bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased heterogeneity of brain perfusion predicts the development of cerebrovascular accidents
Authors: Lin Ting-Syuan , Hsu Pei-Ying , Ko Chi-Lun , Kuo Yu-Min , Lu Cheng-Hsun , Shen Chieh-Yu , Hsieh Song-Chou
Published: April 2021

The heterogeneity of brain perfusion is related to the risk factors of thromboembolic events such as antiphospholipid syndrome. However, the effectiveness of brain perfusion heterogeneity as a marker to predict thromboembolic events has not been confirmed. Our objective was to evaluate the effectiveness of brain perfusion heterogeneity as a marker to predict the development of cerebrovascular accidents. In this retrospective cohort study, patients who underwent Tc-99m ECD brain SPECT from January 1, 2006 through December 31, 2008 were included. Each study was reoriented with the Talairach space provided by the NeuroGam Software package. Heterogeneity of brain perfusion was measured as the coefficient of variation. The study outcome was the risk of cerebral vascular accidents in patients with increased heterogeneity of brain perfusion between January 1, 2006 and December 31, 2015. A multiple Cox proportional hazards model was applied to evaluate the risk of cerebrovascular accidents. A total of 70 patients were included in this study. The median age was 39 years (range, 28 – 59 years). There were 55 (78.6%) women. For increased heterogeneity of brain perfusion, the hazard ratio of cerebrovascular accidents was 2.68 (95% CI, 1.41 – 5.09; P = .003) after adjusting for age, sex, hypertension, diabetes mellitus, and dyslipidemia. Our study suggests that increased heterogeneity of brain perfusion is associated with an increased risk of cerebrovascular accidents.
Multiple arterial and venous thromboembolism in a male patient with hereditary protein C deficiency
Authors: Sun Likun , Li Xin , Li Quanming , Wang Lunchang , Li Jiehua , Shu Chang
Published: April 2021

Rationale:

Hereditary protein C deficiency has a high prevalence in Asian populations, being the important risk factor associated with thrombophilia. Traditionally, conservative medication is the first choice for patients with hereditary protein C deficiency. However, there are few reports on whether aggressive surgical treatment can be performed when patients continue to develop life-threatening ischemic symptoms after adequate anticoagulant and thrombolytic therapy.

Patient concerns:

A 40-year-old male presented with right lower extremity pain for 1 week.

Diagnosis:

Computed tomography angiography (CTA) of lower extremity indicated arterial embolization of the right superficial femoral artery. Vascular ultrasonography showed old extensive thrombus in the deep vein of the left lower extremity. Electrocardiogram reported old anterior myocardial infarction. Sequencing of the gene encoding protein C (PROC) gene revealed that a heterozygous in-frame deletion mutation (c.577–579delAAG, p.192delK). Based on these findings, the diagnosis of hereditary protein C deficiency was made.

Interventions:

The patient was given low-molecular-weight heparin (LMWH) anticoagulation and urokinase treatment immediately. Then we performed the Fogarty catheter embolectomy with about 18.5 cm thrombus being removed and utilized the balloon catheter to dilate the anterior tibial artery. Despite given adequate anticoagulant and thrombolytic therapy postoperatively, the patient still had new thrombosis, and eventually underwent arterial embolectomy and amputation.

Outcomes:

The patient was discharged with good wound healing and continued rivaroxaban treatment at a dose of 20 mg daily. The patient was followed-up monthly until 1 year: there was no adverse ischemic events occurred.

Lessons:

Aggressive surgical treatment may be the effective attempt for life-saving when conservative treatment as the first choice had unsatisfactory results in hereditary protein C deficiency patients. The novel oral anticoagulants (NOACs) could be more suitable than warfarin for the treatment and prevention of recurrence in patients with hereditary protein C deficiency.
Second allogeneic transplantation using umbilical cord blood for a patient with relapsed ALK+ anaplastic large cell lymphoma after allogeneic bone marrow transplantation in the era of ALK inhibitors
Authors: Saito Sumiko , Tashiro Haruko , Sumiyoshi Ritsu , Matsuo Takuji , Yamamoto Tadashi , Matsumoto Kensuke , Ooi Jun , Shirafuji Naoki
Published: April 2021

Rationale:

Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet.

Patient concerns:

An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT).

Diagnosis:

However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy.

Intervention:

Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2nd CR.

Outcomes:

The patient has been in CR under maintenance therapy of alectinib for more than 16 months.

Lessons:

Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.
A Novel Homozygous TRNT1 Mutation in a Child With an Early Diagnosis of Common Variable Immunodeficiency Leading to Mild Hypogammaglobulinemia and Hemolytic Anemia
Authors: Topyildiz Ezgi , Edeer Karaca Neslihan , Bas Ilke , Aykut Ayca , Durmaz Asude , Guven Bilgin Raziye B. , Aksu Guzide , Yilmaz Karapinar Deniz , Kutukculer Necil
Published: April 2021

Although sideroblastic anemias (SAs) may be associated with different etiologies, deterioration of mitochondrial heme biosynthesis in bone marrow erythroid cells is a general abnormality. Congenital SA associated with immunodeficiency, periodic fever, and developmental delay is because of loss-of-function mutations in the TRNT1 gene. We report a patient with a novel homozygous mutation in the TRNT1 gene presenting with anemia with siderocytes, hypogammaglobulinemia, hepatosplenomegaly, and brittle hair but without periodic fever or developmental delay. The patient was presented to emphasize the power of reverse phenotyping in the differential diagnosis of primary immunodeficiency patients with atypical features and to raise awareness for TRNT1 disease in case of coexistent SA and hypogammaglobulinemia.
Detection of Renal Insufficiency in a Cohort of Patients With Beta-thalassemia Major Using Cystatin-C
Authors: Hamdy Mona , Shaheen Iman , El-Gammal Zinab M. , Ramadan Yasmin M.
Published: April 2021

With increased life expectancy among patients with beta-thalassemia major (β-TM) renal insufficiency has been frequently noted because of the persistence of anemia, iron overload and some drug side effects. Serum creatinine becomes elevated in late stage of kidney affection. Cystatin-C is more sensitive biomarker for kidney dysfunction. Our aim was to measure Cystatin-C serum level among patients with β-TM as a marker of early nephropathy. Serum Cystatin-C was measured in 94 patients with β-TM using Enzyme-Linked Immunosorbent Assay (ELISA) and correlated to other clinical, laboratory and radiologic data. Glomerular hyperfiltration was observed in 30.8% while Cystatin-C was elevated in 56.3% of β-TM. Patients having high serum Cystatin-C were older in age and having higher serum levels of aspartate aminotransferases and urea. Cystatin-C level was positively correlated with serum creatinine and urea and negatively correlated with glomerular filtration rate. Periodic assessment of Cystatin-C in patients with β-TM is recommended for early diagnosis of renal dysfunction especially during drug dosing prescription aiming to obtain the maximum effectiveness and safety. Controlling anemia by maintaining appropriate hemoglobin level with close monitoring of iron overload are also recommended to preserve renal function among β-TM patients.
Potential Impact of Climate Change on Human Trafficking
Authors: Sheu Jessica C. , Torres Melissa I.M. , Gordon Mollie R. , Nguyen Phuong T. , Coverdale John H.
Published: April 2021

Climate change is a threat to the public health with wide-reaching impacts that are becoming more studied and recognized. An aspect of climate change that has not yet gained adequate scholarly attention is its potential impact on human trafficking. We review the potential impact of climate change on risk factors to human trafficking including poverty, gender inequality, political instability, migration or forced displacement, and weather disasters. We conclude that climate change is a crucially important consideration in understanding the complex and multifactorial risks for human trafficking. These findings add to the priority for health professionals to embrace efforts to prevent and to mitigate the effects of climate change and to take account of these risk factors in screening and identifying trafficked persons.
Increased substance P and synaptic remodeling occur in the trigeminal sensory system with sustained osteoarthritic temporomandibular joint sensitivity
Authors: Sperry Megan M. , Granquist Eric J. , Winkelstein Beth A.
Published: April 2021

Introduction:

Temporomandibular joint (TMJ) pain is among the most prevalent musculoskeletal conditions and can result from atypical joint loading. Although TMJ pain is typically self-resolving, 15% of patients develop chronic TMJ pain that is recalcitrant to therapy and may be attributed to changes in pain processing centers. Although TMJ overloading induces pain and osteoarthritis, whether neuronal modifications in the trigeminal sensory system contribute to persistent TMJ pain is unknown.

Objective:

This study investigates changes in excitatory neuropeptides and synaptic transmission proteins in cases of transient and persistent TMJ sensitivity in a rat model.

Methods:

Rats underwent repeated jaw loading that produces transient (2N-load) or persistent (3.5N-load) sensitivity. In both groups, immunolabeling was used to assess substance P in the spinal trigeminal nucleus caudalis (Sp5C) and glutamate transporter 1 in the ventroposteriomedial thalamus early after loading. Synaptosomal Western blots were used to measure synaptic proteins in the caudal medulla and thalamus at a later time after loading.

Results:

Substance P increases transiently in the Sp5C early after loading that induces persistent sensitivity. However, glutamate transporter 1 is unchanged in the ventroposteriomedial thalamus. At a later time, synaptosomal Western blots show loss of the presynaptic tethering protein, synapsin, and the inhibitory scaffolding protein, gephyrin, in the thalamus with persistent, but not transient, sensitivity. No changes are identified in synapsin, phosphorylated synapsin, homer, or gephyrin in the caudal medulla.

Conclusions:

Substance P in the Sp5C and later loss of inhibitory synapses in the thalamus likely contribute to, or indicate, persistent TMJ pain.
No evidence that attentional bias towards pain-related words is associated with verbally induced nocebo hyperalgesia: a dot-probe study
Authors: Coleshill Matthew James , Sharpe Louise , Colagiuri Ben
Published: April 2021

Introduction:

Placebo and nocebo effects in pain are well documented. One leading explanation is that instructions indicating that pain will either increase or decrease after receipt of a treatment give rise to expectations for increased or decreased pain. However, the psychological mechanisms through which expectations affect pain perception are not well understood. One possibility is that the expectation of increased pain leads to anticipatory anxiety, which in turn increases attention towards painful sensations.

Objectives:

The aim of this study was to test the hypothesis that attention mediates nocebo hyperalgesia. This was done by measuring attentional bias towards pain using a dot-probe task both before and after a nocebo manipulation.

Methods:

Ninety-six healthy volunteers were randomized to receive one of the following: (1) an inert nasal spray with placebo instructions, (2) an inert nasal spray with nocebo instructions, or (3) no treatment. Participants completed measures of expectations, anxiety, and attention bias (dot-probe paradigm) both before and after randomization.

Results:

Results showed that the nocebo instructions induced expectations for increased pain and resulted in nocebo hyperalgesia. Conversely, the placebo instruction failed to induce expectations for decreases in pain and did not demonstrate any placebo analgesia. Furthermore, despite the significant expectancies for pain and subsequent nocebo hyperalgesia, there were no differences between the nocebo group and either the placebo or no-treatment group for anxiety or attentional bias.

Conclusion:

The results are consistent with the expectancy model of placebo and nocebo effects. That is, changes in expectations seemed to be necessary to induce a placebo or nocebo effect. However, there was no evidence that anxiety or attention bias towards pain-related stimuli was necessary to achieve nocebo hyperalgesia.
Pharmacological Management of Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome Syndrome
Authors: Slouma Maroua , Bettaieb Hiba , Rahmouni Safa , Litaiem Noureddine , Dhahri Rim , Gharsallah Imen , Metoui Leila , Louzir Bassem
Published: April 2021

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare chronic disease with marked clinical and radiological heterogeneity. It is characterized by a combination of dermatological and osteoarticular manifestations. The treatment of SAPHO syndrome is not yet codified. It includes several therapeutic options such as anti-inflammatory drugs, bisphosphonates, antibiotics, conventional disease-modifying antirheumatic drugs, and biological treatment.

This article aims to provide an updated review of the different pharmacological options for SAPHO syndrome. We also propose a therapeutic algorithm for the management of this disease.
Ultrasonic Characteristics of Medullary Thyroid Carcinoma
Authors: Lei Rongqiang , Wang Zongle , Qian Linxue
Published: April 2021

The aim of this study was to evaluate the differences in ultrasonic features of patients with medullary thyroid carcinoma (MTC), papillary thyroid carcinoma (PTC), and benign thyroid nodules. This study included 53 cases of MTC, 151 cases of PTC, and 200 cases of benign thyroid nodule which were pathologically confirmed. There were no significant differences in sex and thyroid gland involvement among the MTC, PTC, and benign thyroid nodule groups. The age among the 3 groups was statistically different (P = 0.002). The TNM stage of MTC was significantly higher than that of PTC (P < 0.001). Compared with PTC, the lesion size, shape, margin, echogenicity, internal nodule component, and blood flow were significantly different in MTC (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P = 0.045, P < 0.001). However, there were no differences in the form of calcification and cervical lymph node involvement between the 2 groups (P = 0.671, P = 0.128). Except for the lesion size and shape (P = 0.068, P = 0.444), MTC group have significant differences in the grade of Thyroid Imaging Reporting and Data System, lesion margin, echogenicity, internal nodule component, calcification, cervical lymph node, and blood flow compared with benign thyroid nodule group (P < 0.001, P = 0.014, P = 0.032, P < 0.001, P < 0.001, P < 0.001). Our data indicate that ultrasound have important value in preoperative diagnosis of MTC. The ultrasonic features of MTC include relatively large nodules, aspect ratio less than 1, smooth edge, solid hypoechoic, microcalcification, and rich blood flow. It is necessary to combine multiple ultrasonic features for the differential diagnosis of MTC, PTC, and benign thyroid nodules.
Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR
Authors: Blankenstein Stéphanie A. , Rohaan Maartje W. , Klop Willem Martin C. , van der Hiel Bernies , van de Wiel Bart A. , Lahaye Max J. , Adriaansz Sandra , Sikorska Karolina , van Tinteren Harm , Sari Aysegül , Grijpink-Ongering Lindsay G. , van Houdt Winan J. , Wouters Michel W. J. M. , Blank Christian U. , Wilgenhof Sofie , van Thienen Johannes V. , van Akkooi Alexander C. J. , Haanen John B. A. G.
Published: April 2021

Objective:

To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma.

Summary Background Data:

Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear.

Methods:

In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection.

Results:

Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7–57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery.

Conclusions:

This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.
Neuromodulation techniques for cancer pain management
Authors: Magee David J. , Schutzer-Weissmann John , Pereira Erlick A.C. , Brown Matthew R.D.
Published: April 2021

Purpose of review

Advanced pain management techniques may be indicated in 5–15% of cancer patients. Despite this, a recent review identified that, over the course of 1 year in England, only 458 patients received a procedure intended to provide analgesia and only 30 patients had intrathecal drug delivery (ITDD) devices implanted. This article describes the emerging evidence for ITDD in cancer pain and provides a narrative review of other neuromodulatory techniques (including spinal cord stimulation, peripheral nerve stimulation and acupuncture), approaches that might be employed to address this area of significant unmet clinical need.

Recent findings

Numerous studies have been published within the last year reporting positive outcomes associated with ITDD in cancer pain management. Neuromodulation represents an important strategy in the management of persistent pain. Whilst the nonmalignant pain evidence-base is rapidly growing, it remains sparse for cancer pain management. The growing cohort of cancer survivors may significantly benefit from neuromodulatory techniques.

ITDD and other neuromodulatory techniques for cancer pain management appear underutilised in the UK and offer the prospect of better treatment for cancer patients with refractory pain or intolerable side-effects from systemic analgesics.
Clinical practice guidelines for cancer pain: problems and solutions
Authors: Farquhar-Smith Paul
Published: April 2021

Purpose of review

Clinical practice guidelines (CPGs) should allow practitioners to follow the best evidence-based management for patients. The increasing specialisation of medicine and pain medicine has increased the number of CPGs, but practitioners are still facing contradictory advice that can be difficult to implement and follow.

Recent findings

A recent comprehensive metareview of 25 reviews have highlighted that the same issues of quality, barriers to implementation and difficulties in applicability are as prevalent as they were years ago when assessment tools (e.g. AGREE II) and recommendations for CPG development were introduced. There remains a lack of consistency of recommendations and quality of evidence for CPGs in cancer pain that impedes the ability to provide the ‘best’ management for patients.

Even the most renowned and apparently high-quality CPGs in many specialities, including cancer pain, still are potentially deficient especially in terms of applicability, implementation, and transparency of conflicts of interest. Despite the increased scrutiny, in part related to the opioid crisis, the situation has not changed. The development of CPGs should engender collaboration with multiple stakeholder groups and focus on transparency and facilitating implementation.
Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine
Authors: Whittaker Dominic G. , Capel Rebecca A. , Hendrix Maurice , Chan Xin Hui S. , Herring Neil , White Nicholas J. , Mirams Gary R. , Burton Rebecca-Ann B.
Published: April 2021

Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-19. Here, we investigate through mathematical modelling the safety profile of HCQ, CQ and other QT-prolonging anti-infective agents to determine their risk categories for
Torsade de Pointes
(TdP) arrhythmia. We performed safety modelling with uncertainty quantification using a risk classifier based on the qNet
torsade metric score
, a measure of the net charge carried by major currents during the action potential under inhibition of multiple ion channels by a compound. Modelling results for HCQ at a maximum free therapeutic plasma concentration (free
C
max
) of approximately 1.2 µM (malaria dosing) indicated it is most likely to be in the high-intermediate-risk category for TdP, whereas CQ at a free
C
max
of approximately 0.7 µM was predicted to most likely lie in the intermediate-risk category. Combining HCQ with the antibacterial moxifloxacin or the anti-malarial halofantrine (HAL) increased the degree of human ventricular action potential duration prolongation at some or all concentrations investigated, and was predicted to increase risk compared to HCQ alone. The combination of HCQ/HAL was predicted to be the riskiest for the free
C
max
values investigated, whereas azithromycin administered individually was predicted to pose the lowest risk. Our simulation approach highlights that the torsadogenic potentials of HCQ, CQ and other QT-prolonging anti-infectives used in COVID-19 prevention and treatment increase with concentration and in combination with other QT-prolonging drugs.
Inactivation of avian influenza viruses by hydrostatic pressure as a potential vaccine development approach
Authors: Barroso Shana Priscila Coutinho , Vicente dos Santos Ana Clara , Souza dos Santos Patrícia , dos Santos Silva Couceiro José Nelson , Fernandes Ferreira Davis , Nico Dirlei , Morrot Alexandre , Lima Silva Jerson , Cheble de Oliveira Andrea
Published: April 2021

Vaccines are a recommended strategy for controlling influenza A infections in humans and animals. Here, we describe the effects of hydrostatic pressure on the structure, morphology and functional characteristics of avian influenza A H3N8 virus. The effect of hydrostatic pressure for 3 h on H3N8 virus revealed that the particles were resistant to this condition, and the virus displayed only a discrete conformational change. We found that pressure of 3 kbar applied for 6 h was able to inhibit haemagglutination and infectivity while virus replication was no longer observed, suggesting that full virus inactivation occurred at this point. However, the neuraminidase activity was not affected at this approach suggesting the maintenance of neutralizing antibody epitopes in this key antigen. Our data bring important information for the area of structural virology of enveloped particles and support the idea of applying pressure-induced inactivation as a tool for vaccine production.
Origin and evolution of nonulosonic acid synthases and their relationship with bacterial pathogenicity revealed by a large-scale phylogenetic analysis
Authors: Vieira Alexandre Zanatta , Raittz Roberto Tadeu , Faoro Helisson
Published: April 2021

Nonulosonic acids (NulOs) are a group of nine-carbon monosaccharides with different functions in nature. N-acetylneuraminic acid (Neu5Ac) is the most common NulO. It covers the membrane surface of all human cells and is a central molecule in the process of self-recognition via SIGLECS receptors. Some pathogenic bacteria escape the immune system by copying the sialylation of the host cell membrane. Neu5Ac production in these bacteria is catalysed by the enzyme NeuB. Some bacteria can also produce other NulOs named pseudaminic and legionaminic acids, through the NeuB homologues PseI and LegI, respectively. In Opisthokonta eukaryotes, the biosynthesis of Neu5Ac is catalysed by the enzyme NanS. In this study, we used publicly available data of sequences of NulOs synthases to investigate its distribution within the three domains of life and its relationship with pathogenic bacteria. We mined the KEGG database and found 425 NeuB sequences. Most NeuB sequences (58.74 %) from the KEGG orthology database were classified as from environmental bacteria; however, sequences from pathogenic bacteria showed higher conservation and prevalence of a specific domain named SAF. Using the HMM profile we identified 13 941 NulO synthase sequences in UniProt. Phylogenetic analysis of these sequences showed that the synthases were divided into three main groups that can be related to the lifestyle of these bacteria: (I) predominantly environmental, (II) intermediate and (III) predominantly pathogenic. NeuB was widely distributed in the groups. However, LegI and PseI were more concentrated in groups II and III, respectively. We also found that PseI appeared later in the evolutionary process, derived from NeuB. We use this same methodology to retrieve sialic acid synthase sequences from Archaea and Eukarya. A large-scale phylogenetic analysis showed that while the Archaea sequences are spread across the tree, the eukaryotic NanS sequences were grouped in a specific branch in group II. None of the bacterial NanS sequences grouped with the eukaryotic branch. The analysis of conserved residues showed that the synthases of Archaea and Eukarya present a mutation in one of the three catalytic residues, an E134D change, related to a

Neisseria meningitidis

reference sequence. We also found that the conservation profile is higher between NeuB of pathogenic bacteria and NanS of eukaryotes than between NeuB of environmental bacteria and NanS of eukaryotes. Our large-scale analysis brings new perspectives on the evolution of NulOs synthases, suggesting their presence in the last common universal ancestor.
A Machine Learning Perspective on Causes of Suicides and identification of Vulnerable Categories using Multiple Algorithms
Authors: Shreemali Jitendra , Chakrabarti Prasun , Chakrabarti Tulika , Poddar Sandeep , Sipple Daniel , Kateb Babak , Nami Mohammad
Published: April 2021

Background

Suicides represent a social tragedy with long term impact for the family. Given the growing incidence of suicides, a better understanding of factors causing it and addressing them has emerged as a social imperative.

Material and Methods

This study analyzed suicide data for three decades (1987-2016) and was carried out in two phases. Machine Learning Models run after pre-processing the suicide data included Neural network, Regression, Random Forest, XG Boost Tree, CHAID, Generalized Linear, Random Trees, Tree-AS and Auto Numeric Model.

Results and Conclusion

Analysis of findings suggested that the key predictors for suicide are Age, Gender, and Country. In the second phase, data from happiness reports were merged with suicide data to check if Country-specific factors impact the list or order of key predictors. While the key predictors remain the same, Country-specific factors like Generosity, Health and Trust impact the suicide rate in the Country.
Refining “long-COVID” by a prospective multimodal evaluation of patients with long-term symptoms related to SARS-CoV-2 infection
Authors: Scherlinger Marc , Felten Renaud , Gallais Floriane , Nazon Charlotte , Chatelus Emmanuel , Pijnenburg Luc , Mengin Amaury , Gras Adrien , Vidailhet Pierre , Arnould-Michel Rachel , Bibi-Triki Sabrina , Carapito Raphaël , Trouillet-Assant Sophie , Perret Magali , Belot Alexandre , Bahram Seiamak , Arnaud Laurent , Gottenberg Jacques-Eric , Fafi-Kremer Samira , Sibilia Jean
Published: April 2021

Background

COVID-19 long-haulers or “long-COVID” represent 10% of COVID-19 patients and remain understudied.

Methods

In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation including clinical, psychological, virological, specific immunological assays and were followed longitudinally.

Results

The median age was 40 [interquartile range: 35-54] and 18 (60%) were female. After a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported as compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients although the median fatigue and pain visual analogic scales were 7 [5-8] and 5 [2-6], respectively.

Extensive biological studies were unremarkable, as were multiplex cytokine and ultra-sensitive interferon-a2 measurements. At this time, nasopharyngeal swab and stool RT-PCR were negative for all tested patients. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with objective evidence of lack or waning of immune response in two. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively.

Conclusions

Half of patients seeking medical help for long-COVID lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity did not cluster clinically or biologically long haulers, who reported severe fatigue, altered quality of life, and exhibited psychological distress.

Key points

Among 30 consecutive patients reporting persistent symptoms (median 6 months) self-attributed to COVID-19, pain, fatigue and disability were reported in virtually all patients.

More than one third of patients suffer from psychological disorders such as anxiety, depression and/or post-traumatic stress disorder, regardless of SARS-CoV-2 immunity.

At the time of evaluation, only 50% of patients had cellular and/or humoral sign of a past SARS-CoV-2, and serology positivity varied depending of the kit used.

Exhaustive clinical, biological and immunological evaluations failed to find an alternative diagnosis, or to identify specific cytokine signature including type I interferon.
Long-Term Acceptability of Hygiene, Face Covering, and Social Distancing Interventions to Prevent Exacerbations in people living with Airways Diseases
Authors: Hurst John R , Cumella Andrew , Niklewicz Camila Nagoda , Philip Keir EJ , Singh Victoria , Hopkinson Nicholas S
Published: April 2021

Introduction

There has been a substantial reduction in admissions to hospital with exacerbations of airways diseases during the COVID-19 pandemic, likely because measures introduced to prevent the spread of SARS-CoV-2 also reduced transmission of other respiratory viruses. The acceptability to patients of continuing such interventions beyond the pandemic as a measure to prevent exacerbations is not known.

Method

An online survey of people living with respiratory disease was created by the Asthma UK – British Lung Foundation Partnership. People were asked what infection control measures they expected to continue themselves, and what they thought should be policy for the population more generally in the future, once the COVID-19 pandemic had subsided.

Results

4442 people completed the survey: 3627 with asthma, 258 with bronchiectasis and 557 with COPD. Regarding personal behaviour, 79.5% would continue increased handwashing, 68.6% social distancing indoors, 46.9% would continue to wear a face covering in indoor public places (45.7% on public transport), and 59.3% would avoid friends and family who were unwell with a respiratory infection. 45.6% wanted healthcare professionals to continue wearing a mask when seeing patients. 60.7% thought that face coverings should continue to be worn by everyone in indoor public spaces during the ‘flu season. Women and older people were, in general, more cautious.

Conclusion

People living with airways diseases are supportive of infection control measures to reduce the risk of exacerbations and such measures should be considered for inclusion in guidelines. Further research to refine understanding of the most effective approaches is needed.
Case fatality rates for COVID-19 are higher than case fatality rates for motor vehicle accidents for individuals over 40 years of age
Authors: Puranik Arjun , Niesen Michiel J.M. , Lindemer Emily , Lenehan Patrick , Cristea-Platon Tudor , Pawlowski Colin , Soundararajan Venky
Published: April 2021

The death toll of the COVID-19 pandemic has been unprecedented, due to both the high number of SARS-CoV-2 infections and the seriousness of the disease resulting from these infections. Here, we present mortality rates and case fatality rates for COVID-19 over the past year compared with other historic leading causes of death in the United States. Among the risk categories considered, COVID-19 is the third leading cause of death for individuals 40 years old and over, with an overall annual mortality rate of 325 deaths per 100K individuals, behind only cancer (385 deaths per 100K individuals) and heart disease (412 deaths per 100K individuals). In addition, for individuals 40 years old and over, the case fatality rate for COVID-19 is greater than the case fatality rate for motor vehicle accidents. In particular, for the age group 40-49, the relative case fatality rate of COVID-19 is 1.5 fold (95% CI: [1.3, 1.7]) that of a motor vehicle accident, demonstrating that SARS-CoV-2 infection may be significantly more dangerous than a car crash for this age group. For older adults, COVID-19 is even more dangerous, and the relative case fatality rate of COVID-19 is 29.4 fold (95% CI: [23.2, 35.7]) that of a motor vehicle accident for individuals over 80 years old. On the other hand, motor vehicle accidents have a 4.5 fold (95% CI: [3.9, 5.1]) greater relative case fatality rate compared to COVID-19 for the age group of 20-29 years. These results highlight the severity of the COVID-19 pandemic especially for adults above 40 years of age and underscore the need for large-scale preventative measures to mitigate risks for these populations. Given that FDA-authorized COVID-19 vaccines have now been validated by multiple studies for their outstanding real-world effectiveness and safety, vaccination of all individuals who are over 40 years of age is one of the most pressing public health priorities of our time.
Post-acute COVID-19 sequelae in cases managed in the community or hospital in the UK: a population based study
Authors: Whittaker Hannah R , Gulea Claudia , Koteci Ardita , Kallis Constantinos , Morgan Ann D , Iwundu Chukwuma , Weeks Mark , Gupta Rikisha , Quint Jennifer K
Published: April 2021

Objective

To compare post-COVID-19 sequelae between hospitalised and non-hospitalised individuals

Design

Population-based cohort study

Setting

1,383 general practices in England contributing to Clinical Practice Research Database Aurum

Participants

46,687 COVID-19 cases diagnosed between 1st August to 17th October 2020 (45.4% male; mean age 40), either hospitalised within two weeks of diagnosis or non-hospitalised, and followed-up for a maximum of three months.

Main outcome measures

Event rates of new symptoms, diseases, prescriptions and healthcare utilisation in hospitalised and non-hospitalised individuals, with between-group comparison using Cox regression. Outcomes compared at 6 and 12 months prior to index date, equating to first UK wave and pre-pandemic. Non-hospitalised group outcomes stratified by age and sex.

Results

45,272 of 46,687 people were non-hospitalised; 1,415 hospitalised. Hospitalised patients had higher rates of 13/26 symptoms and 11/19 diseases post-COVID-19 than the community group, received more prescriptions and utilised more healthcare. The largest differences were noted for rates per 100,000 person-weeks [95%CI] of breathlessness: 536 [432 to 663] v. 85 [77 to 93]; joint pain: 295 [221 to 392] v. 168 [158 to 179]; diabetes: 303 [225 to 416] v. 36 [32 to 42], hypertension: 244 [178 to 344] v. 47 [41 to 53]. Although low, rates of chest tightness, tinnitus and lung fibrosis were higher in the community group. 4.2% (1882/45,272) of the community group had a post-acute burden, most frequently reporting anxiety, breathlessness, chest pain and fatigue. In those non-hospitalised, age and sex differences existed in outcome rates. Healthcare utilisation in the community group increased 28.5% post-COVID-19 relative to pre-pandemic.

Conclusions

Post-COVID-19 sequelae differ between hospitalised and non-hospitalised individuals, with age and sex-specific differences in those non-hospitalised. Most COVID-19 cases managed in the community do not report ongoing issues to healthcare professionals. Post-COVID-19 follow-up and management strategies need to be tailored to specific groups.
Can a second booster dose be delayed in patients who have had COVID-19?
Authors: Taubel Jorg , Spencer Christopher S , Freier Anne , Camilleri Dorothée , Garitaonandia Ibon , Lorch Ulrike
Published: April 2021

Vaccination forms a key part of public health strategies to control the spread of SARS-CoV-2 globally. In the UK, two vaccines (BNT162b2-mRNA produced by Pfizer, and ChAdOx-1-S produced by Oxford-AstraZeneca) have been licensed to date, and their administration is prioritised according to individual risk. This study forms part of a longitudinal assessment of participants ‘SARS-CoV-2-specific antibody levels before and after vaccination. Our results confirm that there is little quantitative difference in the antibody titres achieved by the two vaccines. Our results also suggest that individuals who have previously been infected with SARS-CoV-2 achieve markedly higher antibody titres than those who are immunologically naïve. This finding is useful to inform vaccine prioritisation strategies in the future: individuals with no history of SARS-CoV-2 infection should be prioritised for a second vaccine inoculation.
The Balancing Role of Distribution Speed against Varying Efficacy Levels of COVID-19 Vaccines under Variants
Authors: Kim Daniel , Keskinocak Pınar , Pekgün Pelin , Yildirim Inci
Published: April 2021

Mutations in SARS-CoV-2 raised concerns about diminishing vaccine effectiveness against COVID-19 caused by particular variants. Even with high initial efficacy, if a vaccine’s efficacy drops significantly against variants, or if it cannot be distributed quickly, it is uncertain whether the vaccine can provide better health outcomes than other vaccines. Hence, we evaluated the trade-offs between the speed of distribution vs. efficacy against infection of multiple vaccines when variants emerge by utilizing a Susceptible-Infected-Recovered-Deceased (SIR-D) model and assessing the level of infection attack rate (IAR). Our results show that speed is a key factor to a successful immunization strategy to control the COVID-19 pandemic even when the emerging variants may reduce the efficacy of a vaccine. Due to supply-chain challenges, the accessibility and distribution of the vaccines have been hindered in many regions, especially in low-income countries, while the second or third wave of the pandemic has occurred due to the variants. Understanding the tradeoffs between speed and efficacy and distributing vaccines that are available as quickly as possible are crucial to eradicate the pandemic before new variants spread.
Metabolic Preference Assay for Rapid Diagnosis of Bloodstream Infections
Authors: Rydzak Thomas , Groves Ryan A. , Zhang Ruichuan , Pushpker Rajnigandha , Mapar Maryam , Lewis Ian A.
Published: April 2021

Bloodstream infections (BSIs) cause >500,000 infections and >80,000 deaths per year in North America. The length of time between the onset of symptoms and administration of appropriate antimicrobials is directly linked to mortality rates. It currently takes 2-5 days to identify BSI pathogens and measure their susceptibility to antimicrobials – a timeline that directly contributes to preventable deaths. To address this, we developed a rapid metabolic preference assay (MPA) that uses the pattern of metabolic fluxes observed in ex-vivo microbial cultures to identify common pathogens and determine their antimicrobial susceptibility profiles. In a head-to-head race with a leading platform (VITEK 2) used in diagnostic laboratories, MPA decreased testing timelines from 40 hours to under 20. If put into practice, this assay could reduce septic shock mortality and reduce the use of broad spectrum antibiotics.

One Sentence Summary

Metabolomics enables rapid diagnosis of BSIs.
Differences in Declines in Pediatric ED Utilization During the Covid19 Pandemic by Socioeconomic Disadvantage
Authors: Sen Bisakha , Brisendine Anne , Ghosh Pallavi
Published: April 2021

Background

There is growing evidence that the early months of the COVID19 pandemic saw substantial declines in pediatric Emergency Department (ED) utilization in the U.S. However, less is known about whether utilization changed differentially for children who are socio-economically disadvantaged. We examined how changes pediatric ED visits during the early months of the COVID19 pandemic differed by two markers of socio-economic disadvantage, minoritized race and being publicly insured.

Methods

This retrospective observational study used electronic medical records from a large pediatric ED in a Deep South state for January-June 2020. Three time-periods ╌ pre-COVID19 (TP0), COVID19 with restrictions like stay-at-home (TP1), and COVID19 with restrictions relaxed (TP2) in 2020 were compared with the corresponding time-periods in 2019. Changes in overall visits, visits for minoritized race (MR) versus non-Hispanic white (NHW) children, and Medicaid-enrolled versus privately-insured children were considered, and changes in acuity-mix of ED visits and share of visits resulting in inpatient admits were inspected.

Results

Compared to 2019, total ED visits declined in TP1 and TP2 of 2020 (54.3%, 48.9%). Declines were larger for MR children (57.3%, 57.8%) compared to NHW children (50.5%, 39.3%), and Medicaid enrollees (56.5%, 52.0%) compared to the privately insured (48.3%, 39.0%). Particularly, MR children saw steeper percentage declines in high-acuity visits and visits resulting in inpatient admissions compared to NHW children. The mix of pediatric patients by race and insurance-status, as well as the share of high-acuity visits and visits with inpatient admissions differed between TP1 and TP2 of 2019 and 2020 (p<0.05 for all cases). In contrast, there was little evidence of difference between TP0 of 2019 and 2020.

Conclusion

The role of socioeconomic disadvantage and the potential impacts on pediatric ED visits during COVID19 in the Deep South of the United States changes is understudied. We find evidence of steeper declines in visits among MR and Medicaid-enrolled children, including for high-acuity conditions, than their NHW and privately-insured counterparts. Since disadvantaged children sometimes lack access to a usual source of care, this raises concerns about unmet health needs, and worsening health disparities, in a region that already has poor health indicators.
Drug Sensitivity Prediction From Cell Line-Based Pharmacogenomics Data: Guidelines for Developing Machine Learning Models
Authors: Sharifi-Noghabi Hossein , Jahangiri-Tazehkand Soheil , Smirnov Petr , Hon Casey , Mammoliti Anthony , Nair Sisira Kadambat , Mer Arvind Singh , Ester Martin , Haibe-Kains Benjamin
Published: April 2021

The goal of precision oncology is to tailor treatment for patients individually using the genomic profile of their tumors. Pharmacogenomics datasets such as cancer cell lines are among the most valuable resources for drug sensitivity prediction, a crucial task of precision oncology. Machine learning methods have been employed to predict drug sensitivity based on the multiple omics data available for large panels of cancer cell lines. However, there are no comprehensive guidelines on how to properly train and validate such machine learning models for drug sensitivity prediction. In this paper, we introduce a set of guidelines for different aspects of training gene expression-based predictors using cell line datasets. These guidelines provide extensive analysis of the generalization of drug sensitivity predictors, and challenge many current practices in the community including the choice of training dataset and measure of drug sensitivity. Application of these guidelines in future studies will enable the development of more robust preclinical biomarkers.