Results of the 2023 ISBI challenge to reduce GABA-edited MRS acquisition time.

PURPOSE: Use a conference challenge format to compare machine learning-based gamma-aminobutyric acid (GABA)-edited magnetic resonance spectroscopy (MRS) reconstruction models using one-quarter of the transients typically acquired during a complete scan. METHODS: There were three tracks: Track 1: simulated data, Track 2: identical acquisition parameters with in vivo data, and Track 3: different acquisition parameters with in vivo data. The mean squared error, signal-to-noise ratio, linewidth, and a proposed shape score metric were used to quantify model performance. Challenge organizers provided open access to a baseline model, simulated noise-free data, guides for adding synthetic noise, and in vivo data. RESULTS: Three submissions were compared. A covariance matrix convolutional neural network model was most successful for Track 1. A vision transformer model operating on a spectrogram data representation was most successful for Tracks 2 and 3. Deep learning (DL) reconstructions with 80 transients achieved equivalent or better SNR, linewidth and fit error compared to conventional 320 transient reconstructions. However, some DL models optimized linewidth and SNR without actually improving overall spectral quality, indicating a need for more robust metrics. CONCLUSION: DL-based reconstruction pipelines have the promise to reduce the number of transients required for GABA-edited MRS.

Family Physician-to-Hospital Specialist Electronic Consultation and Access to Hospital Care: A Systematic Review.

Importance: Globally, health care systems face challenges in managing health care costs while maintaining access to hospital care, quality of care, and a good work balance for caregivers. Electronic consultations (e-consultations)-defined as asynchronous, consultative communication between family physicians and hospital specialists-may offer advantages to face these challenges. Objective: To provide a quantitative synthesis of the association of e-consultation with access to hospital care and the avoidance of hospital referrals. Evidence Review: A systematic search through PubMed, MEDLINE, and Embase was conducted. Eligible studies included original research studies published from January 2010 to March 2023 in English, Dutch, or German that reported on outcomes associated with access to hospital care and the avoidance of hospital referrals. Reference lists of included articles were searched for additional studies. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) scores were assigned to assess quality of evidence. Findings: The search strategy resulted in 583 records, of which 72 studies were eligible for data extraction after applying exclusion criteria. Most studies were observational, focused on multispecialty services, and were performed in either Canada or the US. Outcomes on access to hospital care and the avoidance of referrals indicated that e-consultation was associated with improved access to hospital care and an increase in avoided referrals to the hospital specialist, although outcomes greatly differed across studies. GRADE scores were low or very low across studies. Conclusions and Relevance: In this systematic review of the association of e-consultation with access to hospital care and the avoidance of hospital referrals, results indicated that the use of e-consultation has greatly increased over the years. Although e-consultation was associated with improved access to hospital care and avoidance of hospital referrals, it was hard to draw a conclusion about these outcomes due to heterogeneity and lack of high-quality evidence (eg, from randomized clinical trials). Nevertheless, these results suggest that e-consultation seems to be a promising digital health care implementation, but more rigorous studies are needed; nonrandomized trial designs should be used, and appropriate outcomes should be chosen in future research on this topic.

A review of machine learning applications for the proton MR spectroscopy workflow.

This literature review presents a comprehensive overview of machine learning (ML) applications in proton MR spectroscopy (MRS). As the use of ML techniques in MRS continues to grow, this review aims to provide the MRS community with a structured overview of the state-of-the-art methods. Specifically, we examine and summarize studies published between 2017 and 2023 from major journals in the MR field. We categorize these studies based on a typical MRS workflow, including data acquisition, processing, analysis, and artificial data generation. Our review reveals that ML in MRS is still in its early stages, with a primary focus on processing and analysis techniques, and less attention given to data acquisition. We also found that many studies use similar model architectures, with little comparison to alternative architectures. Additionally, the generation of artificial data is a crucial topic, with no consistent method for its generation. Furthermore, many studies demonstrate that artificial data suffers from generalization issues when tested on in vivo data. We also conclude that risks related to ML models should be addressed, particularly for clinical applications. Therefore, output uncertainty measures and model biases are critical to investigate. Nonetheless, the rapid development of ML in MRS and the promising results from the reviewed studies justify further research in this field.

Prognosis of shoulder pain in those with and without a psychological disorder: A prospective cohort study with a six-month follow-up.

BACKGROUND: Because shoulder pain can have an unfavorable prognosis, it is important to have a better understanding of factors that may influence recovery. OBJECTIVE: To determine the association between recovery from shoulder pain and the presence of depression, anxiety, and pain catastrophizing. METHODS: In a prospective cohort study with a six months follow-up, we included patients visiting an orthopaedic department with shoulder pain. Primary outcome was recovery from shoulder pain measured with the Shoulder Pain and Disability Index at three and six months. Information about depression and anxiety (Hospital Anxiety and Depression Scale), pain catastrophizing (Pain Catastrophizing Scale), and demographic and clinical factors were collected at baseline. A linear mixed model was used to estimate the effects of depression, anxiety, pain catastrophizing, and underlying shoulder disorders on recovery. RESULTS: We included 190 patients. There were no statistically significant associations between the presence of depression, anxiety, and pain catastrophizing, and three- and six-month recovery. Also between the underlying shoulder disorders and recovery at three and six months, there were no statistically significant associations. CONCLUSIONS: We could not prove that depression, anxiety, and pain catastrophizing, as well as underlying shoulder disorders, were associated with recovery of shoulder pain at six months.

Effect of a price display intervention on laboratory test ordering behavior of general practitioners.

BACKGROUND: Redundant use of diagnostic tests in primary care has shown to be a contributor to rising Dutch healthcare costs. A price display in the test ordering system of the electronic health records (EHRs) could potentially be a low-cost and easy to implement intervention to a decrease in test ordering rate in the primary care setting by creating more cost-awareness among general practitioners (GPs). The aim of this study was to assess the effect of a price display for diagnostic laboratory tests in the EHR on laboratory test ordering behavior of GPs in the Westelijke Mijnstreek region in the Netherlands. METHODS: A pre-post intervention study among 154 GPs working in 57 general practices was conducted from September 2019, until March 2020, in the Netherlands. The intervention consisted of displaying the costs of 22 laboratory tests at the time of ordering. The primary outcome was the mean test ordering rate per 1.000 patients per month, per general practice. RESULTS: Test ordering rates were on average rising prior to the intervention. The total mean monthly test order volume showed a non-statistically significant interruption in this rising trend after the intervention, with the mean monthly test ordering rate levelling out from 322.4 to 322.2 (P = 0.86). A subgroup analysis for solely individually priced tests showed a statistically significant decrease in mean monthly test ordering rate after implementation of the price display for the sum of all tests from 67.2 to 63.3 (P = 0.01), as well as for some of these tests individually (i.e. thrombocytes, ALAT, TSH, folic acid). Leucocytes, ESR, vitamin B12, anti-CCP and NT-proBNP also showed a decrease, albeit not statistically significant (P > 0.05). CONCLUSIONS: Our study suggests that a price display intervention is a simple tool that can alter physicians order behavior and constrain the expanding use of laboratory tests. Future research might consider alternative study designs and a longer follow-up period. Furthermore, in future studies, the combination with a multitude of interventions, like educational programs and feedback strategies, should be studied, while potentially adverse events caused by reduced testing should also be taken into consideration.

Use of bioengineered human commensal gut bacteria-derived microvesicles for mucosal plague vaccine delivery and immunization.

Plague caused by the Gram-negative bacterium, Yersinia pestis, is still endemic in parts of the world today. Protection against pneumonic plague is essential to prevent the development and spread of epidemics. Despite this, there are currently no licensed plague vaccines in the western world. Here we describe the means of delivering biologically active plague vaccine antigens directly to mucosal sites of plague infection using highly stable microvesicles (outer membrane vesicles; OMVs) that are naturally produced by the abundant and harmless human commensal gut bacterium Bacteroides thetaiotaomicron (Bt). Bt was engineered to express major plague protective antigens in its OMVs, specifically Fraction 1 (F1) in the outer membrane and LcrV (V antigen) in the lumen, for targeted delivery to the gastrointestinal (GI) and respiratory tracts in a non-human primate (NHP) host. Our key findings were that Bt OMVs stably expresses F1 and V plague antigens, particularly the V antigen, in the correct, immunogenic form. When delivered intranasally V-OMVs elicited substantive and specific immune and antibody responses, both in the serum [immunoglobulin (Ig)G] and in the upper and lower respiratory tract (IgA); this included the generation of serum antibodies able to kill plague bacteria. Our results also showed that Bt OMV-based vaccines had many desirable characteristics, including: biosafety and an absence of any adverse effects, pathology or gross alteration of resident microbial communities (microbiotas); high stability and thermo-tolerance; needle-free delivery; intrinsic adjuvanticity; the ability to stimulate both humoral and cell-mediated immune responses; and targeting of primary sites of plague infection.

An aerosol challenge model of tuberculosis in Mauritian cynomolgus macaques.

BACKGROUND: New interventions for tuberculosis are urgently needed. Non-human primate (NHP) models provide the most relevant pre-clinical models of human disease and play a critical role in vaccine development. Models utilising Asian cynomolgus macaque populations are well established but the restricted genetic diversity of the Mauritian cynomolgus macaques may be of added value. METHODS: Mauritian cynomolgus macaques were exposed to a range of doses of M. tuberculosis delivered by aerosol, and the outcome was assessed using clinical, imaging and pathology-based measures. RESULTS: All macaques developed characteristic clinical signs and disease features of tuberculosis (TB). Disease burden and the ability to control disease were dependent on exposure dose. Mauritian cynomolgus macaques showed less variation in pulmonary disease burden and total gross pathology scores within exposure dose groups than either Indian rhesus macaques or Chinese cynomolgus macaques. CONCLUSIONS: The genetic homogeneity of Mauritian cynomolgus macaques makes them a potentially useful model of human tuberculosis.

Physical Activity Is Associated With Glucose Tolerance Independent of Microvascular Function: The Maastricht Study.

CONTEXT AND OBJECTIVE: Moderate-to-vigorous physical activity (MVPA) and physical fitness (PF) are positively associated with glucose tolerance. Such associations may be partly conditioned by microvascular function, which is a common correlate to MVPA, PF, and glucose tolerance. To test this hypothesis, the present study sought to investigate independent associations of MVPA and PF with glucose tolerance and to what extent these associations are mediated by microvascular function. Design, Setting, Participants, and Outcome Measures: Data from The Maastricht Study were used (n = 512 for MVPA and n = 488 for PF analyses; mean age, 59 [SD = 9] y, 52 % men). Glucose tolerance was assessed by 2-hour postload plasma glucose levels (2hPG). The total number of weekly hours of MVPA was estimated with the Community Healthy Activities Model Program for Seniors questionnaire. Walking speed during the 6-minute walk test was used to evaluate PF. Microvascular function was determined by postocclusive capillary recruitment and flowmotion with capillaroscopy and laser Doppler flowmetry in skin microcirculation. RESULTS: In univariate analyses, MVPA, PF, and microvascular function variables were associated with 2hPG. MVPA (n = 512, ß = -0.056, P = .019) and PF (n = 488, ß = -0.368, P = .006) remained associated with 2hPG after adjustment for established cardio-metabolic risk factors and history of cardiovascular disease; addition of microvascular function variables as potential mediators did not materially change the associations of MVPA (ß = -0.054, P = .024) and PF (ß = -0.364, P = .006) with 2hPG. No mediation effects of microvascular function variables were detected. CONCLUSIONS: MVPA and PF were independently associated with 2hPG, irrespective of established risk factors and generalized microvascular function. The possibility that specific microvascular functions, eg, insulin-mediated vasodilation, influence the association of MVPA and PF with 2hPG needs further investigation.

Capillary Rarefaction Associates with Albuminuria: The Maastricht Study.

Albuminuria may be a biomarker of generalized (i.e., microvascular and macrovascular) endothelial dysfunction. According to this concept, endothelial dysfunction of the renal microcirculation causes albuminuria by increasing glomerular capillary wall permeability and intraglomerular pressure, the latter eventually leading to glomerular capillary dropout (rarefaction) and further increases in intraglomerular pressure. However, direct evidence for an association between capillary rarefaction and albuminuria is lacking. Therefore, we examined the cross-sectional association between the recruitment of capillaries after arterial occlusion (capillary density during postocclusive peak reactive hyperemia) and during venous occlusion (venous congestion), as assessed with skin capillaroscopy, and albuminuria in 741 participants of the Maastricht Study, including 211 participants with type 2 diabetes. Overall, 57 participants had albuminuria, which was defined as a urinary albumin excretion ≥30 mg/24 h. After adjustment for potential confounders, participants in the lowest tertile of skin capillary recruitment during postocclusive peak reactive hyperemia had an odds ratio for albuminuria of 2.27 (95% confidence interval, 1.07 to 4.80) compared with those in the highest tertile. Similarly, a comparison between the lowest and the highest tertiles of capillary recruitment during venous congestion yielded an odds ratio of 2.89 (95% confidence interval, 1.27 to 6.61) for participants in the lowest tertile. In conclusion, lower capillary density of the skin microcirculation independently associated with albuminuria, providing direct support for a role of capillary rarefaction in the pathogenesis of albuminuria.

Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques.

Nine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, the Mycobacterium bovis BCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4ß1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

Uric acid and skin microvascular function: the Maastricht study.

OBJECTIVE: Microvascular dysfunction has been suggested as a possible underlying mechanism for the association between uric acid and various diseases, such as hypertension, renal disease and cardiomyopathies. We therefore analysed the association between serum uric acid and skin microvascular function, a model of generalized microvascular function. METHODS: A cross-sectional study was performed in 610 individuals [51.8% men; mean age 58.7 ±â€Š8.6 years; 23.6% with type 2 diabetes (by design)] from The Maastricht Study. We assessed skin capillary density (capillaries/mm) by capillaroscopy at baseline, after 4 min of arterial occlusion, and after 2 min of venous congestion. Capillary recruitment after arterial occlusion and during venous congestion was expressed as the absolute change in capillary density after recruitment and as the percentage change in capillary density from baseline. RESULTS: Crude linear regression analyses showed that serum uric acid [per +1 standard deviation (SD) of 74 µmol/l] was not associated with baseline capillary density [ß = -0.21 (95% confidence interval, 95% CI -1.61 to 1.19) P = 0.765], while an inverse association was found between uric acid and absolute change in capillary density after arterial occlusion [ß = -1.15 (95% CI -2.36 to 0.06) P = 0.062] and during venous congestion [ß = -1.41 (95% CI -2.68 to -0.14) P = 0.029]. However, after adjustment for sex, age and glucose metabolism status, these associations were no longer statistically significant. In addition, we found no association between uric acid and percentage capillary recruitment after arterial occlusion [ß = -1.66 (95% CI -3.97 to 0.65) P = 0.159] or during venous congestion [ß = -2.02 (95% CI -4.46 to 0.42) P = 0.104] in unadjusted analyses; multivariable analyses gave similar results. CONCLUSION: These results do not support the hypothesis that generalized microvascular dysfunction (as estimated in skin microcirculation) is the underlying mechanism for the association between uric acid and cardiovascular and renal diseases. The possibility that uric acid is associated with microvascular dysfunction in specific end-organs, for example heart or kidney, needs further investigation.

Early lesions following aerosol challenge of rhesus macaques (Macaca mulatta) with Mycobacterium tuberculosis (Erdman strain).

Three rhesus macaques (Macaca mulatta) were challenged with Mycobacterium tuberculosis (Mtb), Erdman strain, as part of studies to investigate lesion development at early time points in tuberculosis (TB) and to assess computed tomography (CT) as a method of monitoring disease progression in vivo. Animals were challenged with either a high, mid or low dose of aerosolized Mtb. The low-dose animal was killed humanely at 24 days post challenge (dpc) and the remaining animals at 25 dpc. Abnormalities in clinical parameters were observed in all animals, but clinical signs relating to respiratory disease were not seen. Pulmonary changes consistent with TB infection were detected by CT at 21 dpc and magnetic resonance imaging (MRI) post mortem. Pulmonary nodule counts obtained from both imaging techniques were directly proportional to the challenge dose and correlated with gross and microscopical lesion counts. On gross and microscopical examination, lesions of similar size and morphology were observed in the lungs of all three animals, with the majority containing necrotic foci. Concomitant gross and microscopical, granulomatous lesions were observed in the tracheobronchial lymph nodes of all animals together with evidence of systemic spread. These findings further contribute to our understanding and knowledge of early lesion formation in the lungs of non-human primates.

Age, waist circumference, and blood pressure are associated with skin microvascular flow motion: the Maastricht Study.

OBJECTIVE: Skin microvascular flow motion (SMF)--blood flow fluctuation attributed to the rhythmic contraction and dilation of arterioles--is thought to be an important component of the microcirculation, by ensuring optimal delivery of nutrients and oxygen to tissue and regulating local hydraulic resistance. There is some evidence that SMF is altered in obesity, type 2 diabetes mellitus, and hypertension. Nevertheless, most studies of SMF have been conducted in highly selected patient groups, and evidence how SMF relates to other cardiovascular risk factors is scarce. Therefore, the aim of the present study was to examine in a population-based setting which cardiovascular risk factors are associated with SMF. METHODS: We measured SMF in 506 participants of the Maastricht Study without prior cardiovascular event. SMF was investigated using Fourier transform analysis of skin laser Doppler flowmetry at rest within five frequency intervals in the 0.01-1.6-Hz spectral range. The associations with SMF of the cardiovascular risk factors age, sex, waist circumference, total-to-high-density lipoprotein cholesterol, fasting plasma glucose, 24-h SBP, and cigarette smoking were analysed by use of multiple linear regression analysis. RESULTS: Per 1 SD higher age, waist circumference and 24-h SBP, SMF was 0.16 SD higher [95% confidence interval (CI) 0.07, 0.25; P < 0.001), -0.14 SD lower (95% CI -0.25, -0.04; P = 0.01), and 0.16 SD higher (95% CI 0.07, 0.26; P < 0.001), respectively, in fully adjusted analyses. We found no significant associations of sex, fasting plasma glucose levels, total-to-high-density lipoprotein cholesterol ratio, or pack years of smoking with SMF. CONCLUSION: Age and 24-h SBP are directly, and waist circumference is inversely associated with SMF in the general population. The exact mechanisms underlying these findings remain elusive. We hypothesize that flow motion may be an important component of the microcirculation by ensuring optimal delivery of nutrients and oxygen to tissue and regulating local hydraulic resistance not only under physiological conditions but also under pathophysiological conditions when microcirculatory perfusion is reduced, such as occurs with ageing and higher blood pressure. In addition, obesity may result in an impaired flow motion with negative effects on the delivery of nutrients and oxygen to tissue and local hydraulic resistance.

Flow-mediated dilation in athletes: influence of aging.

PURPOSE: Controversy exists on whether endothelial function is enhanced in athletes. We sought to systematically review the literature and determine whether endothelial function, as assessed by flow-mediated dilation (FMD), is greater in athletes across all ages relative to that in their age-matched counterparts. METHODS: We conducted a systematic search on MEDLINE, Cochrane, Scopus, and Web of Science since their inceptions until July 2013 for articles evaluating FMD in athletes. A meta-analysis was performed to compare the standardized mean difference (SMD) in FMD of the brachial artery between athletes and age-matched control subjects. Subgroup analyses and meta-regression were used to identify sources of heterogeneity. RESULTS: Twenty-one articles were included in this analysis, comprising 530 athletes (452 endurance trained, 49 strength trained, and 29 endurance and strength trained) and 376 control subjects. After data pooling, FMD was higher in athletes than that in control groups (SMD, 0.48; P = 0.008). In subgroup analyses, young athletes (<40 yr) presented increased baseline brachial artery diameter (mean difference, 0.40 mm; P < 0.00001) and similar FMD (SMD, 0.27; P = 0.22) compared with those in controls. In contrast, master athletes (>;50 yr) showed similar baseline brachial artery diameter (mean difference, 0.04 mm; P = 0.69) and increased FMD (SMD, 0.99; P = 0.0005) compared with those in controls. CONCLUSIONS: The current meta-analysis provides evidence that master athletes but not young athletes exhibit greater FMD compared with that in age-matched healthy controls, thus suggesting that the association between high levels of exercise training and increased FMD is age dependent.

Early lesions following aerosol infection of rhesus macaques (Macaca mulatta) with Mycobacterium tuberculosis strain H37RV.

As part of a study to investigate early changes following exposure to aerosols of Mycobacterium tuberculosis (Mtb), 10 rhesus macaques (Macaca mulatta) were infected with high (731 colony forming units [cfu]), medium (70 cfu) or low (7 cfu) doses of Mtb, and tissues were examined at 2 and 3 weeks post infection (wpi). Clinical disease was not observed. Results of advanced imaging and pathological findings were compared with respect to the delivered dose and time post infection. Magnetic resonance imaging revealed lesions in the lungs at these early time points ex vivo immediately prior to detailed post-mortem examination in the absence of clinical disease. In animals exposed to high and medium doses of Mtb that were studied at 2 and 3 wpi, a range of lesions including small foci of mainly mononuclear cells, primarily macrophages (granulomatous lesions), as well as obvious granulomas, were observed microscopically in the lungs, including lymphatics and hilar lymph nodes. In the low-dose group at 3 weeks, small lesions were identified in the lung and hilar lymph nodes of one animal, and the remaining two animals in this group had lesions in either lung or hilar lymph node. Acid fast bacilli were demonstrated in the lung and lymph nodes in all animals that received high and medium doses, and the lymph nodes of two animals at the low dose. A dose-dependent effect was observed with increasing dose and time post infection. Furthermore, early dissemination of bacilli to the draining, hilar lymph nodes with concomitant granulomatous lesion formation was observed. By contributing to the recognition of early lesion development due to aerosol challenge of Mtb in the rhesus macaque, this study forms a basis for further investigation of early lesions and may inform the design of future vaccine and therapeutic studies involving early time points in this species.

Closing the loop: a 21-year audit of strategies for preventing stroke and death following carotid endarterectomy.

The objective of this review was to identify causes of stroke/death after carotid endarterectomy (CEA) and to develop transferable strategies for preventing stroke/death after CEA, via an overview of a 21-year series of themed research and audit projects. Three preventive strategies were identified: (i) intra-operative transcranial Doppler (TCD) ultrasound and completion angioscopy which virtually abolished intra-operative stroke, primarily through the removal of residual luminal thrombus prior to restoration of flow; (ii) dual antiplatelet therapy with a single 75-mg dose of clopidogrel the night before surgery in addition to regular 75 mg aspirin which virtually abolished post-operative thromboembolic stroke and may also have contributed towards a decline in stroke/death following major cardiac events; and (iii) the provision of written guidance for managing post-CEA hypertension which was associated with virtual abolition of intracranial haemorrhage and stroke as a result of hyperperfusion syndrome. The pathophysiology of peri-operative stroke is multifactorial and no single monitoring or therapeutic strategy will reduce its prevalence. Two of the preventive strategies developed during this 21-year project (peri-operative dual antiplatelet therapy, published guidance for managing post-CEA hypertension) are easily transferable to practices elsewhere.

Evaluation of the safety and immunogenicity of a candidate tuberculosis vaccine, MVA85A, delivered by aerosol to the lungs of macaques.

Tuberculosis (TB) is a reemerging disease. The only available vaccine, Mycobacterium bovis BCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-of-concept data for further evaluation of this route of immunization for use in human clinical trials.

Microvascular dysfunction: an emerging pathway in the pathogenesis of obesity-related insulin resistance.

The prevalence of type 2 diabetes mellitus (T2DM) and its major risk factor, obesity, has reached epidemic proportions in Western society. How obesity leads to insulin resistance and subsequent T2DM is incompletely understood. It has been established that insulin can redirect blood flow in skeletal muscle from non-nutritive to nutritive capillary networks, without increasing total blood flow. This results in a net increase of the overall number of perfused nutritive capillary networks and thereby increases insulin-mediated glucose uptake by skeletal muscle. This process, referred to as functional (nutritive) capillary recruitment, has been shown to be endothelium-dependent and to require activation of the phosphatidylinositol-kinase (PI3K) pathway in the endothelial cell. Several studies have demonstrated that these processes are impaired in states of microvascular dysfunction. In obesity, changes in several adipokines are likely candidates to influence insulin signaling pathways in endothelial cells, thereby causing microvascular dysfunction. Microvascular dysfunction, in turn, impairs the timely access of glucose and insulin to their target tissues, and may therefore be an additional cause of insulin resistance. Thus, microvascular dysfunction may be a key feature in the development of obesity-related insulin resistance. In the present review, we will discuss the evidence for this emerging role for the microcirculation as a possible link between obesity and insulin resistance.

Case series evidence for changed interhemispheric relationships in cortical structure in some amputees.

Limb amputation and related changes in body feelings are associated with cortical functional reorganization that is reflected by increased interhemispheric asymmetry of body maps in the postcentral somatosensory cortex (PCS). As a pilot test to determine if limb amputation affects interhemispheric symmetry in PCS structure, we used MRI and computational morphometry to examine interhemispheric relationships of PCS thicknesses in a case series of eight lower limb amputees compared with 11 control subjects. As a further control, the same relationships were compared in the lateral occipital visual cortex (LOV) which, by nature of its visual connectivity, would be expected to be less related to amputation. The PCS thicknesses in the left and right hemispheres were positively related in control subjects, but not in amputees. The range of the PCS interhemispheric thickness differences (ID) in amputees was larger than the range in control subjects, and four of eight amputees had PCS ID that were at or above the maximal control subject ID. In contrast, LOV thicknesses in the two hemispheres were positively related and LOV ID ranges were similar in both amputees and control subjects. The results from this case series suggest the hypothesis that amputation alters PCS interhemispheric thickness relationships in some amputees. Further tests of this hypothesis would be useful to determine whether changes in structural symmetry contribute to known post-amputation alterations in PCS functional map symmetry and body feeling.

Microvascular dysfunction is associated with a higher incidence of type 2 diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVE: Recent data support the hypothesis that microvascular dysfunction may be a potential mechanism in the development of insulin resistance. We examined the association of microvascular dysfunction with incident type 2 diabetes mellitus (T2DM) and impaired glucose metabolism by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. METHODS AND RESULTS: We searched Medline and Embase for articles published up to October 2011. Prospective cohort studies that focused on microvascular measurements in participants free of T2DM at baseline were included. Pooled relative risks were calculated using random effects models. Thirteen studies met the inclusion criteria for this meta-analysis. These studies focused on T2DM or impaired fasting glucose, not on impaired glucose tolerance. The pooled relative risks for incident T2DM (3846 cases) was 1.25 (95% confidence interval, 1.15; 1.36) per 1 SD greater microvascular dysfunction when all estimates of microvascular dysfunction were combined. In analyses of single estimates of microvascular dysfunction, the pooled relative risks for incident T2DM was 1.49 (1.36; 1.64) per 1 SD higher plasma soluble E-selectin levels; 1.21(1.11; 1.31) per 1 SD higher plasma soluble intercellular adhesion molecule-1 levels; 1.48 (1.03; 2.12) per 1 SD lower response to acetylcholine-mediated peripheral vascular reactivity; 1.18 (1.08; 1.29) per 1 SD lower retinal arteriole-to-venule ratio; and 1.43 (1.33; 1.54) per 1 logarithmically transformed unit higher albumin-to-creatinine ratio. In addition, the pooled relative risks for incident impaired fasting glucose (409 cases) was 1.15 (1.01-1.31) per 1 SD greater retinal venular diameters. CONCLUSIONS: These data indicate that various estimates of microvascular dysfunction were associated with incident T2DM and, possibly, impaired fasting glucose, suggesting a role for the microcirculation in the pathogenesis of T2DM.