The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Malaria presents a diagnostic challenge to laboratories in most countries. Endemic malaria, population movements, and travelers all contribute to presenting the laboratory with diagnostic problems for which it may have little expertise available. Drug resistance and genetic variation has altered many accepted morphological appearances of malaria species, and new technology has given an opportunity to review available procedures. Concurrently the World Health Organization has opened a dialogue with scientists, clinicians, and manufacturers on the realistic possibilities for developing accurate, sensitive, and cost-effective rapid diagnostic tests for malaria, capable of detecting 100 parasites/microl from all species and with a semiquantitative measurement for monitoring successful drug treatment. New technology has to be compared with an accepted "gold standard" that makes comparisons of sensitivity and specificity between different methods. The majority of malaria is found in countries where cost-effectiveness is an important factor and ease of performance and training is a major consideration. Most new technology for malaria diagnosis incorporates immunochromatographic capture procedures, with conjugated monoclonal antibodies providing the indicator of infection. Preferred targeted antigens are those which are abundant in all asexual and sexual stages of the parasite and are currently centered on detection of HRP-2 from Plasmodium falciparum and parasite-specific lactate dehydrogenase or Plasmodium aldolase from the parasite glycolytic pathway found in all species. Clinical studies allow effective comparisons between different formats, and the reality of nonmicroscopic diagnoses of malaria is considered.

Rapid Diagnostic Tests for Malaria Parasites

Background

Rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria use antibodies to detect either HRP-2 antigen or pLDH antigen, and can improve access to diagnostics in developing countries.

Objectives

To assess the diagnostic accuracy of RDTs for detecting P. falciparum parasitaemia in persons living in endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria by type and brand.

Search strategy

We undertook a comprehensive search of the following databases:Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; IndMED; to January 14, 2010.

Selection criteria

Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in P. falciparum endemic areas.

Data collection and analysis

For each study, a standard set of data was extracted independently by two authors, using a tailored data extraction form. Comparisons were grouped hierarchically by target antigen, and type and brand of RDT, and combined in meta-analysis where appropriate.

Main results

We identified 74 unique studies as eligible for this review and categorized them according to the antigens they detected. Types 1 to 3 include HRP-2 (from P. falciparum) either by itself or with other antigens. Types 4 and 5 included pLDH (from P. falciparum) either by itself or with other antigens. In comparisons with microscopy, we identified 71 evaluations of Type 1 tests, eight evaluations of Type 2 tests and five evaluations of Type 3 tests. In meta-analyses, average sensitivities and specificities (95% CI) were 94.8% (93.1% to 96.1%) and 95.2% (93.2% to 96.7%) for Type 1 tests, 96.0% (94.0% to 97.3%) and 95.3% (87.3% to 98.3%) for Type 2 tests, and
99.5% (71.0% to 100.0%) and 90.6% (80.5% to 95.7%) for Type 3 tests, respectively.

Overall for HRP-2, the meta-analytical average sensitivity and specificity (95% CI) were 95.0% (93.5% to 96.2%) and 95.2% (93.4% to 99.4%), respectively.

For pLDH antibody-based RDTs verified with microscopy, we identified 17 evaluations of Type 4 RDTs and three evaluations of Type 5 RDTs. In meta-analyses, average sensitivity for Type 4 tests was 91.5% (84.7% to 95.3%) and average specificity was 98.7% (96.9% to 99.5%). For Type 5 tests, average sensitivity was 98.4% (95.1% to 99.5%) and average specificity was 97.5% (93.5% to 99.1%).

Overall for pLDH, the meta-analytical average sensitivity and specificity (95% CI) were 93.2% (88.0% to 96.2%) and 98.5% (96.7% to 99.4%), respectively.

For both categories of test, there was substantial heterogeneity in study results. Quality of the microscopy reference standard could only be assessed in 40% of studies due to inadequate reporting, but results did not seem to be influenced by the reporting quality.

Overall, HRP-2 antibody-based tests (such as the Type 1 tests) tended to be more sensitive and were significantly less specific than pLDH-based tests (such as the Type 4 tests). If the point estimates for Type 1 and Type 4 tests are applied to a hypothetical cohort of 1000 patients where 30% of those presenting with symptoms have P. falciparum, Type 1 tests will miss 16 cases, and Type 4 tests will miss 26 cases. The number of people wrongly diagnosed with P. falciparum would be 34 with Type 1 tests, and nine with Type 4 tests.

Authors’ conclusions

The sensitivity and specificity of all RDTs is such that they can replace or extend the access of diagnostic services for uncomplicated P. falciparum malaria. HRP-2 antibody types may be more sensitive but are less specific than pLDH antibody-based tests, but the differences are small. The HRP-2 antigen persists even after effective treatment and so is not useful for detecting treatment failures.

Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries

Summary The accuracy of techniques for the diagnosis of malaria are usually compared with optical microscopy, which is considered to be a gold standard. However, microscopy is prone to error and therefore makes it difficult to assess the reliability of other diagnostic techniques. We did a systematic review to assess the specificity and sensitivity of diagnostic techniques in different settings, using a statistical method that avoided defining a gold standard. Performance varied depending on species of the malaria parasite, level of parasitaemia, and immunity. Overall, histidine-rich protein 2 (HRP2)-based dipsticks showed a high sensitivity (92·7%) and specificity (99·2%) for Plasmodium falciparum in endemic areas. The acridine orange test was more sensitive (97·1%) in detecting P falciparum in epidemiological studies, with a specificity of 97·9%. In the absence of a gold standard, HRP2 dipsticks and acridine orange could provide an alternative for detecting falciparum infections in endemic areas and epidemiological studies, respectively. Microscopy still remains more reliable in detecting non-falciparum infections.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(06)70579-5.pdf

The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard.

Malaria rapid diagnostic tests in endemic settings

599 iPSC-derived airway basal cells that exhibit increased competence for multipotent differentiation

259 Induced pluripotent stem cell–derived airway basal cells that exhibit greater competence for multipotent differentiation

606 Focused clinical trials of modulator response for rare cystic fibrosis genotypes

Background: CF is a progressive genetic disease leading to reduction in function or complete loss of the CFTR chloride channel that is normally located on the apical plasma membrane of specialized respiratory epithelial cells.Treatments combining CFTR modulators and a potentiator has been very successful, but a significant fraction of people with CF are not amenable to currently approved treatments.To address this unmet need, ReCode Therapeutics is advancing an mRNA-based treatment to rescue CFTR function using its proprietary lipid nanoparticle (LNP) platform to deliver optimized CFTR mRNA as an inhaled aerosol.Methods: Sequence-optimized CFTR (hemagglutinin tagged) mRNA containing modified nucleotides was used in patient-derived primary human bronchial epithelial cells (hBECs).Different CF genotypes (R553X/W1282X, W1282X/W1282X, F508del/F508del, G542X/F508del) and non-CF hBECs were grown at an air-liquid interface (ALI) and treated with aerosolized mRNA LNPs using commercially available mesh nebulizers and exposure systems.Read-outs for the nebulization experiments included transepithelial resistance (TEER) and forskolin-induced chloride conductance measured by multi-transepithelial current clamp (MTECC24), protein levels (Western blot), cytotoxicity (lactate dehydrogenase), and cell tropism (immunofluorescence). Results: We evaluated the impact of cell tropism and mucus accumulation on rescue of CFTR function in hBECs derived from people with different genotypes.Forskolin-induced Cl -currents showed significant rescue after a single dose of aerosolized SORT LNPs.Analysis of protein expression by Western blot indicated successful delivery of mRNA using optimized LNPs and expression of CFTR protein in all donor cultured cells.Data suggest that CFTR is being translated, folded, and glycosylated, whereas immunofluorescence results showed that the newly translated hemagglutinin-tagged protein trafficked to the apical membrane in pulmonary ionocytes and secretory cells.ReCode's leading formulation to treat primary ciliary dyskinesia, which was developed for delivery of DNAI1 mRNA to ciliated cells for rescue ciliary activity, promoted inefficient CFTR functional rescue.Mucus accumulation was studied by subjecting hBECs to stringent dithiothreitol washes (3 mM or 10 mM).Chloride flux results showed a modest effect of sterile mucus in transfection efficiency after LNP exposure.Further studies are being conducted to explore the connection between LNP-specific cell tropism patterns and ability to restore CFTR-dependent Cl -currents.We are also investigating the impact of mucus on LNP survivability and cell transfection in patient-derived mucus and in vivo models.Conclusions: Our results demonstrate the capability of proprietary ReCode SORT LNPs to deliver LNP-formulated CFTR mRNA as an aerosol and increase CFTR function in well-differentiated CF hBEC cultures, including cells from people with mutations unresponsive to current modulator therapies.ReCode's leading formulations to treat CF efficiently transfect pulmonary ionocytes and secretory cells in vitro.These cell-based observations support further development and may provide future treatment options for a significant fraction of people with CF who do not benefit from current CFTR modulator therapy. 

280 Induced pluripotent stem cell–based airway epithelial platform for investigating personalized responses to CFTR modulators

326 Modulator response of rare CFTR missense variants not approved for elexacaftor-tezacaftor-ivacaftor

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