high osmolarity was inhibited partially by DHT, but 17-β-estradiol pretreatment only affected p-p38 for a short time interval. In addition, DHT increased cell viability of hCECs under hyperosmolar conditions.

Conclusions:

Our results demonstrated that DHT and 17-β-estradiol decreased the proinflammatory cytokine gene expression levels which were stimulated by high osmolarity in immortalized hCECs. The mitogen-activated protein kinase signaling pathway is partially involved in the regulatory effects of DHT on hCECs. These findings may contribute to the etiologic role and therapeutic implications of sex steroids in certain ocular surface diseases.
Comparison of visual acuity and complications between primary IOL implantation and aphakia in patients with congenital cataract younger than 2 years: a meta-analysis
Authors: Chen Jiabao , Chen Yile , Zhong Yueyang , Li Jinying
Published: March 2020

To analyze the visual acuity and complications between primary intraocular lens (IOL) implantation and contact lens wearing, this literature search was performed with data on patients with congenital cataract younger than 2 years published in March 2019. Seven identified studies enrolling 675 eyes were selected for analysis. Patients with primary IOL implantation owned better visual acuity than those with aphakia who wore the contact lens (weighted mean difference = 0.161; 95% CI, 0.108-0.214). For visual axis opacification (VAO), primary IOL implantation increases the incidence of VAO compared with contact lens wearing (relative risk = 0.23; 95% CI, 0.13-0.42). No statistically significant difference was found between the 2 groups about the prevalence of glaucoma and strabismus. Primary IOL implantation achieved better visual outcomes after cataract extraction in patients younger than 2 years. In addition, no higher risk for complications among primary IOL implantation compared with contact lens wearing was noted. Therefore, implanting a primary IOL during congenital cataract surgery is a better therapy for children younger than 2 years than wearing a contact lens.
Nonsurgical mouse model of endometriosis-associated pain that responds to clinically active drugs
Authors: Fattori Victor , Franklin Noah S. , Gonzalez-Cano Rafael , Peterse Daniëlle , Ghalali Aram , Madrian Erika , Verri Waldiceu A. , Andrews Nick , Woolf Clifford J. , Rogers Michael S.
Published: March 2020

Endometriosis is an estrogen-dependent inflammatory disease that affects approximately 10% of women. Debilitating pelvic or abdominal pain is one of its major clinical features. Current animal models of endometriosis-associated pain require surgery either to implant tissue or to remove the ovaries. Moreover, existing models do not induce spontaneous pain, which is the primary symptom of patients with chronic pain, including endometriosis. A lack of models that accurately recapitulate the disease phenotype must contribute to the high failure rate of clinical trials for analgesic drugs directed at chronic pain, including those for endometriosis. We set out to establish a murine model of endometriosis-associated pain. Endometriosis was induced nonsurgically by injecting a dissociated uterine horn into a recipient mouse. The induced lesions exhibited histological features that resemble human lesions along with an increase in proinflammatory cytokines and recruitment of immune cells. We also observed the presence of calcitonin gene–related peptide–, TRPA1-, and TRPV1-expressing nerve fibers in the lesions. This model induced mechanical allodynia, spontaneous abdominal pain, and changes in thermal selection behavior that indicate discomfort. These behavioral changes were reduced by drugs used clinically for endometriosis, specifically letrozole (aromatase inhibitor) and danazol (androgen). Endometriosis also induced neuronal changes as evidenced by activation of the NF-κB signaling pathway in TRPA1- and TRPV1-expressing dorsal root ganglion neurons. In conclusion, we have established a model of endometriosis-associated pain that responds to clinically active drugs and can, therefore, be used to identify novel therapies.
Vagus nerve stimulation inhibits cortical spreading depression exclusively through central mechanisms
Authors: Morais Andreia , Liu Tzu-Ting , Qin Tao , Sadhegian Homa , Ay Ilknur , Yagmur Damla , Mendes da Silva Rosangela , Chung David , Simon Bruce , Guedes Rubem , Chen Shih-Pin , Wang Shuu-Jiun , Yen Jiin-Cherng , Ayata Cenk
Published: March 2020

Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. Vagus nerve stimulation acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or noninvasively (nVNS) in male Sprague-Dawley rats. Cortical spreading depression susceptibility was evaluated 40 minutes after the stimulation. iVNS elevated the electrical CSD threshold more than 2-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs sham). By contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius, the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in nucleus tractus solitarius and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.
PAC1 receptor blockade reduces central nociceptive activity: new approach for primary headache?
Authors: Hoffmann Jan , Miller Silke , Martins-Oliveira Margarida , Akerman Simon , Supronsinchai Weera , Sun Hong , Shi Licheng , Wang Judy , Zhu Dawn , Lehto Sonya , Liu Hantao , Yin Ruoyuan , Moyer Bryan D. , Xu Cen , Goadsby Peter J.
Published: March 2020

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.
Treatment options and results of adjuvant treatment in nonmuscle-invasive bladder cancer (NMIBC) during the Bacillus Calmette–Guérin shortage
Authors: Fankhauser Christian Daniel , Teoh Jeremy Yuen-Chun , Mostafid Hugh
Published: March 2020

Purpose of review

Given the worldwide shortage of Bacillus Calmette–Guérin (BCG), we review the efficacy of alternative BCG application schedules, doses or strains and intravesical chemotherapy in patients with nonmuscle-invasive bladder cancer (NMIBC).

Recent findings

Modifying BCG schedules by reducing the dose is preferable to reducing the frequency of BCG that increases recurrence rates and should be avoided if possible. Changing the BCG substrain represents a reasonable option, as current evidence does not suggest different oncological outcomes with specific BCG substrains. Mitomycin C (MMC) alone is inferior to BCG with maintenance, but promising results have been demonstrated when used with chemohyperthermia and electromotive drug administration. Several other intravesical chemotherapies including Gemcitabine and Epirubicin should be used when both BCG and MMC are in short supply.

In case of BCG shortage, much will depend on the severity and length of the BCG shortage, but our review supports several solutions: First, we recommend contacting the local pharmacist or BCG supplier to consider alternative BCG strains or sterile splitting of BCG doses. In the complete absence of BCG, consideration should be given to MMC with chemohyperthermia or electromotive drug administration where available or other intravesical chemotherapy. High-risk patients should be considered for cystectomy.
Current status and future directions of the use of novel immunotherapeutic agents in bladder cancer
Authors: Lenfant Louis , Aminsharifi Alireza , Seisen Thomas , Rouprêt Morgan
Published: March 2020

Purpose of review

To report the available information on the current status and future direction of the use of checkpoint inhibitors as novel immunotherapeutic agents in bladder cancer.

Recent findings

In the past 3 years, five immunotherapies targeting programmed cell death 1 (Pembrolizumab and Durvalumab) or programmed cell death-ligand 1 (PD-L1) (Atezolizumab, nivolumab and Avelumab) pathways have been approved in second-line setting for patients who progressed during or after cisplatin-based chemotherapy. According to the most recent update, these patients should be PD-L1-positive to be eligible for immunotherapy. The use of novel checkpoint inhibitors was also very promising in other settings: Metastatic urothelial carcinoma without prior systemic treatment (IMvigor-130), as neoadjuvant treatment before radical cystectomy in patients with muscle invasive disease (PURE-01), and in Bacillus Calmette-Guérin (BCG) refractory nonmuscle invasive bladder cancer (KEYNOTE 057).

Ongoing trials on the role of checkpoint inhibitors in bladder cancer may change our approach to different stages of bladder cancer. For metastatic urothelial carcinoma, the role of combined immune and chemotherapy may improve survival. For localized bladder cancer, immunotherapy as neoadjuvant therapy may be associated with less toxicity and better tolerability. Finally, in the setting of a BCG-refractory or BCG-naïve nonmuscle invasive disease checkpoint inhibitors may reduce/delay the risk of progression and subsequent cystectomy.
Developments in the follow-up of nonmuscle invasive bladder cancer: what did we learn in the last 24 months: a critical review
Authors: Witjes J. Alfred
Published: March 2020

Purpose of review

Patients with nonmuscle invasive bladder cancer (NMIBC) have a high risk of recurrent tumors, even in spite of contemporary guideline recommended therapy. Follow-up recommendations are also clear (cystoscopy with cytology and upper urinary tract imaging in high-risk patients), but frequency and duration of follow-up are well defined. However, recent developments in follow-up tools might be of interest for clinical practice.

Recent findings

Enhanced endoscopy improves detection and treatment of recurrences, and it can help in tailoring follow-up. However, it remains an invasive procedure. Most recently cystoscopy augmented with artificial intelligence has shown some promising results. Active surveillance, frequently done in prostate cancer patients, is also gaining attention in NMIBC follow-up. Finally markers are being studied and launched. Although not recommended by guidelines, and not used in clinical practice, recent studies have shown marker combinations with very high negative predictive values for (high risk) recurrences in follow-up of NMIBC patients.

New tools for follow-up such as enhanced cystoscopy and urinary markers might help to individualize follow-up, which will result in decreasing patient discomfort, workload and costs while quality of care is maintained.
The Fecal Microbiome in Infants With Biliary Atresia Associates With Bile Flow After Kasai Portoenterostomy
Authors: Tessier Mary Elizabeth M. , Cavallo Laurel , Yeh Jennifer , Harpavat Sanjiv , Hoffman Kristi L. , Petrosino Joseph F. , Shneider Benjamin L.
Published: March 2020

Background:

Biliary atresia's (BA) response to surgical Kasai portoenterostomy (KP) is uneven and dependent upon bile flow; 50% of infants require a liver transplant by 24 months. We hypothesized that the microbiome may identify and associate with outcomes in BA.

Methods:

Stool samples were collected from infants with cholestasis (n = 15), 8 of which with BA were followed longitudinally.16S sequencing was performed on all samples (n = 45). Whole Genome Sequencing (WGS) was performed on BA pre‐KP samples (n = 8). Infants with BA, other forms of cholestasis, BA infants with very good bile flow (VGBF) and not (nVGBF) (VGBF dichotomized by TSBA <40 μmol/L by 6 months) were compared.

Results:

Of the 8 infants with BA, 4 infants had VGBF. Microbial richness was inversely proportional to degree of cholestasis (P = 0.046). IncreasedBifidobacteriumabundance associated with VGBF (P = 0.03) and decreased cholestasis (P < 0.01) at 1 month post‐KP. Pre‐KP, community structure differed in infants with BA versus other cholestasis. Interestingly, infants who subsequently achieved VGBF had increased diversity (P = 0.03) and different community structure at the pre‐KP time point. WGS corroboratedBifidobacterium'spre‐KP importance.

Conclusions:

The microbiome differs between infants with BA and other cholestasis. It additionally differs between infants with BA who have good and poor bile flow, and thus outcomes, post‐KP. These differences are seen even before KP. These data suggest that bile influences the development of the infant microbiome and that there may be possible influences of the pre‐ and post‐KP microbiome on bile flow after KP. Further larger studies are needed to confirm these findings.
Incidence Trends, Comorbidities, and Outcomes of Pyogenic Liver Abscess Among Children
Authors: Thavamani Aravind , Umapathi Krishna Kishore , Khatana Jasmine , Roy Aparna , Augustin Toms , Radhakrishnan Kadakkal
Published: March 2020

Objectives:

Population‐based analysis of incidence, comorbid conditions, microbiological characteristics, and outcomes of pyogenic liver abscess (PLA) in children.

Methodology:

Retrospective analysis of National Inpatient Sample (NIS) and Kids Inpatient database (KID) database from 2003 to 2014 and included patients between 1 and 20 years of age. Using ICD‐9 codes, we identified all hospitalizations with PLA and compared them with 1 : 10 age‐ and gender‐matched controls. Amebic liver abscess and Candida infections were excluded.

Results:

Total number of PLA admissions is 4075. The overall incidence of PLA is 13.5 per 100,000 hospitalizations, which increased by 60% between 2003 and 2014. The mean age of patients was 13.03 ± 6.1 years and were predominantly boys—61%. Of the comorbid conditions, hepatobiliary malignancy had the highest odds ratio (OR 71.8) followed by liver transplant (OR 38.4), biliary disease (OR 29.9), inflammatory bowel disease (IBD) (OR 5.35), other GI malignancies (OR 4.74), primary immune deficiency disorder (OR 4.13). Patients with PLA had 12 times increased odds of having associated severe sepsis. Infective endocarditis (IE) (OR 4.5), appendicitis (OR 1.8), and diverticulitis (OR 8.1) were significantly associated with PLA. Almost 39% (1575) of the PLA patients had positive culture, whereas Streptococcus (10.8%) and Staphylococcus spp (9.2%) were the most common pathogens. About 45% of PLA patients underwent percutaneous liver abscess aspiration whereas 4.1% had hepatic resection for PLA. The mortality rate of PLA was 0.8% (n = 32).

Conclusions:

The incidence of PLA is steadily increasing over the last decade among pediatric population in the United States. Hepatobiliary malignancy and liver transplant are the most common comorbid conditions associated with PLA.
Helicobacter pylori virulence factors expression affect epigenetic factors leading to gastrointestinal carcinoma
Authors: KZK Al-Alo , Al-abodi Hiba R. , Ghaidaa Raheem Lateef Al-Awsi , Alghanimi Yasemin K. , Alshammari Majida M.M. , Mirforughi Seyede A.
Published: March 2020

Disruption in the epigenetic mechanisms is one of the causes of cancer; particularly in the gut. It has been elucidated that multiple genetic and epigenetic alterations during this process caused by chronic inflammation play a crucial role in the cancer progress. DNA methylation impairment as a leading change is caused during the proliferation of Helicobacter pylori. It has been unraveled that numerous tumor suppressor genes are regulated by related promoter methylation, justifying environmental factors inducing gastric carcinoma. H. pylori infection affects various cells through inflammation, changes in apoptosis, proliferation and differentiation of epithelial cells into oncogenic cells. This is exerted through intracellular pathways in epithelial cells such as mitogen-activated protein kinase, Nuclear factor κB, activator protein, Wnt/β-catenin, Phosphoinositide 3-kinase pathways, signal transducers and transcriptional activators. The accumulations of cytosine methylation free radicals damage the DNA; hence nitric oxide (NO) alters the DNA-methylating enzymes function. Accordingly, gastritis due to H. pylori infection results in the inflammation and triggers signaling pathways mostly inducing gastrointestinal cancer. Noticeably, H. pylori-induced microRNAs exert epigenetic changes influencing various processes most of which including immune responses, autophagy, cell cycle and apoptosis. These mechanisms also stimulate gastric cancer progress. It is noteworthy that gene expression regulation through epigenetic mechanisms, including DNA methylation and micro-RNAs include major cellular pathways regulators. These epigenetic alterations represent prominent candidates for describing environmental factors roles in the genomic and cellular function enhancing the gastrointestinal carcinoma by H. pylori.
Early biochemical predictors of sepsis in patients with burn injury: current status and future perspectives
Authors: Erenler Ali K. , Baydin Ahmet , Ay Mehmet O. , Doğan Güvenç , Yasti Ahmet Ç.
Published: March 2020

Sepsis is the leading cause of morbidity and mortality in patients with burn injury and emerges as a clinical challenge for both emergency specialists and critical care staff. Since early diagnosis and appropriate treatment are known to be the milestones of sepsis management, use of biomarkers in diagnosis is highly recommended in the initial stage of sepsis. Although currently used Procalcitonin, as a traditional marker, may accurately indicate the presence of a systemic inflammation in burn patients, there is a need for more accurate markers of sepsis in burn patients. For now, use of a combination of markers may be suggested for a more accurate diagnosis. In the near future, gene therapy may make not only early prediction, but also appropriate treatment of sepsis in burn patients possible. In this article, we aimed to clarify roles of current biomarkers in early diagnosis of sepsis in burn patients and make future reflections in this growing field.
Efficacy and safety of brexpiprazole in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials
Authors: Antoun Reyad Ayman , Girgis Eriny , Mishriky Raafat
Published: March 2020

Brexpiprazole is a new atypical antipsychotic for schizophrenia management and as adjunct in major depressive disorder (MDD). We searched randomized controlled trials (RCT) to review brexpiprazole efficacy and tolerability in acute management of schizophrenia and MDD using PubMed, EUDRACT, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials. A meta-analysis was conducted using the identified 14 RCT to assess its efficacy using positive and negative syndrome scale (PANSS), clinical global impressions – severity of illness (CGI-S), personal and social performance scale (PSP), Montgomery–Åsberg depression rating scale (MADRS), Sheehan disability scale (SDS) and Hamilton depression rating scale (HDRS17). The mean difference comparing brexpiprazole and placebo were PANSS −4.48, CGI-S −0.23 and PSP 3.24 favoring brexpiprazole. Compared to aripiprazole and quetiapine, brexpiprazole showed similar efficacy. In MDD, brexpiprazole showed efficacy compared to placebo demonstrated by MADRS −1.25, SDS −0.37 and HDRS17 −1.28. Brexpiprazole was associated with side effects including akathisia risk ratio (RR) = 1.72; weight increase RR = 2.74 and somnolence RR = 1.87. Compared to 4 mg, brexpiprazole 2 mg was associated with less risk of akathisia and somnolence. Brexpiprazole demonstrated significant improvements in schizophrenia and MDD and is well-tolerated; however, associated with akathisia and somnolence. These findings will guide psychiatrists and pharmacists in their clinical role for supporting psychiatric patients care.
The long-term impact on self-reported health, function and comorbidities from lower limb apophysitis: Protocol of a cross-sectional study
Authors: Krommes Kasper , Thorborg Kristian , Christensen Lasse , Hölmich Per
Published: March 2020

Lower limb apophysitis cause long-term pain, decrease in function, and can reduce or completely hinder participation in sports and physical activity. Yet, there is little knowledge on the long-term consequences for health. Our objective with this investigation is to capture self-reported health-status for all adults diagnosed with lower limb apophysitis in the period of 1977 to 2020 in Danish secondary care and compare these data with normative values for the background population. We are therefore conducting a national cross-sectional study based on data from the Danish National Patient Registry. In this protocol we describe the planned methods.
The potential role of IL-6 in monitoring severe case of coronavirus disease 2019
Authors: Liu Tao , Zhang Jieying , Yang Yuhui , Ma Hong , Li Zhengyu , Zhang Jiaoyu , Cheng Ji , Zhang Xiaoyun , Zhao Yanxia , Xia Zihan , Zhang Liling , Wu Gang , Yi Jianhua
Published: March 2020

Background

The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan City, China has spreads rapidly since December, 2019. Most patients show mild symptoms, but some of them develop into severe disease. There is currently no specific medication. The purpose of this study is to explore changes of markers in peripheral blood of severe COVID-19 patients, which may be of value in disease monitoring.

Methods

Clinical data of patients with nonsevere and severe type COVID-19 diagnosed by laboratory test in our institution were collected. The relationship between peripheral blood cells and cytokines, clinical manifestation and outcome was analyzed.

Results

A total of 69 severe type COVID-19 patients were included. On admission, the median age of severe cases was 56-year old, with 52.17% female patient. The most common symptoms were fever (79.72%), cough (63.77%), shortness of breath (57.97%) and fatigue (50.72%). Diarrhea is less common. The most common comorbidity is hypertension. Upon admission, the proportion of bilateral pulmonary involvement and interstitial abnormalities evidenced by chest computed tomography (CT) imaging in severe cases was 60.87% and 27.54%, respectively. Compared with patients with nonsevere disease, those with severe disease showed obvious lymphocytopenia. Elevated level of lactate dehydrogenase (LDH), C-reactive protein (CRP), ferritin and D-dimer was found in most cases. Two patients (2.9%) needed transfer to the intensive care unit. Baseline immunological parameters and most of the inflammatory parameters were basically within the normal range. However, baseline interleukin-6 (IL-6) was significantly increased in severe type, which was closely related to the maximal body temperature during hospitalization and to CT findings. Baseline IL-6 was also significantly related to the increase of baseline level of CRP, LDH, ferritin and D-dimer. The increase of baseline IL-6 level suggests that it may positively correlate with the severity of COVID-19. Among the 30 severe type patients whose IL-6 was assessed before and after treatment, significant decrease in IL-6 and improved CT assessment was found in 25 patients after treatment. Whereas the IL-6 level was further increased in 3 cases, which was closely related to disease progression. It is suggested that IL-6 may be used as a marker for disease monitoring in severe COVID-19 patients.

Conclusions

On admission, the baseline level of IL-6, CRP, LDH and ferritin was closely related to the severity of COVID-19, and the elevated IL-6 was significantly related to the clinical manifestation of severe type patients. The decrease of IL-6 was closely related to treatment effectiveness, while the increase of IL-6 indicated disease exacerbation. Collectively, the dynamic change of IL-6 level can be used as a marker for disease monitoring in patients with severe COVID-19.
Rapid metagenomic characterization of a case of imported COVID-19 in Cambodia
Authors: Manning Jessica E. , Bohl Jennifer A. , Lay Sreyngim , Chea Sophana , Sovann Ly , Sengdoeurn Yi , Heng Seng , Vuthy Chan , Kalantar Katrina , Ahyong Vida , Tan Michelle , Sheu Jonathan , Tato Cristina M. , DeRisi Joseph L. , Baril Laurence , Duong Veasna , Dussart Philippe , Karlsson Erik A.
Published: March 2020

Rapid production and publication of pathogen genome sequences during emerging disease outbreaks provide crucial public health information. In resource-limited settings, especially near an outbreak epicenter, conventional deep sequencing or bioinformatics are often challenging. Here we successfully used metagenomic next generation sequencing on an iSeq100 Illumina platform paired with an open-source bioinformatics pipeline to quickly characterize Cambodia’s first case of COVID-2019.
Viral Architecture of SARS-CoV-2 with Post-Fusion Spike Revealed by Cryo-EM
Authors: Liu Chuang , Yang Yang , Gao Yuanzhu , Shen Chenguang , Ju Bin , Liu Congcong , Tang Xian , Wei Jinli , Ma Xiaomin , Liu Weilong , Xu Shuman , Liu Yingxia , Yuan Jing , Wu Jing , Liu Zheng , Zhang Zheng , Wang Peiyi , Liu Lei
Published: March 2020

Since December 2019, the outbreak of Coronavirus Disease 2019 (COVID-19) spread from Wuhan, China to the world, it has caused more than 87,000 diagnosed cases and more than 3,000 deaths globally. To fight against COVID-19, we carried out research for the near native SARS-CoV-2 and report here our preliminary results obtained. The pathogen of the COVID-19, the native SARS-CoV-2, was isolated, amplified and purified in a BSL-3 laboratory. The whole viral architecture of SARS-CoV-2 was examined by transmission electron microscopy (both negative staining and cryo-EM). We observed that the virion particles are roughly spherical or moderately pleiomorphic. Spikes have nail-like shape towards outside with a long body embedded in the envelope. The morphology of virion observed in our result indicates that the S protein of SARS-CoV-2 is in post-fusion state, with S1 disassociated. This state revealed by cryo-EM first time could provide an important information for the identification and relevant clinical research of this new coronavirus.