Publications by authors named "Stephen Ward"

371 Publications

Chronic Low Back Pain Occurring in Association With Hypermobility Spectrum Disorder and Ehlers-Danlos Syndrome.

Int J Spine Surg 2021 May 7. Epub 2021 May 7.

Guy's and St Thomas' Hospitals, London, England.

Background: This review paper outlines recent advances in diagnostic criteria for hypermobility spectrum disorder (HSD) and its association with Ehlers-Danlos syndrome (EDS), as well as current literature on the association between joint hypermobility syndrome and lumbar back pain. We outline the optimal multidisciplinary management of lumbar back pain in the context of joint hypermobility syndrome, as well as the indications and possible side effects of surgical management of patients with these conditions.Several studies have suggested a link between chronic low back pain and hypermobility. HSD has been described as an excessive range of motion in a joint, when accounting for patient demographics. The nomenclature surrounding symptomatic joint hypermobility has varied historically, and various groups, including most notably the international EDS consortium, have introduced new classification schemes to acknowledge the systemic effects of joint hypermobility, which were previously poorly understood.

Methods: Narrative literature review.

Results: Not applicable.

Conclusions: Lower back pain experienced in patients on the HSD-EDS spectrum is multifactorial in origin and should not be considered solely in anatomical terms. Caution has been advised in the surgical management of patients on the HSD-hEDS spectrum, particularly where the subtype is unclear. The vascular type of EDS has a particular propensity for severe bleeding complications. Rates of perioperative complications after lumbar spinal surgery in the hypermobile EDS population have been reported to be up to 50%. When hypermobility and chronic lumbar back pain coexist, we advocate management in a multidisciplinary setting involving physiotherapists, pain physicians, surgeons, and psychologists.
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http://dx.doi.org/10.14444/8067DOI Listing
May 2021

EpCam is Required for Maintaining the Integrity of the Biliary Epithelium.

Liver Int 2021 Mar 31. Epub 2021 Mar 31.

Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, USA.

Background & Aims: Tufting enteropathy (TE) is a rare congenital disorder often caused by mutations in the gene encoding epithelial cell adhesion molecule (EpCam). The disease leads to diarrhea, intestinal failure and dependence on total parenteral nutrition (TPN). These patients often have liver impairments, but the pathology and mechanism of the damage are not well understood. We evaluated liver biopsies from TE patients to understand the pathophysiology.

Methods: We identified three patients with TE who underwent liver biopsy. Two normal controls and 45 patients on TPN secondary to short gut syndrome were selected for comparison (5 were age- and TPN duration-matched to the TE patients).

Results: We found that all TE patients showed a complete loss of EpCam expression in enterocytes and biliary epithelial cells, while the normal and TPN groups show basolateral expression. Histologically TE patients showed ductopenia, which was not seen in control groups. E-cadherin and β-catenin are normally located along the lateral membrane of biliary epithelial cells. However, they were relocated to the apical membrane in TE patients, indicating a defect in the apical-basal polarity of cholangiocytes. We examined hepatic reparative cells and found near absence of hepatic progenitor cells and intermediate hepatobiliary cells with mild reactive ductular cells in TE patients.

Conclusion: Our findings show that TE is associated with disrupted polarity of cholangiocyte and ductopenia. We demonstrate for the first time a role of EpCam in the maintenance of integrity of biliary epithelium. We also provided evidence for a disrupted development of hepatic reparative cells.
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http://dx.doi.org/10.1111/liv.14891DOI Listing
March 2021

Quantification of biomarker functionality predicts patient outcomes.

Br J Cancer 2021 May 15;124(10):1618-1620. Epub 2021 Mar 15.

Protein Phosphorylation Laboratory, The Francis Crick Institute, London, UK.

Implementation of a quantitative molecular imaging method (iFRET), which determines receptor-ligand interactions, has led to the finding that patients with a low extent of PD-1/PD-L1 interaction in metastatic NSCLC, and malignant melanoma, display significantly worsened overall survival compared to those with a high level of interaction.
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http://dx.doi.org/10.1038/s41416-021-01291-3DOI Listing
May 2021

Clinical-grade whole-genome sequencing and 3' transcriptome analysis of colorectal cancer patients.

Genome Med 2021 Feb 25;13(1):33. Epub 2021 Feb 25.

Institute of Cancer and Genomic Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3' transcriptome analysis would give new insights into colorectal cancer.

Methods: Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3' RNA-seq.

Results: Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy.

Conclusions: Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.
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http://dx.doi.org/10.1186/s13073-021-00852-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908713PMC
February 2021

Gastric and small bowel perforations secondary to mucormycosis and graft versus host disease in an allogeneic transplant host.

Hematol Transfus Cell Ther 2020 Dec 11. Epub 2020 Dec 11.

The Mount Sinai Hospital, New York, NY, United States.

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http://dx.doi.org/10.1016/j.htct.2020.10.962DOI Listing
December 2020

Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2?

ACS Infect Dis 2020 Dec 22. Epub 2020 Dec 22.

Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.

The rapidly growing COVID-19 pandemic is the most serious global health crisis since the "Spanish flu" of 1918. There is currently no proven effective drug treatment or prophylaxis for this coronavirus infection. While developing safe and effective vaccines is one of the key focuses, a number of existing antiviral drugs are being evaluated for their potency and efficiency against SARS-CoV-2 and in the clinic. Here, we review the significant potential of nitazoxanide (NTZ) as an antiviral agent that can be repurposed as a treatment for COVID-19. Originally, NTZ was developed as an antiparasitic agent especially against spp.; it was later shown to possess potent activity against a broad range of both RNA and DNA viruses, including influenza A, hepatitis B and C, and coronaviruses. Recent assessment of NTZ has confirmed its promising activity against SARS-CoV-2 with an EC of 2.12 μM. Here we examine its drug properties, antiviral activity against different viruses, clinical trials outcomes, and mechanisms of antiviral action from the literature in order to highlight the therapeutic potential for the treatment of COVID-19. Furthermore, in preliminary PK/PD analyses using clinical data reported in the literature, comparison of simulated TIZ (active metabolite of NTZ) exposures at two doses with the potency of NTZ against SARS-CoV-2 gives further support for drug repurposing with potential in combination chemotherapy approaches. The review concludes with details of second generation thiazolides under development that could lead to improved antiviral therapies for future indications.
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http://dx.doi.org/10.1021/acsinfecdis.0c00478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771247PMC
December 2020

High-frequency Ultrasound Assessment of Systemic Sclerosis Skin Involvement: Intraobserver Repeatability and Relationship With Clinician Assessment and Dermal Collagen Content.

J Rheumatol 2020 Nov 1. Epub 2020 Nov 1.

This work was supported by Scleroderma & Raynaud's UK. V.A. Flower, Consultant Rheumatologist, MBBS, PhD, J.D. Pauling, Consultant Rheumatologist and Senior Lecturer, BMBS, PhD, Department of Rheumatology, Royal National Hospital for Rheumatic Diseases, Royal United Hospitals NHS Foundation Trust, Bath, Department of Pharmacy and Pharmacology, University of Bath, Bath; S.L. Barratt, BMBS, PhD, Department of Respiratory Medicine, North Bristol NHS Trust, Bristol, Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol; D.J. Hart, Clinical Scientist, PhD, J.A. Shipley, Clinical Scientist, PhD, Clinical Measurement and Imaging Department, Royal National Hospital for Rheumatic Diseases, Royal United Hospitals NHS Foundation Trust, Bath; A.B. Mackenzie, Senior Lecturer, PhD, Department of Pharmacy and Pharmacology, University of Bath, Bath; S.G. Ward, Professor, PhD, Centre for Therapeutic Innovation & Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. JDP has received speaker's honoraria and research grant support (> $10,000) from Actelion Pharmaceuticals and has undertaken consultancy work for Actelion Pharmaceuticals and Boehringer Ingelheim. SLB has received educational support and has undertaken consultancy work for Boehringer Ingelheim. ABM has received funding from UCB, Janssen, and Pfizer; and holds shares in Ikusda Therapeutics. SGW has received funding from UCB, Pfizer, Novartis, GSK, and Boehringer Ingelheim. VAF, DJH, and JAS have no conflicts of interests. Address correspondence to Dr. V.A. Flower, The Royal National Hospital for Rheumatic Diseases, Royal United Hospitals NHS Foundation Trust, Combe Park, Bath, BA1 3NG, UK. Email: Accepted for publication October 16, 2020.

Objective: The modified Rodnan skin score (mRSS) remains the preferred method for skin assessment in systemic sclerosis (SSc). There are concerns regarding high interobserver variability of mRSS and negative clinical trials utilizing mRSS as the primary endpoint. High-frequency ultrasound (HFUS) allows objective assessment of cutaneous fibrosis in SSc. We investigated the relationship between HFUS with both mRSS and dermal collagen.

Methods: Skin thickness (ST), echogenicity, and novel shear wave elastography (SWE) were assessed in 53 patients with SSc and 15 healthy controls (HCs) at the finger, hand, forearm, and abdomen. The relationship between HFUS parameters with mRSS (n = 53) and dermal collagen (10 patients with SSc and 10 HCs) was investigated. Intraobserver repeatability of HFUS was calculated using intraclass correlation coefficients (ICCs).

Results: HFUS assessment of ST (hand/forearm) and SWE (finger/hand) correlated with local mRSS at some sites. Subclinical abnormalities in ST, echogenicity, and SWE were present in clinically uninvolved SSc skin. Additionally, changes in echogenicity and SWE were sometimes apparent despite objectively normal ST on HFUS. ST, SWE, and local mRSS correlated strongly with collagen quantification (r = 0.697, 0.709, 0.649, respectively). Intraobserver repeatability was high for all HFUS parameters (ICCs for ST = 0.946- 0.978; echogenicity = 0.648-0.865; and SWE = 0.953-0.973).

Conclusion: Our data demonstrate excellent reproducibility and reassuring convergent validity with dermal collagen content. Detection of subclinical abnormalities is an additional benefit of HFUS. The observed correlations with collagen quantification support further investigation of HFUS as an alternative to mRSS in clinical trial settings.
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http://dx.doi.org/10.3899/jrheum.200234DOI Listing
November 2020

Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection.

Cell Mol Gastroenterol Hepatol 2021 28;11(3):763-770. Epub 2020 Sep 28.

Division of Liver Diseases and Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Background & Aims: Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.

Methods: The current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.

Results: The liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.

Conclusions: On the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.
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http://dx.doi.org/10.1016/j.jcmgh.2020.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521427PMC
March 2021

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy.

Mod Pathol 2021 04 28;34(4):823-833. Epub 2020 Sep 28.

Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.
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http://dx.doi.org/10.1038/s41379-020-00679-5DOI Listing
April 2021

Rapid upscale of depot buprenorphine (CAM2038) in custodial settings during the early COVID-19 pandemic in New South Wales, Australia.

Addiction 2021 02 21;116(2):426-427. Epub 2020 Sep 21.

Hunter New England Local Health District, Newcastle, NSW, Australia.

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http://dx.doi.org/10.1111/add.15244DOI Listing
February 2021

High PD-1/PD-L1 Checkpoint Interaction Infers Tumor Selection and Therapeutic Sensitivity to Anti-PD-1/PD-L1 Treatment.

Cancer Res 2020 10 27;80(19):4244-4257. Epub 2020 Aug 27.

FASTBASE Solutions S.L, Astondo bidea, Derio, Spain.

Many cancers are termed immunoevasive due to expression of immunomodulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), respectively, on tumor-infiltrating leukocytes eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionizing cancer treatments, albeit in an inadequately described patient subset. To address the issue of patient stratification for immune checkpoint intervention, we quantitatively imaged PD-1/PD-L1 interactions in tumor samples from patients, employing an assay that readily detects these intercellular protein-protein interactions in the less than or equal to 10 nm range. These analyses across multiple patient cohorts demonstrated the intercancer, interpatient, and intratumoral heterogeneity of interacting immune checkpoints. The PD-1/PD-L1 interaction was not correlated with clinical PD-L1 expression scores in malignant melanoma. Crucially, among anti-PD-1-treated patients with metastatic non-small cell lung cancer, those with lower PD-1/PD-L1 interaction had significantly worsened survival. It is surmised that within tumors selecting for an elevated level of PD-1/PD-L1 interaction, there is a greater dependence on this pathway for immune evasion and hence, they exhibit more impressive patient response to intervention. SIGNIFICANCE: Quantitation of immune checkpoint interaction by direct imaging demonstrates that immunotherapy-treated patients with metastatic NSCLC with a low extent of PD-1/PD-L1 interaction show significantly worse outcome.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1117DOI Listing
October 2020

Explant rates of electrical neuromodulation devices in 1177 patients in a single center over an 11-year period.

Reg Anesth Pain Med 2020 Nov 26;45(11):883-890. Epub 2020 Aug 26.

Pain Department, Guy's and Saint Thomas' Hospitals NHS Trust, London, UK.

Introduction: The publication of explant rates has established risk factors and a definitive objective outcome of failure for spinal cord stimulation (SCS) treating neuropathic pain. We present a UK study analyzing explants of electrical neuromodulation devices for different conditions over 11 years in a single center specializing in neuromodulation.

Methods: A retrospective analysis was performed using a departmental database between 2008 and 2019. Explants were analyzed according to condition, mode of stimulation and other demographics using logistic regression and Kaplan-Meier graphs with log-rank (Mantel-Cox) test.

Results: Out of a total of 1177 patients, the explant rate was 17.8% at 5 years and 25.2% at 10 years. Loss of efficacy was the most frequent reason for explant 119/181 (65%). Multivariant regression analysis indicated patients with back pain without prior surgery had a reduced risk of explant (p=0.03). Patients with SCS systems that had 10 kHz, options of multiple waveforms, and rechargeable batteries also had a decreased risk of explant (p<0.001). None of these findings were confirmed when comparing Kaplan-Meier graphs, however. Contrary to other studies, we found gender and age were not independent variables for explant.

Conclusion: These data contribute to a growing list of explant data in the scientific literature and give indications of what factors contribute to long-term utilization of electrical neuromodulation devices.
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http://dx.doi.org/10.1136/rapm-2020-101681DOI Listing
November 2020

Feasibility and acceptability of take-home naloxone for people released from prison in New South Wales, Australia.

Drug Alcohol Rev 2021 Jan 17;40(1):98-108. Epub 2020 Aug 17.

National Drug and Alcohol Research Centre, UNSW Sydney, Sydney, Australia.

Introduction And Aims: To assess the feasibility and acceptability of a take-home naloxone program for people with a history of opioid use released from prison in New South Wales, Australia.

Design And Methods: Cross-sectional interviews with people with a history of opioid use who were recently released from prison (n = 105), and semi-structured interviews with key clinical and operational staff of Justice Health and Forensic Mental Health Network and Corrective Services NSW (n = 9).

Results: Among people with a history of opioid use who had recently left prison, there was very high awareness of the elevated risk of overdose following release from prison (95%) and the potential for naloxone to reverse an opioid overdose (97%). Participants considered that their personal risk of overdose was low, despite ongoing opioid use being common. Participants were largely supportive of take-home naloxone, but the majority (83%) stated that proactively obtaining naloxone would be a low priority for them following release. Key informants were supportive of introducing naloxone training and supply and identified barriers to implementation, including adequate resourcing, identifying the population for training, and developing an appropriate model of training and implementation.

Discussion And Conclusion: There was widespread support for naloxone training in custody and distribution at release among people recently released from prison and key stakeholders in health-care provision and prisons administration. As proactively accessing naloxone is a low priority for patients, naloxone supply at release may be more effective than programs that refer releasees to local pharmacies, but developing a sustainable supply model requires consideration of several barriers.
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http://dx.doi.org/10.1111/dar.13144DOI Listing
January 2021

Evaluating Relationships Between Sleep and Next-Day Physical Activity in Young Women.

J Phys Act Health 2020 Aug 12:1-7. Epub 2020 Aug 12.

Background: To evaluate the relationship between sleep and next-day physical activity (PA) under free-living conditions in women.

Methods: Sleep and PA were measured objectively for 7 consecutive days by accelerometry in 330 young adult women (aged 17-25 y). A structural equation model was used to evaluate the relationship between the driving factor of sleep (total sleep or morning wake time) and the amount of nonsleep sedentary (SED) and moderate to vigorous physical activity (MVPA) each day.

Results: With sleep duration as the driving factor, the estimates of βSED and βMVPA were -0.415 and -0.093, respectively (P ≤ .05). For every hour slept, a 24.9-minute reduction in SED time and a 5.58-minute reduction in MVPA were observed. With wake time as the driving factor, the estimates of βSED and βMVPA were -0.636 and -0.149, respectively. For every wake time that was 1 hour later, a 38.2-minute decrease in SED and a 8.9-minute decrease in MVPA (P ≤ .05) were observed.

Conclusions: Women who wake later or who sleep longer tend to get less MVPA throughout the day. Getting up earlier and going to bed earlier may support behaviors that improve PA and lifestyle.
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http://dx.doi.org/10.1123/jpah.2020-0014DOI Listing
August 2020

, Human T-cell Lymphotropic Virus Type-1 and Coinfection in an Allogeneic Hematopoietic Stem-Cell Transplant Recipient.

Transplant Direct 2020 Jul 23;6(7):e573. Epub 2020 Jun 23.

Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

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http://dx.doi.org/10.1097/TXD.0000000000001021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339139PMC
July 2020

Steatohepatitic Variant of Hepatocellular Carcinoma Is Associated With Both Alcoholic Steatohepatitis and Nonalcoholic Steatohepatitis: A Study of 2 Cohorts With Molecular Insights.

Am J Surg Pathol 2020 10;44(10):1406-1412

The Department of Pathology, Molecular, and Cell-Based Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a variant of hepatocellular carcinoma (HCC) with established association with nonalcoholic steatohepatitis (NASH), while its association with alcoholic steatohepatitis (ASH) is unclear. We studied 2 cohorts of patients who underwent resection for HCC in the setting of steatohepatitis. In our Mount Sinai (New York) cohort, we found SH-HCC in 17/24 (71%) patients with NASH and in 14/19 (74%) patients with ASH, while SH-HCC was the predominant tumor morphology in 12/24 (50%) in the NASH group and 9/19 (47%) in the ASH group. Upon review, 12/19 patients diagnosed with ASH also had diabetes and/or a body mass index >30. When these patients were removed, we still found similar rates of SH-HCC (6/7 [86%] showed SH-HCC, while SH-HCC was predominant in 3/7 [43%]. Interestingly, glycogenated hepatocyte nuclei were seen in the nontumor liver in 4/7 (57%) of these cases. In our Japan cohort, we also found similar rates of SH-HCC in NASH and ASH patients with HCC, 15/58 (26%), and 16/45 (36%), respectively. We determined molecular subclassification of tumors from the Japan cohort and found no difference in the distribution of S1, S2 and S3 subclasses among the ASH and NASH groups, though, among cases of SH-HCC, there was a trend toward an association of ASH with S1 (P=0.054) and NASH with S3 (P=0.052). Our study shows that SH-HCC is common in both ASH and NASH and that both underlying liver diseases produce tumors with similar molecular profiles, though different pathways may underlie the development of SH-HCC in ASH versus NASH.
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http://dx.doi.org/10.1097/PAS.0000000000001533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942811PMC
October 2020

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

medRxiv 2020 May 6. Epub 2020 May 6.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organisation and urgent treatment and prevention strategies are needed. Many clinical trials have been initiated with existing medications, but assessments of the expected plasma and lung exposures at the selected doses have not featured in the prioritisation process. Although no antiviral data is currently available for the major phenolic circulating metabolite of nitazoxanide (known as tizoxanide), the parent ester drug has been shown to exhibit activity against SARS-CoV-2. Nitazoxanide is an anthelmintic drug and its metabolite tizoxanide has been described to have broad antiviral activity against influenza and other coronaviruses. The present study used physiologically-based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported nitazoxanide 90% effective concentration (EC ) against SARS-CoV-2.

Methods: A whole-body PBPK model was constructed for oral administration of nitazoxanide and validated against available tizoxanide pharmacokinetic data for healthy individuals receiving single doses between 500 mg SARS-CoV-2 4000 mg with and without food. Additional validation against multiple-dose pharmacokinetic data when given with food was conducted. The validated model was then used to predict alternative doses expected to maintain tizoxanide plasma and lung concentrations over the reported nitazoxanide EC in >90% of the simulated population. Optimal design software PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.

Results: The PBPK model was validated with AAFE values between 1.01 SARS-CoV-2 1.58 and a difference less than 2-fold between observed and simulated values for all the reported clinical doses. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food, to provide tizoxanide plasma and lung concentrations over the reported EC of nitazoxanide against SARS-CoV-2. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated.

Conclusion: The PBPK model predicted that it was possible to achieve plasma and lung tizoxanide concentrations, using proven safe doses of nitazoxanide, that exceed the EC for SARS-CoV-2. The PBPK model describing tizoxanide plasma pharmacokinetics after oral administration of nitazoxanide was successfully validated against clinical data. This dose prediction assumes that the tizoxanide metabolite has activity against SARS-CoV-2 similar to that reported for nitazoxanide, as has been reported for other viruses. The model and the reported dosing strategies provide a rational basis for the design (optimising plasma and lung exposures) of future clinical trials of nitazoxanide in the treatment or prevention of SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.05.01.20087130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274229PMC
May 2020

Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.

Clin Pharmacol Ther 2020 10 14;108(4):775-790. Epub 2020 Jun 14.

Department of Molecular and Clinical Pharmacology, Materials Innovation Factory, University of Liverpool, Liverpool, UK.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (C ) at an approved dose in humans (C /EC ratio). Only 14 of the 56 analyzed drugs achieved a C /EC ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (K U ) was also simulated to derive a lung C /half-maximal effective concentration (EC ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC . Nitazoxanide and sulfadoxine also exceeded their reported EC by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.
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http://dx.doi.org/10.1002/cpt.1909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280633PMC
October 2020

M1 macrophage features in severe Plasmodium falciparum malaria patients with pulmonary oedema.

Malar J 2020 May 15;19(1):182. Epub 2020 May 15.

Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.

Background: Pulmonary oedema (PE) is a serious complication of Plasmodium falciparum malaria which can lead to acute lung injury in severe cases. Lung macrophages are activated during malaria infection due to a complex host-immune response. The molecular basis for macrophage polarization is still unclear but understanding the predominant subtypes could lead to new therapeutic strategies where the diseases present with lung involvement. The present study was designed to study the polarization of lung macrophages, as M1 or M2 macrophages, in the lungs of severe P. falciparum malaria patients, with and without evidence of PE.

Methods: Lung tissue samples, taken from patients who died from severe P. falciparum malaria, were categorized into severe malaria with PE and without PE (non-PE). Expression of surface markers (CD68+, all macrophages; CD40+, M1 macrophage; and CD163+, M2 macrophage) on activated lung macrophages was used to quantify M1/M2 macrophage subtypes.

Results: Lung injury was demonstrated in malaria patients with PE. The expression of CD40 (M1 macrophage) was prominent in the group of severe P. falciparum malaria patients with PE (63.44 ± 1.98%), compared to non-PE group (53.22 ± 3.85%, p < 0.05), whereas there was no difference observed for CD163 (M2 macrophage) between PE and non-PE groups.

Conclusions: The study demonstrates M1 polarization in lung tissues from severe P. falciparum malaria infections with PE. Understanding the nature of macrophage characterization in malaria infection may provide new insights into therapeutic approaches that could be deployed to reduce lung damage in severe P. falciparum malaria.
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http://dx.doi.org/10.1186/s12936-020-03254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226720PMC
May 2020

Human Papillomavirus (HPV69/HPV73) Coinfection associated with Simultaneous Squamous Cell Carcinoma of the Anus and Presumed Lung Metastasis.

Viruses 2020 03 22;12(3). Epub 2020 Mar 22.

Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Background: Human papillomaviruses (HPVs) have been linked to a variety of human cancers. As the landscape of HPV-related neoplasia continues to expand, uncommon and rare HPV genotypes have also started to emerge. Host-virus interplay is recognized as a key driver in HPV carcinogenesis, with host immune status, virus genetic variants and coinfection highly influencing the dynamics of malignant transformation. Immunosuppression and tissue tropism are also known to influence HPV pathogenesis.

Methods: Herein, we present a case of a patient who, in the setting of HIV positivity, developed anal squamous cell carcinoma associated with HPV69 and later developed squamous cell carcinoma in the lungs, clinically presumed to be metastatic disease, associated with HPV73. Consensus PCR screening for HPV was performed by real-time PCR amplification of the L1 gene region, amplification of the E6 regions with High-Resolution Melting Curve Analysis followed by Sanger sequencing confirmation and phylogenetic analysis.

Results: Sanger sequencing of the consensus PCR amplification product determined that the anal tissue sample was positive for HPV 69, and the lung tissue sample was positive for HPV 73.

Conclusions: This case underscores the importance of recognizing the emerging role of these rare "possibly carcinogenic" HPV types in human carcinogenesis.
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http://dx.doi.org/10.3390/v12030349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150817PMC
March 2020

A novel fluorescent probe for the detection of AmpC beta-lactamase and the application in screening beta-lactamase inhibitors.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Jun 14;234:118257. Epub 2020 Mar 14.

MOE Joint International Research Laboratory of Synthesis Biology and Medicine, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, PR China. Electronic address:

The rapid detection of β-lactamases (Blas) and effective screening of Bla inhibitors are critically important and urgent for solving antibiotic resistance and improving precision medicine. Here a novel fluorescent probe CDC-559 was designed and synthesized, which can be used for the selective and direct detection of AmpC Blas. More importantly, it can realize screening the Bla inhibitors with sulbactam sodium and tazobactam as model compounds, and the half-maximal inhibitory concentration are 0.279 μM and 0.053 μM, respectively. CDC-559 can be applied not only to examine the resistance of bacterial strains, but also to categorize its mode of action specifically, which is consistent with the essential result of the Blas. The research suggests that CDC-559 probe has tremendous potential in the rapid detection of AmpC Blas as well as the strains with AmpC-encoded gene, which is instructive in promoting better antibiotic stewardship practices and developments.
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http://dx.doi.org/10.1016/j.saa.2020.118257DOI Listing
June 2020

MRI radiomics features predict immuno-oncological characteristics of hepatocellular carcinoma.

Eur Radiol 2020 Jul 21;30(7):3759-3769. Epub 2020 Feb 21.

Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Objective: To assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC).

Methods: This retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months.

Results: Qualitative (r = - 0.41-0.40, p < 0.042) and quantitative (r = - 0.52-0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41-0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = - 0.48-0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76-0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098-0929).

Conclusions: MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation.

Key Points: • MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma. • Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.
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http://dx.doi.org/10.1007/s00330-020-06675-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869026PMC
July 2020

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with uncomplicated malaria in Burkina Faso: an open label trial.

Wellcome Open Res 2019 7;4:45. Epub 2019 Mar 7.

Mahidol-Oxford Tropical Medicine Resarch Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.

: Malaria during pregnancy is a major health risk for both the mother and the foetus. Pregnancy has been shown to influence the pharmacokinetics of a number of different antimalarial drugs. This might lead to an under-exposure in these patients which could increase the risk of treatment failure and the development of drug resistance. The study aim was to evaluate the pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant patients using a population modelling approach. : Twenty-four women in their second and third trimester of pregnancy and twenty-four paired non-pregnant women, all with uncomplicated malaria, were enrolled in this study. Treatment was a fixed-dose combination of oral artesunate and mefloquine once daily for three days. Frequent blood samples were collected and concentration-time data for artesunate and dihydroartemisinin were analysed simultaneously using nonlinear mixed-effects modelling. : Artesunate pharmacokinetics was best described by a transit-compartment absorption model followed by a one-compartment disposition model under the assumption of complete conversion of artesunate into dihydroartemisinin. Dihydroartemisinin pharmacokinetics was best described by a one-compartment disposition model with first-order elimination. Pregnant women had a 21% higher elimination clearance of dihydroartemisinin, compared to non-pregnant women, resulting in proportionally lower drug exposure. In addition, initial parasitaemia and liver status (alanine aminotransferase) were found to affect the relative bioavailability of artesunate. : Results presented here show a substantially lower drug exposure to the antimalarial drug dihydroartemisinin during pregnancy after standard oral treatment of artesunate and mefloquine. This might result in an increased risk of treatment failure and drug resistance development, especially in low transmission settings where relative immunity is lower. : ClinicalTrials.gov NCT00701961 (19/06/2008).
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http://dx.doi.org/10.12688/wellcomeopenres.14849.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974929PMC
March 2019

Predictors of Recurrence and Survival in Patients With Surgically Resected Pancreatic Neuroendocrine Tumors.

Pancreas 2020 02;49(2):249-254

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Objective: Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs.

Methods: Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates. Variables associated with recurrence and disease-related death were identified through Cox multivariate analyses.

Results: Of 307 patients with PanNET who underwent resection, recurrence occurred in 79 (26%) of patients. For stage I and II disease, 5-year RFS rates were 90% and 43%, whereas 5-year DSS rates were 98% and 86% (P < 0.0001 and P = 0.0038, respectively). For grades 1, 2, and 3 disease, 5-year RFS rates were 87%, 49%, and 18%, and 5-year DSS rates were 98%, 89%, and 51% (P < 0.0001 for both). Stage II, grade 2, and grade 3 disease were each associated with increased recurrence and disease-specific death.

Conclusions: Stage and grade are important prognostic factors that should be utilized to tailor postsurgical surveillance after curative resection of PanNET.
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http://dx.doi.org/10.1097/MPA.0000000000001477DOI Listing
February 2020

Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy.

Histopathology 2020 Jun 7;76(7):959-967. Epub 2020 May 7.

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Aims: Nodular regenerative hyperplasia (NRH) and obliterative portal venopathy (OPV), entities that comprise idiopathic non-cirrhotic portal hypertension (INCPH), are under-recognised diseases of uncertain aetiology and the diagnosis can be easily missed on liver biopsy. The expression of CD34 and von Willebrand factor (vWF) in liver sinusoidal endothelial cells (LSEC) and alpha-smooth muscle actin (ASMA) in hepatic stellate cells (HSCs) is unknown in NRH and OPV. We sought to investigate the pathogenesis and potential immunomarkers that might aid in making the diagnosis of NRH and OPV.

Methods And Results: Immunohistochemical (IHC) staining for CD34, vWF and ASMA was performed in clinically and histologically well-characterised NRH (n = 15) and OPV (n = 47) liver specimens. Among the 47 OPV cases, 37 (78.7%) had concurrent features of NRH. CD34 positive staining was mainly confined to small vessels in the portal tracts and LSECs in periportal areas, a finding similar to that in non-NRH/OPV livers. However, expression of vWF in LSECs was positive in the compressed sinusoids of NRH and in a patchy or geographic pattern, particularly prominent in the perivenular areas and dilated sinusoids of OPV cases. HSCs were negative for ASMA in all NRH and OPV cases.

Conclusion: Our findings indicate that NRH may be a subtle but common concurrent morphological feature in OPV. The aberrant expression of vWF in LSECs suggests that endothelial injury may play a role in the pathogenesis, which may thus aid in the recognition and diagnosis of NRH and OPV, particularly when confronted with otherwise apparent normal liver histology on needle biopsy.
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http://dx.doi.org/10.1111/his.14083DOI Listing
June 2020

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.

PLoS Negl Trop Dis 2020 01 27;14(1):e0007957. Epub 2020 Jan 27.

Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.

The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.
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http://dx.doi.org/10.1371/journal.pntd.0007957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004383PMC
January 2020

Intratumoral heterogeneity and clonal evolution in liver cancer.

Nat Commun 2020 01 15;11(1):291. Epub 2020 Jan 15.

Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.
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http://dx.doi.org/10.1038/s41467-019-14050-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962317PMC
January 2020

Co-transmission of Related Malaria Parasite Lineages Shapes Within-Host Parasite Diversity.

Cell Host Microbe 2020 01 31;27(1):93-103.e4. Epub 2019 Dec 31.

Texas Biomedical Research Institute, San Antonio, TX, USA. Electronic address:

In high-transmission regions, we expect parasite lineages within complex malaria infections to be unrelated due to parasite inoculations from different mosquitoes. This project was designed to test this prediction. We generated 485 single-cell genome sequences from fifteen P. falciparum malaria patients from Chikhwawa, Malawi-an area of intense transmission. Patients harbored up to seventeen unique parasite lineages. Surprisingly, parasite lineages within infections tend to be closely related, suggesting that superinfection by repeated mosquito bites is rarer than co-transmission of parasites from a single mosquito. Both closely and distantly related parasites comprise an infection, suggesting sequential transmission of complex infections between multiple hosts. We identified tetrads and reconstructed parental haplotypes, which revealed the inbred ancestry of infections and non-Mendelian inheritance. Our analysis suggests strong barriers to secondary infection and outbreeding amongst malaria parasites from a high transmission setting, providing unexpected insights into the biology and transmission of malaria.
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http://dx.doi.org/10.1016/j.chom.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159252PMC
January 2020

Intracellular Pharmacodynamic Modeling Is Predictive of the Clinical Activity of Fluoroquinolones against Tuberculosis.

Antimicrob Agents Chemother 2019 12 20;64(1). Epub 2019 Dec 20.

Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom

Clinical studies of new antitubercular drugs are costly and time-consuming. Owing to the extensive tuberculosis (TB) treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of preclinical models in predicting the activity of fluoroquinolones underline the importance of developing new and more robust predictive tools that will optimize the design of future trials. Here, we used high-content imaging screening and pharmacodynamic intracellular (PDi) modeling to identify and prioritize fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modeling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilization) rates compared to eight independent clinical trials. In addition, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict the relapse rate. These data further support that PDi-based modeling offers a much-needed decision-making tool for the TB drug development pipeline.
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http://dx.doi.org/10.1128/AAC.00989-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187570PMC
December 2019