The Archaeology of Fazzan, Volume 1

This book seeks to advance knowledge of human settlement and adaptation in the world's largest desert, the sahara. Previous studies focussed on the prehistoric phases but this study takes a wider historical and geographical perspective. It sets out to combine the results of several field campaigns, their histories and methodologies. We look at fieldwork, fortifications, funerary structures, irrigation, rock art and human occupation. The final summary looks at the current state of research and offers a platform for future investigations

High-Sensitivity C Reactive Protein: Associations with Cardiovascular Risk Factors and Tracking in Female Adolescents and Young Adults

Objective. We assessed adolescent anthropometry, lipids, insulin, glucose, and blood pressures to identify factors associated with high-sensitivity C-reactive protein (hsCRP) and its tracking in young adults. Methods. Ten-year prospective study of 589 schoolgirls, 321 black, 268 white. Results. HsCRP did not differ (P > .08) by race or oral contraceptive use. HsCRP tracked from age 16 to 25 (r = 0.77), 16 to 26 (r = 0.50), 24 to 26 (r = 0.66), and 25 to 26 (r = 0.71), all P ≤ .02. By stepwise regression, at age 16, waist circumference accounted for 44.8% of hsCRP variance; BMI accounted for 33.1%, 34.4%, and 31.1% at ages 24, 25, and 26, P < .0001 for all. Changes in cholesterol and BMI were associated with change in hsCRP from age 24–26 (partial R2 = 12.3%  P < .0001, 6.6%  P = .0012). Changes in BMI and triglyceride (partial R2 = 8.5%  P = .0001, 3.3%, P = .0045) were associated with change in hsCRP from age 25 to 26. Conclusions. HsCRP tracks from age 16 to 26, with BMI, waist circumference, and cholesterol as major determinants

The in vitro synthesis and processing of the branched-chain amino acid binding proteins

The synthesis of the leucine-specific and LIV-binding proteins was examined in vitro in a coupled transcription/translation system using the hybrid plasmids pOX7 and pOX13 as templates. Plasmid pOX7 contains the livK gene coding for the leucine-specific binding protein, and pOX13 contains the liv J gene coding for the LIV-binding protein. Both binding proteins were synthesized in vitro as precursor forms with molecular weights approximately 2,500 greater than their respective mature forms. Conversion of the precursor forms to their mature forms occurred during post-translational incubation following synthesis in the presence of membrane. The precursor of the LIV-binding protein was processed more rapidly than the leucine-specific binding protein precursor. Processing activity could be removed from the in vitro synthesis system by centrifugation, suggesting that the processing activity was membrane associated. Restoration of post-translational processing activity was achieved by adding inside-out membrane vesicles to membrane-depleted reaction mixtures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38208/1/400140305_ftp.pd

“What if There's Something Wrong with Her?”‐How Biomedical Technologies Contribute to Epistemic Injustice in Healthcare

While there is a steadily growing literature on epistemic injustice in healthcare, there are few discussions of the role that biomedical technologies play in harming patients in their capacity as knowers. Through an analysis of newborn and pediatric genetic and genomic sequencing technologies (GSTs), I argue that biomedical technologies can lead to epistemic injustice through two primary pathways: epistemic capture and value partitioning. I close by discussing the larger ethical and political context of critical analyses of GSTs and their broader implications for just and equitable healthcare delivery

Public involvement in the priority setting activities of a wait time management initiative: a qualitative case study

<p>Abstract</p> <p>Background</p> <p>As no health system can afford to provide all possible services and treatments for the people it serves, each system must set priorities. Priority setting decision makers are increasingly involving the public in policy making. This study focuses on public engagement in a key priority setting context that plagues every health system around the world: wait list management. The purpose of this study is to describe and evaluate priority setting for the Ontario Wait Time Strategy, with special attention to public engagement.</p> <p>Methods</p> <p>This study was conducted at the Ontario Wait Time Strategy in Ontario, Canada which is part of a Federal-Territorial-Provincial initiative to improve access and reduce wait times in five areas: cancer, cardiac, sight restoration, joint replacements, and diagnostic imaging. There were two sources of data: (1) over 25 documents (e.g. strategic planning reports, public updates), and (2) 28 one-on-one interviews with informants (e.g. OWTS participants, MOHLTC representatives, clinicians, patient advocates). Analysis used a modified thematic technique in three phases: open coding, axial coding, and evaluation.</p> <p>Results</p> <p>The Ontario Wait Time Strategy partially meets the four conditions of 'accountability for reasonableness'. The public was not directly involved in the priority setting activities of the Ontario Wait Time Strategy. Study participants identified both benefits (supporting the initiative, experts of the lived experience, a publicly funded system and sustainability of the healthcare system) and concerns (personal biases, lack of interest to be involved, time constraints, and level of technicality) for public involvement in the Ontario Wait Time Strategy. Additionally, the participants identified concern for the consequences (sustainability, cannibalism, and a class system) resulting from the Ontario Wait Times Strategy.</p> <p>Conclusion</p> <p>We described and evaluated a wait time management initiative (the Ontario Wait Time Strategy) with special attention to public engagement, and provided a concrete plan to operationalize a strategy for improving public involvement in this, and other, wait time initiatives.</p

Regulation of high-affinity leucine transport in escherichia coli

Leucine is transported into E coli by two osmotic shock-sensitive, high-affinity systems (LIV-I and leucine-specific systems) and one membrane bound, low-affinity system (LIV-II). Expression of the high-affinity transport systems is altered by mutations in liv R and 1st R , genes for negatively acting regulatory elements, and by mutations in rho , the gene for transcription termination. All four genes for high-affinity leucine transport ( livJ, livK, livH , and livG ) are closely linked and have been cloned on a plasmid vector, pOX1. Several subcloned fragments of this plasmid have been prepared and used in complementation and regulation studies. The results of these studies suggest that livJ and livK are separated by approximately one kilobase and give a gene order of livJ–livK–livH. livJ and livK appear to be regulated in an interdependent fashion; livK is expressed maximally when the livJ gene is inactivated by mutation or deletion. The results support the existence of separate promoters for the livJ and livK genes. The effects of mutations in the rho and livR genes are additive on one another and therefore appear to be involved in independent regulatory mechanisms. Mutations in the rho gene affect both the LIV-I and leucinespecific transport systems by increasing the expression of livJ and livK , genes for the LIV-specific and leucine-specific binding proteins, respectively.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38209/1/400140410_ftp.pd

Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain

Abstract Background Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients. Methods Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools. Results The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools. Conclusions Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.http://deepblue.lib.umich.edu/bitstream/2027.42/78267/1/1748-5908-5-26.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/2/1748-5908-5-26.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/3/1748-5908-5-26-S3.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/4/1748-5908-5-26-S2.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/5/1748-5908-5-26-S1.TIFFPeer Reviewe

SARS-CoV-2 S2–targeted vaccination elicits broadly neutralizing antibodies

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses

Measurement of Myofilament-Localised Calcium Dynamics in Adult Cardiomyocytes and the Effect of Hypertrophic Cardiomyopathy Mutations

Rationale: Subcellular Ca2+ indicators have yet to be developed for the myofilament where disease mutation, or small molecules may alter contractility through myofilament Ca2+ sensitivity. Here we develop and characterise genetically encoded Ca2+ indicators restricted to the myofilament to directly visualise Ca2 changes in the sarcomere. Objective: To produce and validate myofilament restricted Ca2+ imaging probes in an adenoviral transduction adult cardiomyocyte model using drugs that alter myofilament function (MYK-461, omecamtiv mecarbil and levosimendan) or following co-transduction of two established hypertrophic cardiomyopathy (HCM) disease causing mutants (cTnT R92Q and cTnI R145G) that alter myofilament Ca2+ handling. Methods and Results: When expressed in adult ventricular cardiomyocytes RGECO-TnT/TnI sensors localise correctly to the sarcomere without contractile impairment. Both sensors report cyclical changes in fluorescence in paced cardiomyocytes with reduced Ca2+ on and increased Ca2+ off rates compared with unconjugated RGECO. RGECO-TnT/TnI revealed changes to localised Ca2+ handling conferred by MYK-461 and levosimendan, including an increase in Ca2+ binding rates with both levosimendan and MYK-461 not detected by an unrestricted protein sensor. Co-adenoviral transduction of RGECO-TnT/TnI with HCM causing thin filament mutants showed that the mutations increase myofilament [Ca2+] in systole, lengthen time to peak systolic [Ca2+], and delay [Ca2+] release. This contrasts with the effect of the same mutations on cytoplasmic Ca2+, when measured using unrestricted RGECO where changes to peak systolic Ca2+ are inconsistent between the two mutations. These data contrast with previous findings using chemical dyes that show no alteration of [Ca2+] transient amplitude or time to peak Ca2+. Conclusions: RGECO-TnT/TnI are functionally equivalent. They visualise Ca2+ within the myofilament and reveal unrecognised aspects of small molecule and disease associated mutations in living cells

Combining evidence and values in priority setting: testing the balance sheet method in a low-income country

<p>Abstract</p> <p>Background</p> <p>Procedures for priority setting need to incorporate both scientific evidence and public values. The aim of this study was to test out a model for priority setting which incorporates both scientific evidence and public values, and to explore use of evidence by a selection of stakeholders and to study reasons for the relative ranking of health care interventions in a setting of extreme resource scarcity.</p> <p>Methods</p> <p>Systematic search for and assessment of relevant evidence for priority setting in a low-income country. Development of a balance sheet according to Eddy's explicit method. Eight group interviews (n-85), using a modified nominal group technique for eliciting individual and group rankings of a given set of health interventions.</p> <p>Results</p> <p>The study procedure made it possible to compare the groups' ranking before and after all the evidence was provided to participants. A rank deviation is significant if the rank order of the same intervention differed by two or more points on the ordinal scale. A comparison between the initial rank and the final rank (before deliberation) showed a rank deviation of 67%. The difference between the initial rank and the final rank after discussion and voting gave a rank deviation of 78%.</p> <p>Conclusion</p> <p>Evidence-based and deliberative decision-making does change priorities significantly in an experimental setting. Our use of the balance sheet method was meant as a demonstration project, but could if properly developed be feasible for health planners, experts and health workers, although more work is needed before it can be used for laypersons.</p