Platelet inventory management with demand and supply uncertainty and variable pricing considerations.

Managing the inventory of blood is a crucial operation in hospitals owing to its significance in medical treatment. At the same time, blood is characterized by unique attributes, such as perishability and the unpredictable nature of its supply and demand. While models have been developed to optimize the said process, gaps in literature exist in terms of considering the possibility of variable pricing and extensively accounting for uncertainties in the supply chain. In this light, the present study proposes a stochastic multi-period mixed integer linear programming cost minimization model that determines the optimal inventory plan for a hospital purchasing platelets, assuming that prices fluctuate along with the blood center's supply. To implement uncertain supply and demand, the model considers a discrete set of scenarios for each parameter. A study was performed, and the results indicate a promising direction as inventory costs decreased relative to models without the new considerations.

The role of dopamine in eye growth responses to color and luminance flicker in chicks.

Stroboscopic luminance flicker has been found to prevent the increase in eye growth normally associated with form deprivation through the release of retinal dopamine. In this study, we sought to investigate whether dopamine plays a role in the decreased growth observed with 2 Hz sine-wave luminance flicker and increased growth with color flicker. Starting 5-7 days after hatching, chicks were exposed to 2 Hz sinusoidally modulated illumination (Mean: 680 lux) for 4 days and were otherwise in the dark. Chicks were exposed to color-modulated red and green (RG) light, to luminance modulated RGB components (LUM), or to a no-flicker (NF) control. Chicks received daily 10 µL intravitreal injections of apomorphine, spiperone, or saline. Fellow eyes received no injection. Spiperone injections prevented the decrease in eye growth typically seen with LUM flicker, with a relative increase in eye length, but no other significant effects compared with saline controls. Apomorphine injections prevented the increase in eye growth typically seen with RG flicker, with a relative decrease in eye length compared to saline controls. These results indicate a role for the activation of D2-receptor types in the inhibition of eye growth in response to luminance flicker, and a lack of dopamine receptor activation associated with the increase in eye growth with color flicker.

DNA stretching by bacterial initiators promotes replication origin opening.

Many replication initiators form higher-order oligomers that process host replication origins to promote replisome formation. In addition to dedicated duplex-DNA-binding domains, cellular initiators possess AAA+ (ATPases associated with various cellular activities) elements that drive functions ranging from protein assembly to origin recognition. In bacteria, the AAA+ domain of the initiator DnaA has been proposed to assist in single-stranded DNA formation during origin melting. Here we show crystallographically and in solution that the ATP-dependent assembly of Aquifex aeolicus DnaA into a spiral oligomer creates a continuous surface that allows successive AAA+ domains to bind and extend single-stranded DNA segments. The mechanism of binding is unexpectedly similar to that of RecA, a homologous recombination factor, but it differs in that DnaA promotes a nucleic acid conformation that prevents pairing of a complementary strand. These findings, combined with strand-displacement assays, indicate that DnaA opens replication origins by a direct ATP-dependent stretching mechanism. Comparative studies reveal notable commonalities between the approach used by DnaA to engage DNA substrates and other, nucleic-acid-dependent, AAA+ systems.

Assessing Laboratory Method Validations for Informing Inference Across Survey Cycles in the National Health and Nutrition Examination Survey.

Background and objectives Laboratory tests conducted on survey respondents' biological specimens are a major component of the National Health and Nutrition Examination Survey. The National Center for Health Statistics' Division of Health and Nutrition Examination Surveys performs internal analytic method validation studies whenever laboratories undergo instrumental or methodological changes, or when contract laboratories change. These studies assess agreement between methods to evaluate how methodological changes could affect data inference or compromise consistency of measurements across survey cycles. When systematic differences between methods are observed, adjustment equations are released with the data documentation for analysts planning to combine survey cycles or conduct a trend analysis. Adjustment equations help ensure that observed differences from methodological changes are not misinterpreted as population changes. This report assesses the reliability of statistical methods used by the Division of Health and Nutrition Examination Surveys when conducting method validation studies to address concerns that adjustment equations are being overproduced (recommended too frequently). Methods Public-use 2017-2018 National Health and Nutrition Examination Survey laboratory data were used to simulate "new" measurements for 120 analytic method validation studies. Blinded studies were analyzed to determine the final adjustment recommendation for each study using difference plots, descriptive statistics, t-tests, and Deming regressions. Final recommendations were compared with simulated difference types to assess how often spurious results were observed. Concordance estimates (concordance, misclassification, sensitivity, specificity, and positive and negative predictive values) informed assessments. Results Adjustment equations were appropriately recommended for 75.0% of the studies, over-recommended for 5.8%, under-recommended for 15.8%, and recommended with an inappropriate technique for 3.3%. Across simulated difference types, sensitivity ranged from 65.9% to 84.4% and specificity from 74.7% to 97.5%. Conclusions Findings from this report suggest that the current methodology used by the Division of Health and Nutrition Examination Surveys performs moderately well. Based on these data and analyses, underadjustment was more prevalent than overadjustment, suggesting that the current methodology is conservative.

Origin remodeling and opening in bacteria rely on distinct assembly states of the DnaA initiator.

The initiation of DNA replication requires the melting of chromosomal origins to provide a template for replisomal polymerases. In bacteria, the DnaA initiator plays a key role in this process, forming a large nucleoprotein complex that opens DNA through a complex and poorly understood mechanism. Using structure-guided mutagenesis, biochemical, and genetic approaches, we establish an unexpected link between the duplex DNA-binding domain of DnaA and the ability of the protein to both self-assemble and engage single-stranded DNA in an ATP-dependent manner. Intersubunit cross-talk between this domain and the DnaA ATPase region regulates this link and is required for both origin unwinding in vitro and initiator function in vivo. These findings indicate that DnaA utilizes at least two different oligomeric conformations for engaging single- and double-stranded DNA, and that these states play distinct roles in controlling the progression of initiation.

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis.

Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases. We present clinical and genetic study results from seven adult male subjects with recurrent exertional rhabdomyolysis. In all subject, whole exome sequencing identified multiple heterozygous variants in genes associated with monogenic metabolic and/or mitochondrial disorders. These variants consisted of known pathogenic and/or new likely pathogenic variants in combination with other rare deleterious alleles. The presence of heterozygous pathogenic and rare deleterious variants in multiple genes suggests an oligogenic inheritance for exertional rhabdomyolysis etiology. Our data imply that exertional rhabdomyolysis can reflect cumulative effects or synergistic interactions of deleterious variants in multiple genes that are likely to compromise muscle metabolism under the stress of exercise.

Multifactorial Origin of Exertional Rhabdomyolysis, Recurrent Hematuria, and Episodic Pain in a Service Member with Sickle Cell Trait.

Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by various other acquired and inherited factors. We report an SCT positive service member with an exertional rhabdomyolysis event, recurrent hematuria with transient proteinuria, and episodic burning pain in the lower extremities. Clinical and genetic studies revealed the multifactorial nature of his complex phenotype. The service member was taking prescription medications known to be associated with exertional rhabdomyolysis. He carried a pathogenic mutation, NPHS2 p.V260E, reported in nephropathy and a new variant p.R838Q in SCN11A, a gene involved in familial episodic pain syndrome. Results suggest that drug-to-drug interactions coupled with the stress of exercise, coinheritance of HbAS and NPHS2 p.V260E, and p. R838Q in SCN11A contributed to exertional rhabdomyolysis, recurrent hematuria with proteinuria, and episodic pain, respectively. This case underscores the importance of comprehensive clinical and genetic evaluations to identify underlying causes of health complications reported in SCT individuals.