Molecular Characterization of Hereditary Persistence of Fetal Hemoglobin in the Karen People of Thailand

Hereditary persistence of fetal hemoglobin (HPFH) is the condition whereby a continuously active γ‐globin gene expression leads to elevated fetal hemoglobin (Hb F) levels in adult life [Stamatoyannopoulos G, Grosveld F. Hemoglobin switching. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H, eds. The Molecular Basis of Blood Diseases. Philadelphia: W.B. Saunders, 2001:135–182; Wood WG. Hereditary persistence of fetal hemoglobin and δβ thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press, 2001:356–388; and Weatherall DJ, Clegg JB. Hereditary persistence of fetal hemoglobin. In: Weatherall DJ, Clegg JB, eds. The Thalassaemia Syndromes. Oxford: Blackwell Scientific Publishers, 1981:450–507]. The condition is caused either by mutation of the β‐ and γ‐globin genes, or the γ‐gene controlled region on other chromosomes. Several families with this condition have been reported from Vietnam, Cambodia and China, and the Southeast Asian mutation (or HPFH‐6), a 27 kb deletion, was demonstrated. Here we report on a mother and her daughter of the Karen ethnic group with high levels of Hb F, living in the Suan Pueng District on the border of Thailand and Myanmar. Genotyping showed a heterozygosity for the 27 kb deletion of the β‐globin gene. Their conditions have been confirmed by gap polymerase chain reaction (PCR) with three oligonucleotide primers recently developed by Xu et al. [Xu X‐M, Li Z‐Q, Liu Z‐Y, Zhong X‐L, Zhao Y‐Z, Mo Q‐H. Molecular characterization and PCR detection of a deletional HPFH: application to rapid prenatal diagnosis for compound heterozygotes of this defect with β‐thalassemia in a Chinese family. Am J Hematol 2000; 65:183–188.], and a DNA sequencing method. Thus far there has been no official report of the HPFH‐6 anomaly from Thailand. The compound heterozygosity of β‐thalassemia (thal) and hereditary persistence of Hb F causes the phenotype of thalassemia intermedia; in contrast, homozygotes for this anomaly show only mild microcytic anemia. Hence, genetic counseling for hereditary persistence of Hb F carriers is needed for family planning.     

Comparison of persistence and adherence between fixed-dose combinations and two-pill combinations in Japanese patients with type 2 diabetes

Objective: To compare treatment patterns, persistence and adherence between fixed-dose combinations (FDCs) and two-pill combinations (TPCs) of oral antidiabetic drug (OAD) classes in Japanese patients with type 2 diabetes mellitus (T2DM) using administrative claims databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]).

Methods: This was a retrospective, longitudinal cohort analysis conducted between 2011 and 2015, in patients with T2DM receiving OADs as FDC or TPC. Outcomes included prescribing patterns, treatment persistence and adherence.

Results: Data from 3474 and 3066 patients receiving FDCs, and 4325 and 5192 patients receiving TPCs from the JMDC and MDV databases, respectively, was extracted. The most common OAD combination received by over half of all patients was dipeptidyl peptidase-4 inhibitor (DPP-4i) + thiazolidinediones (TZDs) (64.1% [JMDC] and 70.5% [MDV]). Overall, 12-month persistence rates were higher in patients receiving FDCs compared with TPCs (70.4 vs. 66.2% [JMDC], 75.6 vs. 55.7% [MDV]). In the JMDC population receiving FDCs or TPCs, persistence rates were highest with DPP-4i schedules (67.5–83.5%). Median time to discontinuation was significantly longer with biguanide?+?TZD, and DPP-4i?+?TZD FDC schedules (p < .05) than TPC; adherence rates were ≥80% across all antidiabetic drug classes in both database populations.

Conclusions: Persistence with and adherence to OADs in Japanese patients with T2DM were greater with FDCs than with TPCs, which may suggest increased patient satisfaction due to reduced treatment burden. Further studies are warranted to investigate the impact of adherence and persistence of FDCs of OADs on glycemic control.     

One or two doses of hepatitis A vaccine in universal vaccination programs in children in 2020: A systematic review

BackgroundHepatitis A virus (HAV) is a global health concern as outbreaks continue to occur. Since 1999, several countries have introduced universal vaccination (UV) of children against HAV according to approved two-dose schedules. Other countries have implemented one-dose UV programs since 2005; the long-term impact of this schedule is not yet known.MethodsWe conducted a systematic literature search in four electronic databases for data published between January 2000 and July 2019 to assess evidence for one-dose and two-dose UV of children with non-live HAV vaccines and describe their global impact on incidence, mortality, and severity of hepatitis A, vaccine effectiveness, vaccine efficacy, and antibody persistence.ResultsOf 3739 records screened, 33 peer-reviewed articles and one conference abstract were included. Rapid declines in incidence of hepatitis A and related outcomes were observed in all age groups post-introduction of UV programs, which persisted for at least 14 years for two-dose and six years for one-dose programs according to respective study durations. Vaccine effectiveness was ≥95% over 3–5 years for two-dose programs. Vaccine efficacy was >98% over 0.1–7.5 years for one-dose vaccination. Antibody persistence in vaccinated individuals was documented for up to 15 years (≥90%) and ten years (≥74%) for two-dose and one-dose schedules, respectively.ConclusionExperience with two-dose UV of children against HAV is extensive, demonstrating an impact on the incidence of hepatitis A and antibody persistence for at least 15 years in many countries globally. Because evidence is more limited for one-dose UV, we were unable to draw conclusions on immune response persistence beyond ten years or the need for booster doses later in life. Ongoing epidemiological monitoring is essential in countries implementing one-dose UV against HAV. Based on current evidence, two doses of non-live HAV vaccines are needed to ensure long-term protection.     

Antibody persistence 5 years after vaccination at 2 to 10 years of age with Quadrivalent MenACWY-CRM conjugate vaccine,and responses to a booster vaccination

BackgroundIn a multi-center extension study, children 2–10 years of age, initially vaccinated with one or two doses (2–5 year-olds) or one dose (6–10 year-olds) of quadrivalent meningococcal CRM₁₉₇-conjugate vaccine (MenACWY-CRM), were assessed five years later for antibody persistence and booster response using serum bactericidal assay with human complement (hSBA).MethodsChildren 7–10 and 11–15 years of age, who received MenACWY-CRM in the original study, and age-matched vaccine-naïve children, were enrolled in this extension study. After an initial blood draw, children received one dose of MenACWY-CRM as booster or primary dose, with a second blood draw 28 days later.ResultshSBA titers decreased five years after primary vaccination, but were higher than in non-vaccinated controls against serogroups C, W and Y, with substantial proportions having titers ≥8: 7–22% for A, 32–57% for C, 74–83% for W, and 48–54% for Y. Previously-vaccinated children demonstrated booster responses to revaccination against all four serogroups. Responses to primary vaccination in vaccine-naïve controls were lower and similar to primary responses observed in the original study. All vaccinations were generally well tolerated, with no safety concern raised.ConclusionsApproximately half the children vaccinated as 2–10 year-olds maintained protective antibodies against serogroups C, W and Y five years later, but fewer did against serogroup A. Declining titers five years after vaccination and robust booster responses suggest that five years may be an appropriate interval to revaccinate children, subject to epidemiology and delivery considerations.     

Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations

Postmenopausal osteoporosis is common and underrecognized among elderly women. Osteoporotic fractures cause disability and disfigurement and threaten patients’ mobility, independence, and survival. Care for incident fractures in this age group must go beyond orthopedic repair, to assessment and treatment of the underlying bone fragility. Fracture risk can be reduced by vitamin D and calcium supplementation along with antiresorptive drug treatment. First-line osteoporosis pharmacotherapy employs nitrogen-containing bisphosphonates. The inconvenience of daily oral treatment has motivated development of weekly, monthly, and intermittent oral regimens, as well as quarterly and yearly intravenous (iv) regimens. Ibandronate is the first bisphosphonate to have shown direct anti-fracture efficacy with a non-daily regimen; it was approved for once-monthly oral dosing in 2005 and for quarterly iv dosing in 2006. Intermittent oral risedronate and yearly iv zoledronic acid were approved in 2007. Newly available regimens with extended dosing intervals reduce the inconvenience of bisphosphonate therapy and provide patients with a range of options from which to select a maximally sustainable course of treatment. This review discusses the development, efficacy, safety, and tolerability of extended-interval bisphosphonate regimens and examines their potential to improve patient acceptance and long-term success of osteoporosis treatment.     

Persistence of blood (DNA/RNA) on shoe soles under varying casework related conditions

Blunt force traumas by footwear can result in severe and even fatal head and upper body injuries. Oftentimes, footwear impressions are only partially available and evidential value is limited. DNA evidence on shoe soles could provide crucial evidence helping to solve crimes by linking target DNA to the activity of interest. Little is known about the persistence and detectability of biological material post such offenses and the interplay of factors affecting the analytical success. In this study, we assessed the persistence of blood on shoe soles under varying parameters such as blood location, different sneakers, weather condition, gait, amount of blood, underground and step count. We applied an optimized DNA/RNA workflow adapted to micro-traces without constraints for the primary DNA pipeline. There is a high probability to link donor DNA to the shoe sole for up to 300–400 steps, regardless of the underground, blood location, and amount of blood. Depending on the sole material and the degree of abrasion of the sole, a longer blood persistence can be observed. Considering blood, 98.2% of the initial DNA amount (1 μl initial blood volume) was lost after 100 steps walked on sole areas that are in constant contact with the ground. Proportion of foreign DNA was marginal (avg. 4.4 alleles), minimizing the probability of unintentional DNA transfer in this context. RNA typing showed high specificity but lower sensitivity than presumptive tests used for body fluid identification (BFI). Luminol is essential for targeted sampling on shoe soles, as latent blood traces (>100–200 steps) provided sufficient biological material for DNA/RNA typing. The generated data help to address the activity of interest and evaluate probabilities about prevalence of target DNA important for casework implications and assessments on activity level.     

Building trophic modules into a persistent food web

Understanding what maintains species and perpetuates their coexistence in a network of feeding relationships (the food web) is of great importance for biodiversity conservation. A food web can be viewed as consisting of a number of simple subunits called trophic modules. Intraguild predation (IGP), in which a prey and its predator compete for the same resource, is one of the best-studied trophic modules. According to theory, there are two ways to yield a large persistent system from such modules: (i) to use persistent subunits as building blocks or (ii) to arrange the subunits in a way that externally supports the nonpersistent subunits. Here, I show that the complex food web of the Caribbean marine ecosystem is constructed in both ways. I show that IGP modules, which convey internal persistence because of the fact that prey are superior competitors for the resources, are overrepresented in the Caribbean ecosystem. The other modules, consisting of competitively inferior prey, are not persistent in isolation. However, competitively inferior prey in these modules tend to receive more advantage from extra-module interactions, which allows persistence of the IGP module. In addition, those exterior interactions tend to be provided by intrinsically persistent IGP modules to prevent cascading extinction of interacting IGP modules. The food web can be viewed as a set of interacting modules, nonrandomly arranged to enhance the maintenance of biodiversity.