Gray Rainbows.

"You fooled me. I never dreamt," George said to the pasty gray face in the mirror. As a child, he had worked out complicated schemes of how the world must be constructed. This led to that, and that led to this. When this and that no longer fit together, he began to squint, and limit his view to the essential. At any moment, the sky might break open and rain body parts and end times. He never imagined that it would be colors that would give way.

Lost in Translation.

"Scleroderma," the rheumatologist said after examining my stiff swollen arms and legs. "Unfortunately, given your biomarkers, it's likely to get worse before it gets better, but you never know." She gave a quick rundown of what I might expect-rapidly progressive skin and joint tightening, GI symptoms, high likelihood of multi-organ involvement…. "Let's hope for the best." She paused, then asked if I had any questions.

Double Talk.

In this series of short essays, stories, poems, and personal observations, Robert A. Burton, neurologist and writer, uses both fiction and nonfiction to explore many paradoxes and contradictions inherent in scientific inquiry. A novelist as well as author of On Being Certain and A Skeptic's Guide to the Mind, Burton brings story to science and science to story.

Effect of aspirin on short-term outcomes in hospitalized patients with COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of antiplatelet agents in attenuating thrombosis is unknown. We aimed to determine if the antiplatelet effect of aspirin may mitigate risk of myocardial infarction, cerebrovascular accident, and venous thromboembolism in COVID-19. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. Thus, aspirin does not appear to prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appear distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation.

Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies.

Mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of Plasmodium falciparum malaria. However, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. We estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using polymerase chain reaction if treatment levels are high and screening is conducted during the dry season. Along with other factors, such as coverage, choice of drug, timing of the intervention, importation of infections, and seasonality, the sensitivity of the diagnostic can play a part in increasing the chance of interrupting transmission.

Plague Journal.

Given a strong family history of early heart attacks, the future has always been an iffy proposition. Miraculously, I have bypassed the early off-ramps and find myself approaching 80, stents in place, considering the very real but previously unimaginable possibility of still more. But what kind of more? With dopamine on the wane and no longer supercharged by the push and shove of unbridled ambition and pride, bigger and grander are out of the question. Tired clichés poke through the widening cracks in my thinking to become uninvited bulletins of compromise and consolation. Be grateful. Relax, reminisce, enjoy sunsets, learn the backyard birds' names, maybe even sing to them, and count blessings.

When Will the News be Bad Enough?

The cardiac rehab nurse calls out each of our group's blood pressures and pulse rates. It is my first posthospitalization class and I am relieved to be in the middle of the pack. Although fully aware that numbers are not fate, I cannot help wondering if the worst performers will fully satisfy the dark needs of heart disease statistics. I presume that others are making similar calculations, yet wince at the ugly direction of my mind. Maybe it is not necessary to do better than another; if we take our meds, eat wisely, and exercise to the max, it is possible that our entire group will do well.

Pneumococcus with the "6E" cps Locus Produces Serotype 6B Capsular Polysaccharide.

Genetic studies of serogroup 6 isolates ofStreptococcus pneumoniaeidentified putative serotype 6E. Although its capsular polysaccharide structure has not been elucidated, putative serotype 6E is described in an increasing number of studies as a potentially new serotype. We show here that SPEC6B, which is widely used as a target strain for serotype 6B opsonophagocytosis assays, has the genetic features of the putative serotype 6E but produces capsular polysaccharide identical to 6B capsular polysaccharide as determined by one-dimensional (1D) and 2D nuclear magnetic resonance (NMR). Thus, putative serotype 6E is a mere genetic variant of serotype 6B. Also, SPEC6B is appropriate as a target strain for serotype 6B opsonophagocytosis assays. This example illustrates the difficulties of assigning new bacterial serotypes based on genetic findings alone.

Impact of IgM Antibodies on Cross-Protection against Pneumococcal Serogroups 6 and 19 after Immunization with 7-Valent Pneumococcal Conjugate Vaccine in Children.

Although it is well known that pneumococcal conjugate vaccines provide cross-protection against some vaccine-related serotypes, these mechanisms are still unclear. This study was performed to investigate the role of cross-protective IgM antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in children aged 12-23 months after immunization with 7-valent pneumococcal conjugate vaccine (PCV7). We obtained serum samples from 18 Korean children aged 12-23 months after a PCV7 booster immunization. The serum IgG and IgM concentrations of serotypes 6B and 19F were measured by enzyme-linked immunosorbent assay (ELISA) in serum. The opsonic indices (OIs) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were determined by an opsonophagocytic killing assay (OPA) in IgM-depleted and control serum. Both IgG and IgM antibodies in ELISA and opsonic indices in OPA against serotypes 6B and 19F were demonstrated in the immune serum. IgM depletion decreased the OIs against vaccine serotypes 6B (geometric means of OIs (GMIs) of 3,009 vs. 1,396, 38% reduction) and 19F (1,117 vs. 750, 36% reduction). In addition, IgM depletion markedly decreased the OIs against vaccine-related serotypes 6A (GMIs of 961 vs. 329, 70% reduction), 6C (432 vs. 185, 72% reduction), and 19A (301 vs. 166, 58% reduction). The booster immunization PCV7 induced protective antibodies in the form of both IgG and IgM isotypes. IgM antibodies contributed to eliciting cross-protection against vaccine-related serotypes as well as against vaccine serotypes.

Evaluation of non-instrumented nucleic acid amplification by loop-mediated isothermal amplification (NINA-LAMP) for the diagnosis of malaria in Northwest Ethiopia.

BACKGROUND: Malaria is a major public health problem in sub-Saharan African countries including Ethiopia. Early and accurate diagnosis followed by prompt and effective treatment is among the various tools available for prevention, control and elimination of malaria. This study aimed to evaluate the performance of non-instrumented nucleic acid amplification loop-mediated isothermal amplification (NINA-LAMP) compared to standard thick and thin film microscopy and nested PCR as gold standard for the sensitive diagnosis of malaria in Northwest Ethiopia. METHODS: A cross-sectional study was conducted in North Gondar, Ethiopia from March to July 2014. Eighty-two blood samples were collected from malaria suspected patients visiting Kola Diba Health Centre and analysed for Plasmodium parasites by microscopy, NINA-LAMP and nested PCR. The NINA-LAMP method was performed using the Loopamp Malaria Pan/Pf detection kits for detecting DNA of the genus Plasmodium and more specifically Plasmodium falciparum using an electricity-free heater. Diagnostic accuracy outcome measures (analytical sensitivity, specificity, predictive values, and Kappa scores) of NINA-LAMP and microscopy were compared to nested PCR. RESULTS: A total of 82 samples were tested in the primary analysis. Using nested PCR as reference, the sensitivity and specificity of the primary NINA-LAMP assay were 96.8% (95% confidence interval (CI), 83.2% - 99.5%) and 84.3% (95% CI, 71.4% - 92.9%), respectively for detection of Plasmodium genus, and 100% (95% CI, 75.1% - 100%) and 81.2% (95% CI, 69.9% - 89.6%), respectively for detection of P. falciparum parasite. Microscopy demonstrated sensitivity and specificity of 93.6% (95% CI, 78.5% - 99.0%) and 98.0% (95% CI, 89.5% - 99.7%), respectively for the detection of Plasmodium parasites. Post-hoc repeat NINA-LAMP analysis showed improvement in diagnostic accuracy, which was comparable to nested PCR performance and superior to microscopy for detection at both the Plasmodium genus level and P. falciparum parasites. CONCLUSION: NINA-LAMP is highly sensitive for the diagnosis of malaria and detection of Plasmodium parasite infection at both the genus and species level when compared to nested PCR. NINA-LAMP is more sensitive than microscopy for the detection of P. falciparum and differentiation from non-falciparum species and may be a critical diagnostic modality in efforts to eradicate malaria from areas of low endemicity.

Letter in response: breast cancer screening of women aged 70-74 years.

The purpose of this study is to critically appraise the claim by Nickson et al. [1] that they have evidence supporting the Australian Government's recent decision to extend the national free invitation for biennial mammography program (BreastScreen) to women aged 70-74 years. Since their claim was made on the basis of a significant difference in the incidence of larger primary breast cancers between women in this age group who are already participating in BreastScreen versus those who are not, an analysis of the stage at diagnosis of breast cancer in the USA versus mammographic screening over 30 years, evidence from breast cancer adjuvant endocrine and chemotherapy (adjuvant therapy) trials and data from an evaluation of BreastScreen and adjuvant therapy use in Australia were examined. By 1999, most Australian women aged 40-79 years were receiving adjuvant therapy that could cure breast cancer no matter what the size of the primary cancer. Further, the incidence primary breast cancers of all sizes had doubled in the USA during 30 years of mammographic screening, but the incidence of more advanced breast cancers had almost remained constant, indicating that adjuvant therapy, not mammographic screening, was the main cause of the 28 % reduction in breast cancer mortality that had been observed. In conclusion, the claim by Nickson et al. is not supported by available evidence. Further, BreastScreen should not have been extended to these older women before the UK trial, which is testing the efficacy of mammographic screening of women aged 70-74 years [8], had reported its results.

Role of aortic valve replacement in moderate aortic stenosis: a 10-year outcomes study.

OBJECTIVE: Patients with moderate aortic stenosis (AS) exhibit high morbidity and mortality. Limited evidence exists on the role of aortic valve replacement (AVR) in this patient population. To investigate the benefit of AVR in moderate AS on survival and left ventricular function. METHODS: In a retrospective cohort study, patients with moderate AS between 2008 and 2016 were selected from the Cleveland Clinic echocardiography database and followed until 2018. Patients were classified as receiving AVR or managed medically (clinical surveillance). All-cause and cardiovascular mortality were assessed by survival analyses. Temporal haemodynamic and structural changes were assessed with longitudinal analyses using linear mixed effects models. RESULTS: We included 1421 patients (mean age, 75.3±5.4 years and 39.9% women) followed over a median duration of 6 years. Patients in the AVR group had lower risk of all-cause (adjusted HR (aHR)=0.51, 95% CI: 0.34 to 0.77; p=0.001) and cardiovascular mortality (aHR=0.50, 95% CI: 0.31 to 0.80; p=0.004) compared with those in the clinical surveillance group irrespective of sex, receipt of other open-heart surgeries and underlying malignancy. These findings were seen only in those with preserved left ventricular ejection fraction (LVEF) ≥50%. Further, patients in the AVR group had a significant trend towards an increase in LVEF and a decrease in right ventricular systolic pressure compared with those in the clinical surveillance group. CONCLUSIONS: In patients with moderate AS, AVR was associated with favourable clinical outcomes and left ventricular remodelling.

The 7-valent pneumococcal conjugate vaccine elicits cross-functional opsonophagocytic killing responses to Streptococcus pneumoniae serotype 6D in children.

BACKGROUND: We investigated the immune response to serogroup 6 with the opsonophagocytic killing assay (OPKA) in children aged 12-23 months of age after immunization with the 7-valent pneumococcal conjugate vaccine (PCV7) containing serotype 6B. METHODS: Blood samples were obtained from 59 children who had blood sampling for medical examination. Immunization status against PCV7 was confirmed by immunization records and samples were categorized according to immunization status into a booster, primary, or control group. The OPKA was performed for serotypes 6A, 6B, 6C, and 6D. RESULTS: Subjects with no previous PCV7 immunization history showed opsonic activity for serogroup 6 in 5-30% (according to serotype). In subjects vaccinated with a 3-dose primary series, 81% showed opsonic activity for serotypes 6B and 6D, and 29% showed opsonic activity for serotypes 6A and 6C. Among subjects vaccinated with a booster dose, all subjects had opsonic activity against serotype 6B. Subjects in the booster group with opsonic activity against serotypes 6A, 6C, and 6D were 100%, 78%, and 89%, respectively. CONCLUSIONS: In subjects aged 12-23 months, an immune response is elicited after a primary series of immunizations with PCV7 for serotypes 6B and 6D, and a booster dose enhances a cross reactive immune response against serotypes 6A, 6C and 6D.

Pneumococcal vaccine and opsonic pneumococcal antibody.

Streptococcus pneumoniae is a major human pathogen responsible for the majority of bacterial pneumonia cases as well as invasive pneumococcal diseases with high mortality and morbidity. Use of conjugate vaccines targeting the pneumococcal capsule has dramatically reduced the incidence of invasive diseases, and there are active efforts to further improve the conjugate vaccines. However, in children new pneumococcal vaccines can no longer be tested with placebo-based clinical trials because effective vaccines are currently available. Thus, vaccine studies must depend on surrogate markers of vaccine efficacy. Although traditional antibody levels (e.g., ELISA) are useful as a surrogate marker of protection, they have limitations, and a bioassay measuring the capacity of antibodies to opsonize pneumococci has been developed. This opsonophagocytosis assay (OPA) replicates the in vivo mechanism of antibody protection and should therefore better reflect protection by vaccine-induced antibodies. Technical improvements of OPA have made this bioassay rapid, multiplexed, and practical for analyzing small samples including those from children. Strong correlations between ELISA and OPA have been observed in many studies of young children. However, poor correlations have been found in some important clinical situations (such as determination of protection by cross-reactive antibodies) and populations (such as elderly adults and immunodeficient patients). In these settings, OPA has become a useful supplementary measure of pneumococcal vaccine immunogenicity. Current efforts to standardize OPA will further expand its uses.

Pneumococcal polysaccharide vaccine at 12 months of age produces functional immune responses.

BACKGROUND: Infections with Streptococcus pneumoniae (pneumococcus) are a cause of significant child mortality. Pneumococcal glycoconjugate vaccines are expensive and provide limited serotype coverage. The 23-valent pneumococcal polysaccharide vaccine (Pneumovax) might provide wider serotype coverage but is reported to be weakly immunogenic in children less than 2 years of age. We have previously reported that Pneumovax administered to healthy 12-month-old Fijian infants elicits significant serotype-specific IgG responses. However, the functional capacity of these responses in 12-month-old infants is not known. OBJECTIVE: We sought to assess the functional, serotype-specific immune response of 12-month-old infants after immunization with Pneumovax. METHODS: Functional responses of 12-month-old infants were assessed by using the opsonophagocytic and antibody avidity assay against 8 serotypes and 23 serotypes, respectively. RESULTS: Seventy-one percent of infants produced strong opsonophagocytic activity against 4 of 8 serotypes, and 30% produced high-avidity serotype-specific IgG antibodies to 10 of 23 serotypes at 2 weeks after Pneumovax. Responses were protective for most serotypes that cause disease in Western countries, whereas responses to most of the epidemiologically relevant serotypes for developing countries were low. CONCLUSION: This is the first comprehensive study evaluating the functional antibody response to Pneumovax in 12-month-old infants. Pneumovax induced functional antibody responses to several serotypes causing disease in Western countries but induced poorer responses to serotypes that are responsible for the majority of disease in developing countries. Pneumovax might be of benefit in some populations, but further studies are required before this can be recommended in developing countries.

The 15-valent pneumococcal conjugate vaccine V114 induces cross-reactive antibodies against pneumococcal serotype 6C.

Pneumococcal serogroups consist of structurally related serotypes, and serotype-specific antibodies can cross-react against other serotypes within the same serogroup. Cross-reactivity of vaccine-induced serotype 6A antibodies, and, to a lesser extent, serotype 6B antibodies, to serotype 6C has been demonstrated following receipt of the 13-valent pneumococcal conjugate vaccine (PCV13), which contains serotypes 6A and 6B. V114 is a 15-valent PCV containing the 13 PCV13 serotypes plus two additional serotypes, 22F and 33F. This study assessed cross-reactivity to serotype 6C in recipients of V114 and PCV13 as well as specificity of opsonophagocytic activity (OPA) responses in serogroup 6. Following receipt of V114 or PCV13, the observed OPA geometric mean titers to serotypes 6A, 6B, and 6C were comparable across both vaccination groups (post-single dose in adults ≥50 years of age [n = 250] and from pre- to post-dose 4 in pediatric participants 12-15 months of age [n = 150]). Based on OPA inhibition studies, V114 induced cross-reactive antibodies to serotype 6C in adult and pediatric populations that were specific and comparable to those induced by PCV13. Based on experience with PCV13, V114 may also provide comparable protection against pneumococcal disease caused by serotype 6C; however, this will have to be evaluated in real-world studies.