Prevalence of Abnormal Lipid Profiles and the Relationship With the Development of Microalbuminuria in Adolescents With Type 1 Diabetes

OBJECTIVE: To explore the prevalence of lipid abnormalities and their relationship with albumin excretion and microalbuminuria in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study population comprised 895 young subjects with type 1 diabetes (490 males); median age at the baseline assessment was 14.5 years (range 10-21.1), and median diabetes duration was 4.8 years (0.2-17). A total of 2,194 nonfasting blood samples were collected longitudinally for determination of total cholesterol, LDL cholesterol, HDL cholesterol, TG, and non-HDL cholesterol. Additional annually collected data on anthropometric parameters, A1C, and albumin-to-creatinine ratio (ACR) were available. RESULTS: Total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were higher in females than in males (all P 5.2 mmol/l (18.6%), non-HDL cholesterol >3.4 mmol/l (25.9%), TG >1.7 mmol/l (20.1%), and LDL cholesterol >3.4 mmol/l (9.6%). Age and duration were significantly related to all lipid parameters (P < 0.001); A1C was independently related to all parameters (P < 0.001) except HDL cholesterol, whereas BMI SD scores were related to all parameters (P < 0.05) except total cholesterol. Total cholesterol and non-HDL cholesterol were independently related to longitudinal changes in ACR (B coefficient +/- SE): 0.03 +/- 0.01/1 mmol/l, P = 0.009, and 0.32 +/- 0.014/1 mmol/l, P = 0.02, respectively. Overall mean total cholesterol and non-HDL cholesterol were higher in microalbuminuria positive (n = 115) than in normoalbuminuric subjects (n = 780): total cholesterol 4.7 +/- 1.2 vs. 4.5 +/- 0.8 mmol/l (P = 0.04) and non-HDL cholesterol 3.2 +/- 1.2 vs. 2.9 +/- 0.8 mmol/l (P = 0.03). CONCLUSIONS: In this longitudinal study of adolescents with type 1 diabetes, sustained lipid abnormalities were related to age, duration, BMI, and A1C. Furthermore, ACR was related to both total cholesterol and non-HDL cholesterol, indicating a potential role in the pathogenesis of diabetic nephropathy

Azotobacter genomes: the genome of Azotobacter chroococcum NCIMB 8003 (ATCC 4412)

The genome of the soil-dwelling heterotrophic N2-fixing Gram-negative bacterium Azotobacter chroococcum NCIMB 8003 (ATCC 4412) (Ac-8003) has been determined. It consists of 7 circular replicons totalling 5,192,291 bp comprising a circular chromosome of 4,591,803 bp and six plasmids pAcX50a, b, c, d, e, f of 10,435 bp, 13,852, 62,783, 69,713, 132,724, and 311,724 bp respectively. The chromosome has a G+C content of 66.27% and the six plasmids have G+C contents of 58.1, 55.3, 56.7, 59.2, 61.9, and 62.6% respectively. The methylome has also been determined and 5 methylation motifs have been identified. The genome also contains a very high number of transposase/inactivated transposase genes from at least 12 of the 17 recognised insertion sequence families. The Ac-8003 genome has been compared with that of Azotobacter vinelandii ATCC BAA-1303 (Av-DJ), a derivative of strain O, the only other member of the Azotobacteraceae determined so far which has a single chromosome of 5,365,318 bp and no plasmids. The chromosomes show significant stretches of synteny throughout but also reveal a history of many deletion/insertion events. The Ac-8003 genome encodes 4628 predicted protein-encoding genes of which 568 (12.2%) are plasmid borne. 3048 (65%) of these show > 85% identity to the 5050 protein-encoding genes identified in Av-DJ, and of these 99 are plasmid-borne. The core biosynthetic and metabolic pathways and macromolecular architectures and machineries of these organisms appear largely conserved including genes for CO-dehydrogenase, formate dehydrogenase and a soluble NiFe-hydrogenase. The genetic bases for many of the detailed phenotypic differences reported for these organisms have also been identified. Also many other potential phenotypic differences have been uncovered. Properties endowed by the plasmids are described including the presence of an entire aerobic corrin synthesis pathway in pAcX50f and the presence of genes for retro-conjugation in pAcX50c. All these findings are related to the potentially different environmental niches from which these organisms were isolated and to emerging theories about how microbes contribute to their communities

Impact of the F508del mutation on ovine CFTR, a Cl- channel with enhanced conductance and ATP-dependent gating

Cross-species comparative studies are a powerful approach to understand the epithelial Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in the genetic disease cystic fibrosis (CF). Here, we investigate the single-channel behaviour of ovine CFTR and the impact of the most common CF mutation, F508del-CFTR, using excised inside-out membrane patches from transiently transfected CHO cells. Like human CFTR, ovine CFTR formed a weakly inwardly rectifying Cl- channel regulated by PKA-dependent phosphorylation, inhibited by the open-channel blocker glibenclamide. However, for three reasons, ovine CFTR was noticeably more active than human CFTR. First, single-channel conductance was increased. Second, open probability was augmented because the frequency and duration of channel openings were increased. Third, with enhanced affinity and efficacy, ATP more strongly stimulated ovine CFTR channel gating. Consistent with these data, the CFTR modulator phloxine B failed to potentiate ovine CFTR Cl- currents. Like its impact on human CFTR, the F508del mutation caused a temperature-sensitive folding defect, which disrupted ovine CFTR protein processing and reduced membrane stability. However, the F508del mutation had reduced impact on ovine CFTR channel gating in contrast to its marked effects on human CFTR. We conclude that ovine CFTR forms a regulated Cl- channel with enhanced conductance and ATP-dependent channel gating. This phylogenetic analysis of CFTR structure and function demonstrates that subtle changes in structure have pronounced effects on channel function and the consequences of the CF mutation F508del. This article is protected by copyright. All rights reserved

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

India's Nuclear Options and Escalation Dominance

Since the early 2000s, Indian strategists have wrestled with the challenge of motivating Pakistan to demobilize anti-India terrorist groups while managing the potential for conflict escalation during a crisis. The growing prominence of nuclear weapons in Pakistan’s national security strategy casts a shadow of nuclear use over any potential military strategy India might consider to strike this balance. However, augmenting its nuclear options with tactical nuclear weapons is unlikely to bolster Indian deterrence in convincing ways.Naval Postgraduate School’s Project on Advanced Systems and Concepts for Countering Weapons of Mass Destruction via Assistance Grant/Agreement No. N00244-15-1-0024 awarded by the Naval Supply Systems Command’s Fleet Logistics Center San Diego, Californi

Plus Ça Change? Prospects of a Nuclear Deterrence Multipolarity in Southern Asia

ABSTRACTSome scholars assess that Southern Asia comprises a nuclear chain or a deterrence trilemma. Although the region is home to three states with nuclear weapons, there is only one clear nuclear deterrence dyad. India and Pakistan have explored the contours of nuclear deterrence in several past military crises, while nuclear weapons have been notably absent from recent Sino-Indian border tensions. What factors or developments might push the region toward a nuclear deterrence multipolarity? The key variable is the India–China relationship and the extent to which nuclear weapons become more prominent in respective national security belief systems in New Delhi and Beijing. Notable trends already favor such a development, including changing geopolitics in the region, the rise of nationalist domestic politics, technology competition, and growing crisis escalation concerns. Two fulcrums that might tip the region from the status quo into a deterrence multipolarity are parallel nuclear posture changes in India and China that create nuclear coupling, and hardening of geopolitical alignments into more adversarial blocs. Preventing deterrence multipolarity through new nuclear confidence-building measures will be difficult owing to divergent interests, power and institutions in the region. Upgrades to existing nuclear CBMs may be more politically feasible. Even in the absence of new nuclear CBMs, however, China, India, and Pakistan could build predictability in the region and mitigate potential sources of conflict through new measures to manage common-pool resource competition, dangerous behaviours in space, and a range of crises and emergencies

Armed for Arms Control? Presidents, Bureaucrats and the Role of Government Structure in Policymaking

Reorganizations of government structure are a common political solution to organizational challenges. But do such major changes in structure yield optimized policy or improve decisionmaking? Are independent agencies more or less effective and do they exert a greater or lesser impact on the policy they were created to shape and implement than they would be if subordinated to a larger bureaucratic structure? This dissertation analyzes the relationship between government structure, decisionmaking, and policy effectiveness as applied to a central national security policy priority of the last 60 years: strategic arms control. It utilizes a case assessment to compare the role and impact of the US Arms Control and Disarmament Agency (ACDA) in interagency policymaking during the US-Soviet Strategic Arms Limitation Talks and the Strategic Arms Reduction Treaty negotiations, with the role and impact of ACDA's successor functions--after they were incorporated into the State Department in 1999--during the US-Russia New START negotiation. The dissertation assesses whether small, independent agencies are or can be more effective than if the same government function is embedded in a larger, cabinet department; which factors lend credibility (or audibility) to these policy voices; and the extent to which government structure as opposed to other factors, namely presidential interest or interagency management, impacts policy effectiveness. In addition to policy effectiveness, the dissertation also analyzes the relationship between government structure, agency design and national security decisionmaking, a broader topic of relevance to the policy sciences. In particular, by exploring how changes in structure affect the interagency policy process and outcomes and the extent to which structure interacts with government politics, the dissertation assesses how the sources of power of the two sets of major actors in government (presidents and bureaucrats) are conditioned by structure, and how those actors in turn can use structure to manipulate process and outcomes. The case analysis affirms that specialized agencies like ACDA can fulfill an important staffing requirement when the government otherwise lacks sufficient expertise, but in general such agencies struggle to influence major national security policy decisions, regardless of the dominant decisionmaking paradigm. An independent mission and statutory authority are insufficient to guarantee an agency's policy effectiveness, particularly if they operate in an ideologically charged policy milieu. Instead, policy effectiveness is tied more to expertise and key relationships between an agency director and principals at other agencies, particularly if decisionmaking is dominated by presidents rather than government politics, as arms control has tended to be. Government administrations have often used reorganization as a way to highlight priorities and seek more effective policies. Instead of utilizing structural reforms, however, future administrations seeking to adequately arm the government for arms control negotiations should focus on building a cadre of qualified and respected expertise to staff the issues, both civil servants and political appointees. Harnessing the right experts and vesting them with presidential confidence is more likely to achieve effective policy than moving boxes on the organization chart

Melt electrospinning today: An opportune time for an emerging polymer process

Over the last decade, melt electrospinning has emerged as an alternative polymerprocessing technology to alleviate concerns associated with solvents in traditional elec-trospinning. This has resulted in the fabrication of ultrafine fibers from an increasing rangeof synthetic polymers and composite systems, to materials including ceramics, drivingnew applications in technical areas such as textiles, filtration, environment and energyas well as biomedicine. In this article, we review the significant advancements in theoret-ical modeling of the underlying physical principles, coupled with experimental validationusing a variety of technical devices and designs that allows well-controlled fiber formationusing optimized material and operating parameters. Innovative device designs are indi-cating avenues towards higher throughput of randomly collected melt electrospun fibersfor the production of commodity nonwoven substrates, similar to solution electrospinningand many other industrial fiber-forming processes. However, we identify a recent shift inperception towards melt electrospinning in the literature, where the adaptation of additivemanufacturing approaches to device designs enables precise fiber placement with filamentresolutions not yet demonstrated by more established melt-extrusion based direct writingtechnologies. New, highly ordered arrangements of ultrafine fibers with distinctive surfacetopology, encapsulating and sensing properties are opening new fields of application inareas such as drug delivery, biosensors and regenerative medicine as high performancematerials. The development of these materials is reviewed with an emphasis on an area ofcurrent research, where melt electrospun scaffolds are contributing to promising treatmentstrategies to regenerate or replace human tissue and for the new field of in vitro diseasemodels as well as humanized mice models