The HLA genetic constitution of the Bushmen (San)

The HLA-A, -B, and -C antigens of 290 and the DR antigens of 212 !Kung San individuals were characterized. The most frequent antigens were HLA-A30 gene frequency (gf) = 0.193, Bw58 (gf = 0.303), Cw6 (gf = 0.327), DR4 (gf = 0.273), and DQw3 (gf = 0.553). An unexpected finding was the low frequency of the classic African black antigen Bw42 (gf = 0.004). Marked differences as well as similarities in HLA gene frequencies were observed between the San and the South African Negroes, supporting the view that they had a common origin and were then separated for a very long time. During this period differences developed as a result of selective advantage in the Negroes following the pastoralist-agriculturalist way of life as opposed to the hunter-gatherer way of life. The picture is further complicated by the fact that gene flow, mostly from the San to the southern African Negroes, took place when they met again a few hundred years ago. The data also illustrate HLA haplotypes, linkage disequilibria, and four-locus haplotypes not previously seen in other human populations. The most frequent four-locus haplotype in the San, HLA-Aw43, Cw7, B7, DRw6 was also different from A30, Cw2, Bw42, DR3, the most common among the South African Negroes.     

Statistical Considerations for Embedded Pragmatic Clinical Trials in People Living with Dementia

There is overwhelming need for nonpharmacological interventions to improve the health and well-being of people living with dementia (PLWD). The National Institute on Aging Imbedded Pragmatic Alzheimer's Disease (AD) and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory supports clinical trials of such interventions embedded in healthcare systems. The embedded pragmatic clinical trial (ePCT) is ideally suited to testing the effectiveness of complex interventions in vulnerable populations at the point of care. These trials, however, are complex to conduct and interpret, and face challenges in efficiency (i.e., statistical power) and reproducibility. In addition, trials conducted among PLWD present specific statistical challenges, including difficulty in outcomes ascertainment from PLWD, necessitating reliance on reports by caregivers, and heterogeneity in measurements across different settings or populations. These and other challenges undercut the reliability of measurement, the feasibility of capturing outcomes using pragmatic designs, and the ability to validly estimate interventions' effectiveness in real-world settings. To address these challenges, the IMPACT Collaboratory has convened a Design and Statistics Core, the goals of which are: to support the design and conduct of ePCTs directed toward PLWD and their caregivers; to develop guidance for conducting embedded trials in this population; and to educate quantitative and clinical scientists in the design, conduct, and analysis of these trials. In this article, we discuss some of the contemporary methodological challenges in this area and develop a set of research priorities the Design and Statistics Core will undertake to meet these goals. J Am Geriatr Soc 68:S68–S73, 2020 .     

Effect of 200 μG/day of vitamin k1 on the variability of anticoagulation control in patients on warfarin: A randomized controlled trial

Background

Controversy exists whether low-dose vitamin K supplementation can improve anticoagulation control in patients with unstable anticoagulation under warfarin. In a single- centre randomized, double-blind, placebo-controlled study, we evaluated the effectiveness of 200 μg/day of vitamin K1 in patients with unstable control under warfarin.

Methods

Effectiveness of Vitamin K1 supplementation was primarily assessed by the percentage (%) of Time-in-Therapeutic-Range (TTR) and secondarily by the standard deviation (SD) of the patient’s INR values; the proportion of out-of-range INRs; and the number of dose changes on warfarin. Their change scores were obtained by subtracting the mean value in the 6 months pre-randomization from the mean value in the 6 months post-randomization. Multivariable linear-regressions identified factors associated with anticoagulation instability.

Results

Fifty out of 54 patients were analyzed (intervention: n = 26; placebo: n = 24). Most indications (87%) for anticoagulation were venous thromboembolism (VTE). The intervention was associated with a greater reduction in the change scores for the SD of INRs between the pre and post-randomization periods compared with placebo. The mean change score was -0.259 ± 0.307 with the intervention and -0.046 ± 0.345 with placebo (p = 0.026). There was no effect on the change scores of the (%) TTR (p = 0.98), the number of INRs out-of-range (p = 0.58) and the number of dose changes (p = 0.604). Factors independently associated with increased variability in the SD of INRs were increased alcoholic drinks/week (p = 0.017), dosing errors (p = 0.0009) and missed INR appointments (p = 0.035).

Conclusion

Vitamin K1 supplementation reduces the SD of INRs as an indicator of the variability in anticoagulation control in patients treated with warfarin for VTE.     

Modeling clustering and treatment effect heterogeneity in parallel and stepped‐wedge cluster randomized trials

Cluster randomized trials are frequently used in health service evaluation. It is common practice to use an analysis model with a random effect to allow for clustering at the analysis stage. In designs where clusters are exposed to both control and treatment conditions, it may be of interest to examine treatment effect heterogeneity across clusters. In designs where clusters are not exposed to both control and treatment conditions, it can also be of interest to allow heterogeneity in the degree of clustering between arms. These two types of heterogeneity are related. It has been proposed in both parallel cluster trials, stepped‐wedge, and other cross‐over designs that this heterogeneity can be allowed for by incorporating additional random effect(s) into the model. Here, we show that the choice of model parameterization needs careful consideration as some parameterizations for additional heterogeneity induce unnecessary or implausible assumptions. We suggest more appropriate parameterizations, discuss their relative advantages, and demonstrate the implications of these model choices using a real example of a parallel cluster trial and a simulated stepped‐wedge trial.     

Beta-adrenoceptors on lymphocytes of patients with major depressive disorder

3H-Dihydroalprenolol binding to lymphocyte membranes of patients with primary, unipolar major depressive disorder was compared to that of a normal, healthy control population. No significant difference could be demonstrated between the Kd values of the two different groups, but the Bmax values of the depressed patients were significantly lower than those of the controls. Positive correlations were observed between the lymphocyte beta-adrenoceptor Bmax values of the patients and their Beck self-evaluation and Hamilton depression ratings. We propose that decreased lymphocyte beta-adrenoceptor Bmax values may be used as a biological marker for major depressive disorder.     

Altered dopaminergic function in the prefrontal cortex, nucleus accumbens and caudate-putamen of an animal model of attention-deficit hyperactivity disorder — the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for Attention-Deficit Hyperactivity Disorder (ADHD). The behavioural problems of ADHD have been suggested to be secondary to altered reinforcement mechanisms resulting from dysfunction of the mesolimbic and mesocortical dopaminergic systems. The present study therefore investigated whether there are regional differences in dopamine (DA) and acetylcholine (ACh) release and DA D₂-receptor function in SHR compared to their normotensive Wistar-Kyoto (WKY) controls. The DA D₂-receptor agonist, quinpirole, caused significantly greater inhibition of DA release from caudate-putamen but not from nucleus accumbens or prefrontal cortex slices of SHR relative to WKY. DA D₂-receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in DA release from nucleus accumbens slices of SHR compared to WKY suggesting increased efficacy of DA autoreceptors at low endogenous agonist concentrations in the nucleus accumbens of SHR. The electrically-stimulated release of DA was significantly lower in caudate-putamen and prefrontal cortex slices of SHR than in slices of WKY. This could be attributed to increased autoreceptor-mediated inhibition of DA release in caudate-putamen slices but not in the prefrontal cortex. No difference was observed between SHR and WKY with respect to DA D₂-receptor-mediated inhibition of ACh release from caudate-putamen or nucleus accumbens slices, suggesting that postsynaptic DA D₂-receptor function is not altered in SHR relative to WKY.     

The complete primary structure of toxin CM-1b from Hemachatus haemachatus (Ringhals) snake venom

Toxin CM-1b was purified from Hemachatus haemachatus venom. The purified toxin contains 57 amino acids including 8 half-cystine residues in a single polypeptide chain. The complete primary structure of CM-1b has been established. The sequence and the invariant amino acid residues of CM-1b resemble those of the Naja-type toxins. In toxin CM-1b one of the structurally invariant amino acid residues proline 48, of the short neurotoxins has been replaced by a arginine, while it contains none of the functionally invariant amino acid residues.     

Comparative sequence analysis of the South African vaccine strain and two virulent field isolates of Lumpy skin disease virus

Summary.  The genomic sequences of 3 strains of Lumpy skin disease virus (LSDV) (Neethling type) were compared to determine molecular differences, viz. the South African vaccine strain (LW), a virulent field-strain from a recent outbreak in South Africa (LD), and the virulent Kenyan 2490 strain (LK). A comparison between the virulent field isolates indicates that in 29 of the 156 putative genes, only 38 encoded amino acid differences were found, mostly in the variable terminal regions. When the attenuated vaccine strain (LW) was compared with field isolate LD, a total of 438 amino acid substitutions were observed. These were also mainly in the terminal regions, but with notably more frameshifts leading to truncated ORFs as well as deletions and insertions. These modified ORFs encode proteins involved in the regulation of host immune responses, gene expression, DNA repair, host-range specificity and proteins with unassigned functions. We suggest that these differences could lead to restricted immuno-evasive mechanisms and virulence factors present in attenuated LSDV strains. Further studies to determine the functions of the relevant encoded gene products will hopefully confirm this assumption. The molecular design of an improved LSDV vaccine is likely to be based on the strategic manipulation of such genes. Received November 25, 2002; accepted February 17, 2003 Published online May 5, 2003     

Quantitative determination of lymphocyte ACTH1-39

A method was developed for quantitative measurement of ACTH1-39, produced by human lymphocytes. It was shown that pH adjustment to 2 was essential for processing of the precursor molecule proopiomelanocortin (POMC). Linearity between time of incubation and ACTH production was shown. The existence of specific endopeptidases in lymphocytes for processing of the POMC molecule remains doubtful.