Drug procurement, the Global Fund and misguided competition policies

In an effort to increase competition and decrease price, the Global Fund to Fight AIDS, Tuberculosis and Malaria recently began asking some grant recipients to use international competitive bidding processes for certain drug purchases. Unfortunately, for countries like Kenya, this request has caused more harm than good. After awarding the tender for its annual supply of the anti-malarial artemether-lumefantrine to the lowest bidder, Ajanta Pharma, Kenya experienced wide stock-outs in part due to the company's inability to supply the order in full and on time. Similar problems could arise in Uganda. Despite Kenya's experience, Uganda has awarded its next tender for artemether-lumefantrine to Ajanta Pharma. Uganda is already facing wide stock-outs and risks exacerbating an already dire situation the longer it takes to fulfil the procurement contract. A tender process based primarily on price cannot account for a company's ability to consistently supply sufficient product in time

Iodine supplementation for women during the preconception, pregnancy and postpartum period

Background Iodine is an essential nutrient required for the biosynthesis of thyroid hormones, which are responsible for regulating growth, development and metabolism. Iodine requirements increase substantially during pregnancy and breastfeeding. If requirements are not met during these periods, the production of thyroid hormones may decrease and be inadequate for maternal, fetal and infant needs. The provision of iodine supplements may help meet the increased iodine needs during pregnancy and the postpartum period and prevent or correct iodine deficiency and its consequences. Objectives To assess the benefits and harms of supplementation with iodine, alone or in combination with other vitamins and minerals, for women in the preconceptional, pregnancy or postpartum period on their and their children's outcomes. Search methods We searched Cochrane Pregnancy and Childbirth's Trials Register (14 November 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (17 November 2016), contacted experts in the field and searched the reference lists of retrieved studies and other relevant papers. Selection criteria Randomized and quasi‐randomized controlled trials with randomisation at either the individual or cluster level comparing injected or oral iodine supplementation (such as tablets, capsules, drops) during preconception, pregnancy or the postpartum period irrespective of iodine compound, dose, frequency or duration. Data collection and analysis Two review authors independently assessed trial eligibility, risk of bias, extracted data and conducted checks for accuracy. We used the GRADE approach to assess the quality of the evidence for primary outcomes. We anticipated high heterogeneity among trials, and we pooled trial results using random‐effects models and were cautious in our interpretation of the pooled results. Main results We included 14 studies and excluded 48 studies. We identified five ongoing or unpublished studies and two studies are awaiting classification. Eleven trials involving over 2700 women contributed data for the comparisons in this review (in three trials, the primary or secondary outcomes were not reported). Maternal primary outcomes Iodine supplementation decreased the likelihood of the adverse effect of postpartum hyperthyroidism by 68% (average risk ratio (RR) 0.32; 95% confidence interval (CI) 0.11 to 0.91, three trials in mild to moderate iodine deficiency settings, 543 women, no statistical heterogeneity, low‐quality evidence) and increased the likelihood of the adverse effect of digestive intolerance in pregnancy by 15 times (average RR 15.33; 95% CI 2.07 to 113.70, one trial in a mild‐deficiency setting, 76 women, very low‐quality evidence). There were no clear differences between groups for hypothyroidism in pregnancy or postpartum (pregnancy: average RR 1.90; 95% CI 0.57 to 6.38, one trial, 365 women, low‐quality evidence, and postpartum: average RR 0.44; 95% CI 0.06 to 3.42, three trials, 540 women, no statistical heterogeneity, low‐quality evidence), preterm birth (average RR 0.71; 95% CI 0.30 to 1.66, two trials, 376 women, statistical heterogeneity, low‐quality evidence) or the maternal adverse effects of elevated thyroid peroxidase antibodies (TPO‐ab) in pregnancy or postpartum (average RR 0.95; 95% CI 0.44 to 2.07, one trial, 359 women, low‐quality evidence, average RR 1.01; 95% CI 0.78 to 1.30, three trials, 397 women, no statistical heterogeneity, low‐quality evidence), or hyperthyroidism in pregnancy (average RR 1.90; 95% CI 0.57 to 6.38, one trial, 365 women, low‐quality evidence). All of the trials contributing data to these outcomes took place in settings with mild to moderate iodine deficiency. Infant/child primary outcomes Compared with those who did not receive iodine, those who received iodine supplements had a 34% lower likelihood of perinatal mortality, however this difference was not statistically significant (average RR 0.66; 95% CI 0.42 to 1.03, two trials, 457 assessments, low‐quality evidence). All of the perinatal deaths occurred in one trial conducted in a severely iodine‐deficient setting. There were no clear differences between groups for low birthweight (average RR 0.56; 95% CI 0.26 to 1.23, two trials, 377 infants, no statistical heterogeneity, low‐quality evidence), neonatal hypothyroidism/elevated thyroid‐stimulating hormone (TSH) (average RR 0.58; 95% CI 0.11 to 3.12, two trials, 260 infants, very low‐quality evidence) or the adverse effect of elevated neonatal thyroid peroxidase antibodies (TPO‐ab) (average RR 0.61; 95% CI 0.07 to 5.70, one trial, 108 infants, very low‐quality evidence). All of the trials contributing data to these outcomes took place in areas with mild to moderate iodine deficiency. No trials reported on hypothyroidism/elevated TSH or any adverse effect beyond the neonatal period. Authors' conclusions There were insufficient data to reach any meaningful conclusions on the benefits and harms of routine iodine supplementation in women before, during or after pregnancy. The available evidence suggested that iodine supplementation decreases the likelihood of postpartum hyperthyroidism and increases the likelihood of the adverse effect of digestive intolerance in pregnancy ‐ both considered potential adverse effects. We considered evidence for these outcomes low or very low quality, however, because of study design limitations and wide confidence intervals. In addition, due to the small number of trials and included women in our meta‐analyses, these findings must be interpreted with caution. There were no clear effects on other important maternal or child outcomes though these findings must also be interpreted cautiously due to limited data and low‐quality trials. Additionally, almost all of the evidence came from settings with mild or moderate iodine deficiency and therefore may not be applicable to settings with severe deficiency. More high‐quality randomised controlled trials are needed on iodine supplementation before, during and after pregnancy on maternal and infant/child outcomes. However, it may be unethical to compare iodine to placebo or no treatment in severe deficiency settings. Trials may also be unfeasible in settings where pregnant and lactating women commonly take prenatal supplements with iodine. Information is needed on optimal timing of initiation as well as supplementation regimen and dose. Future trials should consider the outcomes in this review and follow children beyond the neonatal period. Future trials should employ adequate sample sizes, assess potential adverse effects (including the nature and extent of digestive intolerance), and be reported in a way that allows assessment of risk of bias, full data extraction and analysis by the subgroups specified in this review

A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

A multilaboratory comparison of calibration accuracy and the performance of external references in analytical ultracentrifugation.

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century