bluuebunny/crossref_metadata_2025 huggingface dataset:
Advances in hepatitis B therapeutics
Authors: Soriano Vicente , Barreiro Pablo , Cachay Edward , Kottilil Shyamasundaran , Fernandez-Montero José V. , de Mendoza Carmen
Published: October 2020

Despite the availability of both effective preventive vaccines and oral antivirals, over 250 million people are chronically infected with the hepatitis B virus (HBV). Globally, chronic hepatitis B is the leading cause of hepatocellular carcinoma, which represents the third cause of cancer mortality, accounting for nearly 1 million annual deaths. Current oral nucleos(t)ide therapy with tenofovir or entecavir suppresses serum HBV-DNA in most treated patients, but rarely is accompanied by HBsAg loss. Thus, treatment has to be given lifelong to prevent viral rebound. A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors. Some of them exhibit higher potency than current oral nucleos(t)ides. Drugs in more advanced stages of clinical development are bulevirtide, JNJ-6379, ABI-H0731, ARO-HBV and REP-2139. To date, only treatment with ARO-HBV and with REP-2139 have resulted in HBsAg loss in a significant proportion of patients. Combination therapies using distinct antivirals and/or immune modulators are expected to maximize treatment benefits. The current goal is to achieve a ‘functional cure’, with sustained serum HBsAg after drug discontinuation. Ultimately, the goal of HBV therapy will be virus eradication, an achievement that would require the elimination of the cccDNA reservoir within infected hepatocytes.
Reasons for nonparticipation in the Valuing Active Life in Dementia randomised controlled trial of a dyadic occupational therapy intervention: An interview study
Authors: Mundy Jacqueline , Stansfeld Jacki , Orrell Martin , Cartwright Martin , Wenborn Jennifer
Published: October 2020

Objectives:

There is currently little known about why people decline to participate in dyadic, psychosocial dementia research. This interview study aims to explore the reasons why people declined to participate in the Valuing Active Life in Dementia research trial.

Methods:

Ten family carers of people with dementia, who were part of a dyad that had declined to take part in the randomised controlled trial, participated in qualitative telephone interviews to explore their reasons for declining. Inductive thematic analysis was used to identify themes.

Findings:

Two themes with related sub-themes were identified: (1) Protectiveness – protecting the person with dementia, themselves as carers and their current lifestyle; (2) ‘It’s not for us’ – the time commitment, and the possible unsuitability of the intervention, was seen to outweigh the perceived benefit of taking part. People with dementia were not always involved in the decision-making process, with carers stating the decision not to participate was made in the usual way as all their decisions. No apparent differences between the spousal and the child carers were apparent in the small sample.

Conclusion:

Recruitment to randomised controlled trials can be considered difficult or unfair because some participants will miss out on the desired intervention. However, this study shows that concern about the time and inconvenience of being involved in the trial can put people off research participation. Identifying possible reasons for declining research participation contributes to the design of future trials and recruitment strategies, so that the potential benefit is considered relative to the time and effort involved. Offering research opportunities to people with dementia and their families at the right stage of the dementia trajectory for their needs, facilitating personalised recruitment strategies with finely tailored researcher communication skills should help maximise recruitment, reduce attrition and deliver a more successful trial.
Favipiravir-based regimen for coronavirus disease 2019 pneumonia for a 47-day-old male newborn
Authors: Moolasart Visal , Wongsawat Jurai , Phokhom Priyanut , Thienthong Varaporn
Published: October 2020

Coronavirus disease 2019 pneumonia in the newborn is a difficult-to-treat condition. Early clinical signs of pneumonia are nonspecific and present as respiratory distress of varying severity, and tachypnea is a predominant clinical sign. A 47-day-old, asymptomatic male newborn of coronavirus disease 2019 infected mother tested positive for coronavirus disease 2019 by reverse transcription polymerase chain reaction. During hospitalization, he developed progressive tachypnea, tachycardia, and chest radiography abnormalities, and was diagnosed as coronavirus disease 2019 pneumonia. He was treated with favipiravir, hydroxychloroquine, and lopinavir/ritonavir. A favipiravir- based regimen may be the drug of choice for coronavirus disease 2019 pneumonia in the newborn.
It’s complicated: A case report on a COVID-19-positive HIV patient presenting with rhabdomyolysis and acute kidney injury
Authors: Foster Allison , Khan Zohaib , Siddiqui Aisha , Singh Sukhdev , Atere Muhammed , Nfonoyim Jay M
Published: October 2020

The SARS-Cov-2/COVID-19 pandemic in early 2020 has had a devastating impact on health systems around the world. While viral pneumonia remains the most common complication, reports are surfacing of cases with neurological, cardiac, and renal involvement. Even less is known about the implications in special high-risk populations. In this report, we discuss a unique case of an HIV-positive patient in New York City who presented with a 2-week history of worsening fatigue, cough, dyspnea, and myalgias and was found to have COVID-19 pneumonia and acute kidney injury. He was managed for severe uremic metabolic acidosis and electrolyte abnormalities with emergent hemodialysis and supportive therapy with subsequent improvement. Direct involvement of SARS-CoV-2 and pneumonia-induced rhabdomyolysis were identified as the precipitating factors of his acute kidney injury. The pathophysiologic mechanisms of acute kidney injury, SARS-CoV-2 renal tropism, and the impact of highly active antiretroviral therapy on COVID-19 pneumonia are discussed. We highlight the importance of clinician awareness of this potentially fatal complication of COVID-19 pneumonia, particularly in the HIV-positive population as early recognition and management can have favorable outcomes.
Renal-Limited Antiglomerular Basement Membrane Disease Related To Alemtuzumab: A Case Report
Authors: Harrigan Amye M. , West Michael L. , Geldenhuys Laurette , Poyah Penelope
Published: October 2020

Rationale:

Alemtuzumab is a monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Many autoimmune-mediated adverse events have been associated with alemtuzumab, including renal-limited anti-glomerular basement membrane (GBM) disease.

Presenting concern:

A 52-year-old female with RRMS presented with acute kidney injury 39 months after receiving 1 cycle of alemtuzumab. She had a history of alemtuzumab-associated hypothyroidism and thrombocytopenia, urinary tract infections, and chronically abnormal urinalyses.

Diagnosis:

A diagnosis of renal-limited anti-GBM disease was made based on renal biopsy and positive anti-GBM serology. Alemtuzumab was thought to be the trigger of the anti-GBM disease as there were no other exposures or serologic findings suggesting other causes.

Interventions:

She was treated with corticosteroids, cyclophosphamide, and plasmapheresis. She required hemodialysis for acute renal failure.

Outcomes:

Despite treatment, the patient’s renal function did not recover. She remained dialysis-dependent and anti-GBM antibody titers remained elevated 6 months after presentation.

Teaching points:

Anti-GBM disease is a life-altering adverse event that can be associated with alemtuzumab. Our case highlights the limitations of monitoring urinalyses as a trigger for anti-GBM antibody testing in patients who have received alemtuzumab and have baseline abnormal urinalyses; such patients may require further protocolized anti-GBM antibody testing, although the optimal frequency of such antibody screening remains unclear.
Tracheal pseudomembrane secondary to aspiration pneumonia in a 6-year-old Ragdoll
Authors: Kwong Hannah , Fry Darren , Birnie Gemma
Published: October 2020

Case summary

A 6-year-old female spayed Ragdoll presented with a 4-day history of acute onset non-productive retching, coughing and anorexia. A complete blood count, serum biochemistry, thoracic radiography and abdominal ultrasound were performed. Initially, aspiration pneumonia was suspected owing to an alveolar lung pattern in the right cranial ventral lung lobes seen on radiographs. The cat did not improve with empirical antibiotic therapy. Bronchoscopy and bronchoalveolar lavage were performed. An intraluminal tracheal mass was identified and removed via endoscopic guidance and gentle traction. Histopathology results were consistent with a fibrinous tracheal pseudomembrane. The cat was concurrently diagnosed with Pseudomonas aeruginosa pneumonia, which was confirmed on bronchoalveolar lavage. Pseudomonas aeruginosa was also cultured within the pseudomembrane. The cat was received antimicrobial therapy for his Pseudomonas pneumonia. In humans, fibrinous tracheal pseudomembranes occur uncommonly as a complication following endotracheal intubation and rarely due to infectious organisms. As there was no prior history of endotracheal intubation, the development of fibrinous tracheal pseudomembrane in this cat was suspected to be secondary to Pseudonomas aeruginosa aspiration pneumonia.

Relevance and novel information

The present case report is the first to describe a tracheal pseudomembrane in a cat. Bronchoscopy-guided gentle traction and subsequent removal of the tracheal pseudomembrane resulted in a complete resolution of the clinical signs.
Apparent Ixodes tick paralysis in a cat from North America
Authors: Honnas Cheri M , Athey Jillian M , Verocai Guilherme G , Snowden Karen F , Esteve-Gasent Maria D , Mankin Joseph M
Published: October 2020

Case summary

A 2-year-old castrated male domestic longhair cat presented for acute, diffuse, flaccid paralysis. Thoracic and abdominal radiographs, biochemistry panel and complete blood count were unremarkable. Titers to Toxoplasma gondii, myasthenia gravis radioimmunoassay testing and creatinine kinase levels were within normal limits. The most likely differentials included acute toxicity (coral snake envenomation, organophosphate toxicity), botulism and, less likely, acute polyradiculoneuritis. A thorough physical examination revealed a single engorged tick attached to the ventral neck of the cat, which was later identified as an adult female Ixodes species. Topical fipronil and (S)-methoprene was administered. Over the next 48 h, the cat recovered full motor function and at 5 days post-tick removal the cat had resumed all normal activities.

Relevance and novel information

Tick paralysis is considered endemic in Australia by bites from, most commonly, the Ixodes holocyclus tick. However, this phenomenon is rarely reported in the USA. This is the first report of a domestic cat suffering from acute tick paralysis in North America.
Perception of Small-Scale Miners on Interventions to Eradicate Illegal Small-Scale Mining in Ghana
Authors: Wireko-Gyebi Rejoice Selorm , Asibey Michael Osei , Amponsah Owusu , King Rudith Sylvana , Braimah Imoro , Darko Godfred , Lykke Anne Mette
Published: October 2020

The proliferation of illegal mining in Ghana, coupled with its environmental impacts, especially on water bodies has compelled the government to ban all artisanal small-scale mining (ASM) activities in the country. The ban is intended to promote environmental sustainability while the government takes steps to provide sustainable health, and environmental-friendly ASM in Ghana. This paper assesses the perception of registered miners on the current approach by the Ghanaian government to stop illegal mining. Analyses of data from focus group discussions and key informant interviews revealed that the miners felt “left out” of the entire process. They maintained that they were not directly involved in the process to ban illegal mining in Ghana. To them, the proliferation of illegal mining in Ghana is the result of non-performing government institutions, corruption, and cumbersome licensing procedures. The article calls for improvement in the collaboration between the government and miners through a simplified participatory framework for the management of ASM in Ghana.
Block-Level Analysis of the Attractors of Robbery in a Downtown Area
Authors: Ejiogu Kingsley U.
Published: October 2020

This article examines the predictions of crime pattern theory in a unique neighborhood type. It tested potential crime attracting facilities against street robbery data from 2009 to 2013 in the Police Districts I & II in Downtown Houston. The analysis modeled the four daily human routine periods described in the American Time Use Survey (ATUS). Generalized linear simultaneous negative binomial regression model was used to determine the size of the influence of the variables (beta coefficients) and their significance for each model outcome. The findings show some distinct patterns of street robbery due to the immediate and lagged effects of the variables relatable to the study environment’s unique setting. Two variables, geographic mobility, and barbershops were particularly significant across three of the outcome models. The results suggest that the physical and social structure of neighborhoods determined by land-use regulations would enhance understanding of the time-based influence on robbery patterns due to crime-attracting facilities.
Atypical Bilateral Multifocal Congenital Toxoplasmosis Retinochoroiditis: Case Report With Literature Review
Authors: Reed Gavin , Agarwal-Sinha Swati
Published: October 2020

Background

Toxoplasmosis gondii is ubiquitously present on earth and infection, including congenital infection, is common. Neurological, developmental, and ocular effects can be devastating in the congenital toxoplasmosis population. At present, there is no standard, nation-wide neonatal screening for this disease in the United States.

Case Presentation

A 17-month-old Caucasian female presented to our institution by way of referral for macular scarring. She was diagnosed with intrauterine growth retardation and born with low birth weight and microcephaly at an outside institution, but no systemic workup was conducted at that time. On ocular examination, she was found to have nystagmus and extensive multifocal chorioretinal pigmented scars involving the macula and peripheral retina in both eyes with fibrous vitreous strands extending between scars in the right eye. Toxoplasmosis immunoglobulin G was found to be highly positive. Magnetic resonance imaging of the brain showed supratentorial intracranial calcifications.

Conclusions

Our patient presented with severe chorioretinal lesions, microcephaly, and nystagmus with a positive immunoglobulin G toxoplasmosis titer. She did not receive any evaluation, including TORCH infectious panel workup, on being born with low birth weight and microcephaly. There are currently no national programs in place for toxoplasmosis to be included in routine neonatal screening, despite the grave sequelae of congenital infection or that studies in other countries have shown cost-effectiveness in early screening and treatment.
Audiovisual Speech Recognition With a Cochlear Implant and Increased Perceptual and Cognitive Demands
Authors: Tinnemore Anna R. , Gordon-Salant Sandra , Goupell Matthew J.
Published: October 2020

Speech recognition in complex environments involves focusing on the most relevant speech signal while ignoring distractions. Difficulties can arise due to the incoming signal’s characteristics (e.g., accented pronunciation, background noise, distortion) or the listener’s characteristics (e.g., hearing loss, advancing age, cognitive abilities). Listeners who use cochlear implants (CIs) must overcome these difficulties while listening to an impoverished version of the signals available to listeners with normal hearing (NH). In the real world, listeners often attempt tasks concurrent with, but unrelated to, speech recognition. This study sought to reveal the effects of visual distraction and performing a simultaneous visual task on audiovisual speech recognition. Two groups, those with CIs and those with NH listening to vocoded speech, were presented videos of unaccented and accented talkers with and without visual distractions, and with a secondary task. It was hypothesized that, compared with those with NH, listeners with CIs would be less influenced by visual distraction or a secondary visual task because their prolonged reliance on visual cues to aid auditory perception improves the ability to suppress irrelevant information. Results showed that visual distractions alone did not significantly decrease speech recognition performance for either group, but adding a secondary task did. Speech recognition was significantly poorer for accented compared with unaccented speech, and this difference was greater for CI listeners. These results suggest that speech recognition performance is likely more dependent on incoming signal characteristics than a difference in adaptive strategies for managing distractions between those who listen with and without a CI.
Delayed Presentation of Urethral Valves: A Diagnosis That Should Be Suspected Despite a Normal Prenatal Ultrasound
Authors: Shields Lisa B. E. , White Jeffrey T. , Mohamed Ahmad Z. , Peppas Dennis S. , Rosenberg Eran
Published: October 2020

Background. Congenital urethral obstruction occurs most frequently as a result of urethral valves. The diagnosis is usually confirmed pre- or neonatally. Though not ideal, delayed diagnosis can occur in childhood, adolescence, or adulthood. Despite a normal prenatal ultrasound, there may still be a delayed diagnosis of urethral valves. Methods. We present 4 patients with delayed diagnosis of posterior urethral valves (PUV) and 1 patient with delayed diagnosis of anterior urethral valves (AUV) who were evaluated by a pediatric urologist at our Institution. We determined the age and symptoms at presentation, physical examination, micturating cystourethrogram (MCU) findings prior to the valve ablation, renal function before and after valve ablation, type of valve ablation, and urine culture and sensitivity. The urological courses following urethral valve ablation including urodynamic study findings are described. Results. The median age at presentation was 33 months. All 5 patients presented with decreased urine output and urinary retention. All 5 patients underwent a MCU that demonstrated bladder trabeculations (3 cases), vesicoureteral reflux (3 cases), and bladder diverticula (2 cases). A urethral valve ablation was performed in all cases. Four patients underwent a renal function panel prior to this procedure, and their serum BUN/creatinine levels decreased 1 day postoperatively. Conclusion. Pediatricians should consider urethral valves as causing urethral obstruction although the prenatal ultrasound may be normal. Early diagnosis and prompt treatment of urethral valves may mitigate the potentially devastating morbidities such as renal failure, congestive heart failure, and respiratory distress that may ensue.
Lessons From Other Disciplines About Communication, Human Performance and Situational Awareness While Wearing Personal Protective Equipment
Authors: Scott Margaret , Unsworth John
Published: October 2020

Introduction

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) has quickly accelerated into a pandemic. As COVID-19 has swept across the globe, health systems have adapted, including the cessation of routine surgery and the re-deployment of staff to critical care settings. Prompt interventions such as endotracheal (ET) intubation, are deemed essential in patients with Acute Respiratory Distress Syndrome. Intubation requires a coordinated approach and effective teamwork, as it is a high-risk procedure not least because it is an aerosol-generating intervention with increased infection risk. As a result, teams responsible for performing ET intubation are required to wear Personal Protective Equipment (PPE), which in turn hinders communication and situational awareness, and can hamper team work.

Method

This review considers the effects of wearing PPE on performance and situational awareness in a healthcare environment. Drawing on literature from the fire service and military, the review will explore approaches to improving communication and situational awareness for teams who, at times, are unfamiliar with one another. The review will consider human factors and, identify approaches that assist teams, including teams that are unfamiliar with one another, to adapt to new ways of working while performing high-risk procedures.

Conclusion

Literature indicates that standardisation, pre-brief and training are important elements of developing improved situational awareness and team working in individuals whose senses may be affected by PPE. In addition, checklists provide a useful way of standardising procedures and can form the basis of a structured pre-brief. Checklists exist for both intubation and patient proning, which, alongside simulation-based team training, provide a useful method of preparing an often unfamiliar workforce for their roles during an epidemic or pandemic. The multi-phase nature of most pandemics provides an opportunity to review processes and implement such procedures, and to develop staff using team-based training during the post-peak period.
Delivering a work-integrated learning postgraduate course during COVID-19: Experiences, challenges and strategies
Authors: Prior Sarah J , Griffin Phoebe , O’Brien Lauri , Van Dam Pieter J
Published: October 2020

COVID-19 has had a significant impact on teaching and learning in postgraduate education. In particular, work integrated learning, in health care settings, has been disrupted in many ways negatively impacting student learning. Our Clinical Redesign courses are designed to deliver work-integrated learning in partnership with healthcare organisations to deliver workplace projects in real time, which has been complicated by COVID-19. This reflection examines the challenges that arose in the healthcare redesign teaching and learning space during the COVID-19 pandemic. We explore the experiences of our work-integrated learning students using Johns’ reflection model.1 Our students faced disruption to their education, workplaces and personal lives, and the experiences of our teaching team whose teaching philosophies were challenged. In response to the ongoing challenges, we developed strategies for supporting our students including the development of virtual projects for students who no longer had access to their workplaces or project appropriate resources.
Gender and palliative care: a call to arms
Authors: Gott Merryn , Morgan Tessa , Williams Lisa
Published: October 2020

There has been a systematic and largely unconscious neglect of gender in palliative care research, practice and policy. This is despite significant, although previously uncollated, evidence that gender influences almost all aspects of end-of-life preferences, experiences and care. The social situations of women, transgender people and men often differ from one another while also intersecting in complex ways with sex differences rooted in biology. If palliative care is to meet its aspiration of providing universal benefit, it urgently needs to address a range of gender inequalities currently (re)produced at the level of the laboratory all the way through to government departments. In this call to arms, we spotlight specific instances where gender inequalities have been documented, for example, regarding end-of-life caregiving, end-of-life intervention and palliative care access and benefit. We highlight how gender inequalities intersect with other social determinants of health including ethnicity and economic status to exacerbate situations of marginality. We conclude by offering some practical steps that can be taken to support the discipline to adopt a more critical gender lens to support more equitable research, policy and practice.
Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension
Authors: Swietlik Emilia M. , Ghataorhe Pavandeep , Zalewska Kasia I. , Wharton John , Howard Luke S. , Taboada Dolores , Cannon John E. ,   UK National Cohort Study of PAH, Morrell Nicholas W. , Wilkins Martin R. , Toshner Mark , Pepke-Zaba Joanna , Rhodes Christopher J.
Published: October 2020

Pulmonary hypertension is a condition with limited effective treatment options. Chronic thromboembolic pulmonary hypertension (CTEPH) is a notable exception, with pulmonary endarterectomy (PEA) often proving curative. This study investigated the plasma metabolome of CTEPH patients, estimated reversibility to an effective treatment and explored the source of metabolic perturbations.

We performed untargeted analysis of plasma metabolites in CTEPH patients compared to healthy controls and disease comparators. Changes in metabolic profile were evaluated in response to PEA. A subset of patients were sampled at three anatomical locations and plasma metabolite gradients calculated.

We defined and validated altered plasma metabolite profiles in patients with CTEPH. 12 metabolites were confirmed by receiver operating characteristic analysis to distinguish CTEPH and both healthy (area under the curve (AUC) 0.64–0.94, all p<2×10−5) and disease controls (AUC 0.58–0.77, all p<0.05). Many of the metabolic changes were notably similar to those observed in idiopathic pulmonary arterial hypertension (IPAH). Only five metabolites (5-methylthioadenosine, N1-methyladenosine, N1-methylinosine, 7-methylguanine, N-formylmethionine) distinguished CTEPH from chronic thromboembolic disease or IPAH. Significant corrections (15–100% of perturbation) in response to PEA were observed in some, but not all metabolites. Anatomical sampling identified 188 plasma metabolites, with significant gradients in tryptophan, sphingomyelin, methionine and Krebs cycle metabolites. In addition, metabolites associated with CTEPH and gradients showed significant associations with clinical measures of disease severity.

We identified a specific metabolic profile that distinguishes CTEPH from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and IPAH patients. Plasma metabolite gradients implicate cardiopulmonary tissue metabolism of metabolites associated with pulmonary hypertension and metabolites that respond to PEA surgery could be a suitable noninvasive marker for evaluating future targeted therapeutic interventions.
Mitochondrial dysfunction in lung ageing and disease
Authors: Cloonan Suzanne M. , Kim Kihwan , Esteves Pauline , Trian Thomas , Barnes Peter J.
Published: October 2020

Mitochondrial biology has seen a surge in popularity in the past 5 years, with the emergence of numerous new avenues of exciting mitochondria-related research including immunometabolism, mitochondrial transplantation and mitochondria-microbe biology. Since the early 1960s mitochondrial dysfunction has been observed in cells of the lung in individuals and in experimental models of chronic and acute respiratory diseases. However, it is only in the past decade with the emergence of more sophisticated tools and methodologies that we are beginning to understand how this enigmatic organelle regulates cellular homeostasis and contributes to disease processes in the lung. In this review, we highlight the diverse role of mitochondria in individual lung cell populations and what happens when these essential organelles become dysfunctional with ageing and in acute and chronic lung disease. Although much remains to be uncovered, we also discuss potential targeted therapeutics for mitochondrial dysfunction in the ageing and diseased lung.
The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis
Authors: Platé Manuela , Guillotin Delphine , Chambers Rachel C
Published: October 2020

Idiopathic pulmonary fibrosis (IPF) is characterised by the progressive deposition of excessive extracellular matrix proteins within the lung parenchyma and represents the most rapidly progressive and fatal of all fibrotic conditions. Current anti-fibrotic drugs approved for the treatment of IPF fail to halt disease progression and have significant side-effect profiles. Therefore, there remains a pressing need to develop novel therapeutic strategies for IPF. Mammalian target of rapamycin (mTOR) forms the catalytic subunit of two complexes, mTORC1 and mTORC2. mTORC1 acts as critical cellular sensor which integrates intracellular and extracellular signals to reciprocally regulate a variety of anabolic and catabolic processes. The emerging evidence for a critical role for mTORC1 in influencing extracellular matrix production, metabolism, autophagy and senescence in the setting of IPF highlights this axis as a novel therapeutic target with the potential to impact multiple IPF pathomechanisms.
Systematic review of diagnostic methods for acute respiratory distress syndrome
Authors: Hagens Laura A. , Heijnen Nanon F.L. , Smit Marry R. , Schultz Marcus J. , Bergmans Dennis C.J.J. , Schnabel Ronny M. , Bos Lieuwe D.J.
Published: October 2020

Rationale

Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS.

Methods

Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising.

Results

Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72�0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population.

Conclusion

This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed.
High-sensitivity troponin I for risk stratification in normotensive pulmonary embolism
Authors: Ebner Matthias , Guddat Niklas , Keller Karsten , Merten Marie Christine , Lerchbaumer Markus H. , Hasenfuß Gerd , Konstantinides Stavros V. , Lankeit Mareike
Published: October 2020

While numerous studies have confirmed the prognostic role of high-sensitivity troponin T (hsTnT) in pulmonary embolism (PE), high-sensitivity troponin I (hsTnI) is inappropriately studied. This study aimed to investigate the prognostic relevance of hsTnI in normotensive PE, establish the optimal cut-off value for risk stratification and to compare the prognostic performances of hsTnI and hsTnT.

Based on data from 459 consecutive PE patients enrolled in a single-centre registry, receiver operating characteristic analysis was used to identify an optimal hsTnI cut-off value for prediction of in-hospital adverse outcomes (PE-related death, cardiopulmonary resuscitation or vasopressor treatment) and all-cause mortality.

Patients who suffered an in-hospital adverse outcome (4.8%) had higher hsTnI concentrations compared with those with a favourable clinical course (57 (interquartile range (IQR) 22–197)versus15 (IQR 10–86) pg·mL−1, p=0.03). A hsTnI cut-off value of 16 ng·mL−1provided optimal prognostic performance and predicted in-hospital adverse outcomes (OR 6.5, 95% CI 1.9–22.4) and all-cause mortality (OR 3.7, 95% CI 1.0–13.3). Between female and male patients, no relevant differences in hsTnI concentrations (17 (IQR 10–97)versus17 (IQR 10–92) pg·mL−1, p=0.79) or optimised cut-off values were observed. Risk stratification according to the 2019 European Society of Cardiology algorithm revealed no differences if calculated based on either hsTnI or hsTnT (p=0.68).

Our findings confirm the prognostic role of hsTnI in normotensive PE. HsTnI concentrations >16 pg·mL−1predicted in-hospital adverse outcome and all-cause mortality; sex-specific cut-off values do not seem necessary. Importantly, our results suggest that hsTnI and hsTnT can be used interchangeably for risk stratification.
Correction to: An integrative phylogenomic approach to elucidate the evolutionary history and divergence times of Neuropterida (Insecta: Holometabola)
Authors: Vasilikopoulos Alexandros , Misof Bernhard , Meusemann Karen , Lieberz Doria , Flouri Tomáš , Beutel Rolf G. , Niehuis Oliver , Wappler Torsten , Rust Jes , Peters Ralph S. , Donath Alexander , Podsiadlowski Lars , Mayer Christoph , Bartel Daniela , Böhm Alexander , Liu Shanlin , Kapli Paschalia , Greve Carola , Jepson James E. , Liu Xingyue , Zhou Xin , Aspöck Horst , Aspöck Ulrike
Published: October 2020

An amendment to this paper has been published and can be accessed via the original article.
Lower urinary tract symptoms in men: challenges to early hospital presentation in a resource-poor health system
Authors: Nnabugwu Ikenna I. , Okoronkwo Ijeoma L. , Nnabugwu Chinwe A.
Published: October 2020

Background

The point at which men seek medical care for lower urinary tract symptoms (LUTS) varies between individuals. Presentation to hospital with complications beyond LUTS appears prevalent in our setting. The aim of this survey is to assess from the community perspective in southeast Nigeria, the challenges to early presentation for medical evaluation for LUTS by men.

Methods

A questionnaire-based cross-sectional survey of randomly-selected men ≥40 years. The questionnaire captured respondent’s age; presence, duration and severity of LUTS; access to health information; wealth-index; and when (and why) medical care for LUTS was sought. Analysis was with SPSS® version 20.

Results

In all, responses from 1319 men (mean age 54.2 ± 10.2 years) are analysed. Of these, 267 report LUTS: 58.4% (156) report moderate to severe LUTS and 51.7% (138) are yet to seek medical care. As regards seeking medical care, all the men reporting LUTS of 3 months, 35.7% of 126 men reporting moderate LUTS, and 20.0% of 30 men reporting severe LUTS are yet to seek medical care. LUTS being non-bothersome (not financial constraint) is the most prevalent reason for not seeking medical care early. Delay is encouraged by limited access to health information (OR 3.10; p < 0.001), but discouraged by literacy (OR 0.86; p < 0.001) and aging (OR 0.93; p = 0.002).

Conclusion

From the community perspective, the prevalent challenge to seeking medical care for LUTS early is absence of bother. Empowering men through formal education and researched health information will influence positively the time that LUTS in men is appreciated as bothersome.
Determining the cost-effectiveness requirements of an exoskeleton preventing second hip fractures using value of information
Authors: Manetti Stefania , Turchetti Giuseppe , Fusco Francesco
Published: October 2020

Background

Falls may lead to hip fractures, which have a detrimental effect on the prognosis of patients as well as a considerable impact on healthcare expenditures. Since a secondary hip fracture (SHF) may lead to even higher costs than primary fractures, the development of innovative services is crucial to limit falls and curb costs in high-risk patients. An early economic evaluation assessed which patients with a second hip fracture could benefit most from an exoskeleton preventing falls and whether its development is feasible.

Methods

The life-course of hip fractured patients presenting with dementia or cardiovascular diseases was simulated using a Markov model relying on the United Kingdom administrative data and complemented by published literature. A group of experts provided the exoskeleton parameters. Secondary analyses included a threshold analysis to identify the exoskeleton requirements (e.g. minimum impact of the exoskeleton on patients’ quality of life) leading to a reimbursable incremental cost-effectiveness ratio. Similarly, the uncertainty around these requirements was modelled by varying their standard errors and represented alongside population Expected Value of Perfect Information (EVPI).

Results

Our base-case found the exoskeleton cost-effective when providing a statistically significant reduction in SHF risk. The secondary analyses identified 286 cost-effective combinations of the exoskeleton requirements. The uncertainty around these requirements was explored producing further 22,880 scenarios, which showed that this significant reduction in SHF risk was not necessary to support the exoskeleton adoption in clinical practice. Conversely, a significant improvement in women quality of life was crucial to obtain an acceptable population EVPI regardless of the cost of the exoskeleton.

Conclusions

Our study identified the exoskeleton requisites to be cost-effective and the value of future research. Decision-makers could use our analyses to assess not only whether the exoskeleton could be cost-effective but also how much further research and development of the exoskeleton is worth to be pursued.
The best execution of the DuoStim strategy (double stimulation in the follicular and luteal phase of the same ovarian cycle) in patients who are poor ovarian responders
Authors: Luo Yanqun , Sun Li , Dong Mei , Zhang Xiqian , Huang Li , Zhu Xiulan , Nong Yingqi , Liu Fenghua
Published: October 2020

Background

Patients found to be poor ovarian responders (POR) are a challenging patient population for any assisted reproduction technology. Despite attempts at various controlled ovarian stimulation schemes, reproductive outcomes in this patient population have not improved. In recent years, the DuoStim protocol (both follicular and luteal phase stimulation during the same menstrual cycle) has shown a potential for use in patients with POR.

Methods

This retrospective study reviewed the medical records of 304 women who were diagnosed as POR and underwent the DuoStim protocol. We compared follicular phase stimulation (FPS) data and luteal phase stimulation (LPS) data of the same patients. We also compared the effects of different trigger drugs including urine human chorionic gonadotropin (uHCG; 10,000 IU), recombinant human chorionic gonadotropin (rHCG; 250 μg), and gonadotropin-releasing hormone agonist (GnRH-a; 0.2 mg) at the FPS and LPS stages.

Results

POR undergoing the DuoStim protocol resulted in a significantly higher number of oocytes retrieved, normal fertilised oocytes, cleaved embryos, cryopreserved embryos, and good quality embryos at the LPS stage than at the FPS stage. Trigger drugs at the FPS stage did not affect the FPS stage data. Regardless of the stage, rHCG and GnRH-a yielded significantly more cryopreserved embryos and good quality embryos than uHCG.

Conclusion

The use of GnRH-a or rHCG as the trigger drug may be better than uHCG in both the FPS and LPS stages for POR undergoing the DuoStim protocol. This will increase the number of good quality embryos at the LPS stage. We found that the LPS stage results in more oocytes (and therefore more embryos) than the FPS stage.
Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer
Authors: Ni Huan-he , Zhang Lin , Huang He , Dai Shu-qin , Li Jiang
Published: October 2020

Background

Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC).

Methods

Specimens of paraffin embedded tumour from 197 CC patients were collected. The expression levels of METTL3 and CD33 were measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson’s or Spearman’s chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses. METTL3 in CD33+ cells or CC-derived cells was knocked down by METTL3-specific siRNA, and MDSC induction in vitro was performed in a co-culture system in the presence of METTL3-siRNA and METTL3-knockdown-CC-derived cells compared with that of the corresponding controls.

Results

We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour-adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). We further found that the direct CD33+CD11b+HLA-DR− MDSC induction and tumour-derived MDSC induction in vitro were decreased in the absence of METTL3. The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stage. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while the CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II–IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P = 0.010) and OS (HR = 5.140, P = 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037).

Conclusion

Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.
Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease
Authors: Kong Fan’ge , Jiang Xue , Wang Ruochen , Zhai Siyu , Zhang Yizhi , Wang Di
Published: October 2020

Background

Neuroinflammation is a principal element in Alzheimer’s disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells.

Methods

APP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B.

Results

In APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity.

Conclusions

FTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.
A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner: microglial IL-6 regulation of experimental autoimmune encephalomyelitis
Authors: Sanchis Paula , Fernández-Gayol Olaya , Comes Gemma , Aguilar Kevin , Escrig Anna , Giralt Mercedes , Palmiter Richard D. , Hidalgo Juan
Published: October 2020

Background

Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6.

Methods

To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss ofIl6expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglialIl6expression in IL6-DIO-KO mice through breeding toCx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10–16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) 7 weeks after TAM treatment to induce EAE. Clinical symptoms and demyelination, CD3 infiltration, and gliosis in the spinal cord were evaluated.

Results

IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglialIl6was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology.

Conclusions

IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.