Publications by authors named "A M James Shapiro"

2,128 Publications

  • Page 1 of 1

Final Results of the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII.

J Blood Med 2021 20;12:991-1001. Epub 2021 Nov 20.

Centre for Outcomes and Experience Research in Children's Health Illness and Disability (ORCHID), Great Ormond Street Hospital, London, UK.

Introduction: Neutralizing antibodies to coagulation factor VIII (FVIII) remain a major complication associated with FVIII replacement therapy.

Aim: To assess safety and efficacy of immune tolerance induction (ITI) therapy with ADVATE (antihemophilic factor [recombinant] [rAHF]) in patients who participated in the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study.

Methods: The PAIR study was an international, multicenter, open-label, prospective, observational study in patients with hemophilia A and inhibitors, prescribed rAHF ITI therapy in clinical practice. The primary endpoint was adverse event (AE) reporting; the secondary endpoints included incidence of central venous access device-related complications and success rates of ITI therapy. Maintenance of immune tolerance was monitored for 12 months post-ITI therapy.

Results: Of 44 patients, 36 completed ITI therapy, including 31 completing the 12-month follow-up. Most patients received rAHF 90-130 IU/kg/day (59.1%) and a mean of 6.0 doses/week; the median duration of rAHF ITI therapy during the PAIR study was 600 days. Overall, 284 AEs were reported; 56 AEs were serious, of which none were considered rAHF-related. Of 228 nonserious AEs, 14 (in six patients) were deemed rAHF-related: increase of FVIII inhibitors titer due to anamnestic response, nausea, catheter site pain, pyrexia, urticaria, upper respiratory tract infection, arthralgia, and hemarthrosis. None were severe or led to ITI discontinuation. Eighteen patients experienced ≥1 central venous access device-related complication, and 21 of 36 completers achieved a negative inhibitor titer. The Kaplan-Meier estimate of success for achievement of first negative titer at 18 months of ITI therapy was 68.3% (95% confidence interval 51.8-83.6%) among completers. Of patients with partial or complete success post-ITI, 87% (20/23) maintained immune tolerance at 12-month follow-up.

Conclusion: Data suggest that rAHF ITI therapy in the PAIR study was effective, with no unexpected safety signals reported.
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http://dx.doi.org/10.2147/JBM.S329883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612659PMC
November 2021

Through-the-needle biopsy of pancreatic cystic lesions: current evidence and implications for clinical practice.

Expert Rev Med Devices 2021 Nov 27. Epub 2021 Nov 27.

Department of Medicine, Gastroenterology and Digestive Endoscopy Unit, The Pancreas Institute, University Hospital of Verona, Verona, Italy.

Introduction: : There is increasing evidence to support the efficacy of endoscopic ultrasound (EUS)-guided through-the-needle biopsy (TTNB) technique as a means of sampling pancreatic cystic lesions (PCLs). Results provide evidence demonstrating the benefits of this procedure over standard EUS fine-needle aspiration (FNA), thus supporting a push for its widespread implementation in clinical practice. Though this technique has demonstrated advantages, achieving these advantages in clinical practice is contingent upon careful considerations to ensure safety and efficacy.

Areas Covered: : The purpose of this review is to assess the level of evidence supporting the use of through-the-needle biopsy, revise its main technical and procedural characteristics, and to develop suggested guidelines outlining the safe assimilation of this device in clinical practice.

Expert Opinion: : EUS-TTNB enables more definitive and accurate diagnosis of PCLs by providing higher quality histological samples. However, EUS-TTNB is not appropriate for all PCLs. Selection of suitable patients as well as morphology and risk factors of the cystic lesion is a crucial component of achieving the described benefits of this procedure while minimizing risks of adverse effects. Subjects with weak or absent indications for this procedure are susceptible to a range of complications and may even result in fatality.
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http://dx.doi.org/10.1080/17434440.2021.2012450DOI Listing
November 2021

Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets.

Cell Rep 2021 Nov;37(8):110037

Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA, USA; Department of Medicine, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA. Electronic address:

Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent glucose-driven pro-survival pathway. We find that pyruvate carboxylase is required for glutathione synthesis in islets and promotes their antioxidant capacity to counter inflammation and nitrosative stress. Loss- and gain-of-function studies indicate that pyruvate carboxylase is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response. Altered redox metabolism and cellular capacity to replenish glutathione pools are relevant in multiple pathologies beyond obesity and diabetes. Our findings reveal a direct interplay between glucose metabolism and glutathione biosynthesis via pyruvate carboxylase. This metabolic axis may also have implications in other settings where sustaining glutathione is essential.
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http://dx.doi.org/10.1016/j.celrep.2021.110037DOI Listing
November 2021

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

Lancet Infect Dis 2021 Nov 17. Epub 2021 Nov 17.

Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.

Background: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.

Methods: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.

Findings: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively.

Interpretation: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications.

Funding: World Health Organization.
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http://dx.doi.org/10.1016/S1473-3099(21)00387-XDOI Listing
November 2021

Overcoming technical and cultural challenges to delivering equitable care for LGBTQ+ individuals in a rural, underserved area.

J Am Med Inform Assoc 2021 Nov 13. Epub 2021 Nov 13.

Community Medicine, Geisinger, Mountain Top, Pennsylvania, USA.

The lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ+) community is vulnerable to health-care disparities. Many health-care organizations are working to collect sexual orientation and gender identity in their electronic health records (EHRs), with the goal of providing more inclusive care to their LGBTQ+ patients. There are significant human and technical barriers to making these efforts successful. Based on our 5-year experience at Geisinger (an integrated health system located in a rural, generally conservative area), this case report provides insights to overcome challenges in 4 critical areas: (1) enabling the EHR to collect and use information to support the health-care needs of LGBTQ+ patients, (2) building a culture of awareness and caring, empowering members of the health-care team to break down barriers of misunderstanding and mistrust, (3) developing services to support the needs of LGBTQ+ patients, and (4) partnering with local communities to become a trusted health-care provider.
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http://dx.doi.org/10.1093/jamia/ocab227DOI Listing
November 2021
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