A 44-year-old man with eye, kidney, and brain dysfunction

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of the three-prime repair exonuclease-1 (TREX1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient’s multisystem presentation, retinal involvement interpreted as “retinal vasculitis”, and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet’s disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy

ACORN (A Clinically-Oriented Antimicrobial Resistance Surveillance Network) II: protocol for case based antimicrobial resistance surveillance

Background: Antimicrobial resistance surveillance is essential for empiric antibiotic prescribing, infection prevention and control policies and to drive novel antibiotic discovery. However, most existing surveillance systems are isolate-based without supporting patient-based clinical data, and not widely implemented especially in low- and middle-income countries (LMICs). Methods: A Clinically-Oriented Antimicrobial Resistance Surveillance Network (ACORN) II is a large-scale multicentre protocol which builds on the WHO Global Antimicrobial Resistance and Use Surveillance System to estimate syndromic and pathogen outcomes along with associated health economic costs. ACORN-healthcare associated infection (ACORN-HAI) is an extension study which focuses on healthcare-associated bloodstream infections and ventilator-associated pneumonia. Our main aim is to implement an efficient clinically-oriented antimicrobial resistance surveillance system, which can be incorporated as part of routine workflow in hospitals in LMICs. These surveillance systems include hospitalised patients of any age with clinically compatible acute community-acquired or healthcare-associated bacterial infection syndromes, and who were prescribed parenteral antibiotics. Diagnostic stewardship activities will be implemented to optimise microbiology culture specimen collection practices. Basic patient characteristics, clinician diagnosis, empiric treatment, infection severity and risk factors for HAI are recorded on enrolment and during 28-day follow-up. An R Shiny application can be used offline and online for merging clinical and microbiology data, and generating collated reports to inform local antibiotic stewardship and infection control policies. Discussion: ACORN II is a comprehensive antimicrobial resistance surveillance activity which advocates pragmatic implementation and prioritises improving local diagnostic and antibiotic prescribing practices through patient-centred data collection. These data can be rapidly communicated to local physicians and infection prevention and control teams. Relative ease of data collection promotes sustainability and maximises participation and scalability. With ACORN-HAI as an example, ACORN II has the capacity to accommodate extensions to investigate further specific questions of interest

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

It is, is it not? - Path PPT

A 44-year-old man presented with visual loss, confusion, apraxia, and left-sided weakness. His medical history included retinal vasculopathy, chronic kidney disease, hypertension, and hypertensive cardiomyopathy that had presented over the preceding six years. The retinal vasculopathy had been termed "posterior uveitis with retinal vasculitis." The condition had been treated with several immunosuppressive medications, including prednisone, cyclosporine, mycophenolate mofetil, adalimumab, methotrexate, and interferon-alpha. Additional treatments included retinal laser photocoagulation, intravitreal glucocorticoids, and bevacizumab. The patient had undergone two kidney biopsies, which were reported to show focal segmental glomerulosclerosis with thrombotic microangiopathy and mild nephrosclerosis. No tubulointerstitial disease was present. His father had died at age 36 years from Hodgkin lymphoma. His paternal uncle had died in his early forties from unclear causes, accompanied by renal dysfunction. The patient denied any history of oral, genital, or skin lesions, sicca symptoms, musculoskeletal, respiratory or gastrointestinal symptoms. He had undergone extensive diagnostic evaluations, including two brain biopsies, at another hospital. Glucocorticoids had been prescribed for cerebral edema. After five weeks, the patient was transferred to our institution for further management. On arrival, physical examination was remarkable for an irregularly irregular pulse and 3+ pitting edema of the lower extremities. Best-corrected visual acuity was 20/80 in the right eye and 20/50-1 in the left eye. There was bilateral dyschromatopsia. A relative afferent pupillary defect was not present. Slit lamp examination showed moderate bilateral symmetrical optic disc pallor, epiretinal membranes, cotton wool spots, retinal arteriole obstruction with sclerosis and resulting ghost vessels, and extensive pan-retinal photocoagulation scars. Neurological examination was remarkable for nonspecific visual field defects on confrontation testing, mild left lower facial weakness, mild left pronator drift, and unsteady gait. Cognitive abnormalities documented five weeks earlier were no longer present. Brain MRI revealed a right temporo-parieto-occipital tumefactive lesion with vasogenic edema extending through the splenium of the corpus callosum and the left periventricular white matter. Laboratory evaluations for systemic and CNS-related autoimmunity and inflammation, HLA-B51 antigen, and analysis of blood and cerebrospinal fluid for various infectious agents were negative. Specimens from the two brain biopsies demonstrated a vasculopathy with abnormally thickened vessel walls and focal necrosis of the white matter with areas of dystrophic calcification. Because the retinal vasculopathy, in combination with the tumefactive cerebral lesion, raised the possibility of Behçet disease or other inflammatory conditions, high-dose dexamethasone, weekly adalimumab, and daily cyclophosphamide were initiated. Decrease in the vasogenic edema with resolution of the mass effect was noted after 10 weeks of dexamethasone. His vision, however, continued to deteriorate. We took a direct approach toward reaching a diagnosis

It is, is it not? - Presentation PPT

A 44-year-old man presented with visual loss, confusion, apraxia, and left-sided weakness. His medical history included retinal vasculopathy, chronic kidney disease, hypertension, and hypertensive cardiomyopathy that had presented over the preceding six years. The retinal vasculopathy had been termed "posterior uveitis with retinal vasculitis." The condition had been treated with several immunosuppressive medications, including prednisone, cyclosporine, mycophenolate mofetil, adalimumab, methotrexate, and interferon-alpha. Additional treatments included retinal laser photocoagulation, intravitreal glucocorticoids, and bevacizumab. The patient had undergone two kidney biopsies, which were reported to show focal segmental glomerulosclerosis with thrombotic microangiopathy and mild nephrosclerosis. No tubulointerstitial disease was present. His father had died at age 36 years from Hodgkin lymphoma. His paternal uncle had died in his early forties from unclear causes, accompanied by renal dysfunction. The patient denied any history of oral, genital, or skin lesions, sicca symptoms, musculoskeletal, respiratory or gastrointestinal symptoms. He had undergone extensive diagnostic evaluations, including two brain biopsies, at another hospital. Glucocorticoids had been prescribed for cerebral edema. After five weeks, the patient was transferred to our institution for further management. On arrival, physical examination was remarkable for an irregularly irregular pulse and 3+ pitting edema of the lower extremities. Best-corrected visual acuity was 20/80 in the right eye and 20/50-1 in the left eye. There was bilateral dyschromatopsia. A relative afferent pupillary defect was not present. Slit lamp examination showed moderate bilateral symmetrical optic disc pallor, epiretinal membranes, cotton wool spots, retinal arteriole obstruction with sclerosis and resulting ghost vessels, and extensive pan-retinal photocoagulation scars. Neurological examination was remarkable for nonspecific visual field defects on confrontation testing, mild left lower facial weakness, mild left pronator drift, and unsteady gait. Cognitive abnormalities documented five weeks earlier were no longer present. Brain MRI revealed a right temporo-parieto-occipital tumefactive lesion with vasogenic edema extending through the splenium of the corpus callosum and the left periventricular white matter. Laboratory evaluations for systemic and CNS-related autoimmunity and inflammation, HLA-B51 antigen, and analysis of blood and cerebrospinal fluid for various infectious agents were negative. Specimens from the two brain biopsies demonstrated a vasculopathy with abnormally thickened vessel walls and focal necrosis of the white matter with areas of dystrophic calcification. Because the retinal vasculopathy, in combination with the tumefactive cerebral lesion, raised the possibility of Behçet disease or other inflammatory conditions, high-dose dexamethasone, weekly adalimumab, and daily cyclophosphamide were initiated. Decrease in the vasogenic edema with resolution of the mass effect was noted after 10 weeks of dexamethasone. His vision, however, continued to deteriorate. We took a direct approach toward reaching a diagnosis

Field evaluation of rapid diagnostic tests to determine dengue serostatus in Timor-Leste.

The live attenuated tetravalent CYD-TDV vaccine (Dengvaxia) is effective but has scarcely been used due to safety concerns among seronegative recipients. Rapid diagnostic tests (RDTs) which can accurately determine individual dengue serostatus are needed for use in pre-vaccination screening. This study aimed to determine the performance of existing RDTs (which have been designed to detect levels of immunoglobulin G, IgG, associated with acute post-primary dengue) when repurposed for detection of previous dengue infection (where concentrations of IgG are typically lower). A convenience sample of four-hundred-and-six participants including 217 children were recruited during a community serosurvey. Whole blood was collected by phlebotomy and tested using Bioline Dengue IgG/IgM (Abbott) and Standard Q Dengue IgM/IgG (SD Biosensor) RDTs in the field. Serum samples from the same individuals were also tested at National Health Laboratory. The Panbio indirect IgG ELISA was used as a reference test. Reference testing determined that 370 (91.1%) participants were dengue IgG seropositive. Both assays were highly specific (100.0%) but had low sensitivity (Bioline = 21.1% and Standard Q = 4.6%) when used in the field. Sensitivity was improved when RDTs were used under laboratory conditions, and when assays were allowed to run beyond manufacturer recommendations and read at a delayed time-point, but specificity was reduced. Efforts to develop RDTs with high sensitivity and specificity for prior dengue infection which can be operationalised for pre-vaccination screening are ongoing. Performance of forthcoming candidate assays should be tested under field conditions with blood samples, as well as in the laboratory

It Is, Is It Not? - Video

A 44-year-old man presented with visual loss, confusion, apraxia, and left-sided weakness. His medical history included retinal vasculopathy, chronic kidney disease, hypertension, and hypertensive cardiomyopathy that had presented over the preceding six years. The retinal vasculopathy had been termed "posterior uveitis with retinal vasculitis." The condition had been treated with several immunosuppressive medications, including prednisone, cyclosporine, mycophenolate mofetil, adalimumab, methotrexate, and interferon-alpha. Additional treatments included retinal laser photocoagulation, intravitreal glucocorticoids, and bevacizumab. The patient had undergone two kidney biopsies, which were reported to show focal segmental glomerulosclerosis with thrombotic microangiopathy and mild nephrosclerosis. No tubulointerstitial disease was present. His father had died at age 36 years from Hodgkin lymphoma. His paternal uncle had died in his early forties from unclear causes, accompanied by renal dysfunction. The patient denied any history of oral, genital, or skin lesions, sicca symptoms, musculoskeletal, respiratory or gastrointestinal symptoms. He had undergone extensive diagnostic evaluations, including two brain biopsies, at another hospital. Glucocorticoids had been prescribed for cerebral edema. After five weeks, the patient was transferred to our institution for further management. On arrival, physical examination was remarkable for an irregularly irregular pulse and 3+ pitting edema of the lower extremities. Best-corrected visual acuity was 20/80 in the right eye and 20/50-1 in the left eye. There was bilateral dyschromatopsia. A relative afferent pupillary defect was not present. Slit lamp examination showed moderate bilateral symmetrical optic disc pallor, epiretinal membranes, cotton wool spots, retinal arteriole obstruction with sclerosis and resulting ghost vessels, and extensive pan-retinal photocoagulation scars. Neurological examination was remarkable for nonspecific visual field defects on confrontation testing, mild left lower facial weakness, mild left pronator drift, and unsteady gait. Cognitive abnormalities documented five weeks earlier were no longer present. Brain MRI revealed a right temporo-parieto-occipital tumefactive lesion with vasogenic edema extending through the splenium of the corpus callosum and the left periventricular white matter. Laboratory evaluations for systemic and CNS-related autoimmunity and inflammation, HLA-B51 antigen, and analysis of blood and cerebrospinal fluid for various infectious agents were negative. Specimens from the two brain biopsies demonstrated a vasculopathy with abnormally thickened vessel walls and focal necrosis of the white matter with areas of dystrophic calcification. Because the retinal vasculopathy, in combination with the tumefactive cerebral lesion, raised the possibility of Behçet disease or other inflammatory conditions, high-dose dexamethasone, weekly adalimumab, and daily cyclophosphamide were initiated. Decrease in the vasogenic edema with resolution of the mass effect was noted after 10 weeks of dexamethasone. His vision, however, continued to deteriorate. We took a direct approach toward reaching a diagnosis

It is, is it not? - Abstract

A 44-year-old man presented with visual loss, confusion, apraxia, and left-sided weakness. His medical history included retinal vasculopathy, chronic kidney disease, hypertension, and hypertensive cardiomyopathy that had presented over the preceding six years. The retinal vasculopathy had been termed "posterior uveitis with retinal vasculitis." The condition had been treated with several immunosuppressive medications, including prednisone, cyclosporine, mycophenolate mofetil, adalimumab, methotrexate, and interferon-alpha. Additional treatments included retinal laser photocoagulation, intravitreal glucocorticoids, and bevacizumab. The patient had undergone two kidney biopsies, which were reported to show focal segmental glomerulosclerosis with thrombotic microangiopathy and mild nephrosclerosis. No tubulointerstitial disease was present. His father had died at age 36 years from Hodgkin lymphoma. His paternal uncle had died in his early forties from unclear causes, accompanied by renal dysfunction. The patient denied any history of oral, genital, or skin lesions, sicca symptoms, musculoskeletal, respiratory or gastrointestinal symptoms. He had undergone extensive diagnostic evaluations, including two brain biopsies, at another hospital. Glucocorticoids had been prescribed for cerebral edema. After five weeks, the patient was transferred to our institution for further management. On arrival, physical examination was remarkable for an irregularly irregular pulse and 3+ pitting edema of the lower extremities. Best-corrected visual acuity was 20/80 in the right eye and 20/50-1 in the left eye. There was bilateral dyschromatopsia. A relative afferent pupillary defect was not present. Slit lamp examination showed moderate bilateral symmetrical optic disc pallor, epiretinal membranes, cotton wool spots, retinal arteriole obstruction with sclerosis and resulting ghost vessels, and extensive pan-retinal photocoagulation scars. Neurological examination was remarkable for nonspecific visual field defects on confrontation testing, mild left lower facial weakness, mild left pronator drift, and unsteady gait. Cognitive abnormalities documented five weeks earlier were no longer present. Brain MRI revealed a right temporo-parieto-occipital tumefactive lesion with vasogenic edema extending through the splenium of the corpus callosum and the left periventricular white matter. Laboratory evaluations for systemic and CNS-related autoimmunity and inflammation, HLA-B51 antigen, and analysis of blood and cerebrospinal fluid for various infectious agents were negative. Specimens from the two brain biopsies demonstrated a vasculopathy with abnormally thickened vessel walls and focal necrosis of the white matter with areas of dystrophic calcification. Because the retinal vasculopathy, in combination with the tumefactive cerebral lesion, raised the possibility of Behçet disease or other inflammatory conditions, high-dose dexamethasone, weekly adalimumab, and daily cyclophosphamide were initiated. Decrease in the vasogenic edema with resolution of the mass effect was noted after 10 weeks of dexamethasone. His vision, however, continued to deteriorate. We took a direct approach toward reaching a diagnosis

Summary of previous studies assessing performance of rapid diagnostic tests in determining dengue serostatus.

Summary of previous studies assessing performance of rapid diagnostic tests in determining dengue serostatus.</p

Study data.

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