Safety, Efficacy, and Durability of Outcomes: Results from SECURE: A Single Arm, Multicenter, Prospective, Clinical Study on a Minimally Invasive Posterior Sacroiliac Fusion Allograft Implant.

Introduction: Research suggests that sacroiliac joint (SIJ) dysfunction is responsible for 15% to 30% of reported low back pain cases. Recently, there has been an increasing interest in SIJ fusion using minimally invasive surgery (MIS) due to safety. Initially, devices designed for MIS were intended for lateral approaches. A minimally invasive sacroiliac fusion implant for use with a posterior approach has been developed and is regulated for clinical use under the regulatory framework required for human cells, tissues, or cellular or tissue-based products (HCT/Ps). Methods: A multi-center, prospective, single-arm study was launched after initial studies provided preliminary data to support safety, efficacy, and durability of this minimally invasive sacroiliac posterior fusion LinQ allograft implant (NCT04423120). Preliminary results were reported previously. Final results for the full participant cohort are presented here. Results: One-hundred and fifty-nine (159) participants were enrolled across 16 investigational sites in the US between January 2020 and March 2022. One-hundred and twenty-two (122) participants were implanted. At the 1-month follow-up, 82 participants satisfied all criteria for the composite responder endpoint, representing 73.2% of the study cohort. These results stayed consistent across the remaining study timepoints with 66.0%, 74.4%, and 73.5% of participants classified as responders at the 3-, 6- and 12-month follow-up visits, respectively. VAS scores were significantly reduced (p < 0.0001) and ODI scores were significantly improved (p < 0.0001). All domains of the PROMIS-29 were also significantly improved (all p's <0.0001). Only one procedure-related serious AE was reported in the study. Conclusion: These results suggest that the posterior approach LinQ Implant System is a safe and effective treatment for sacroiliac joint dysfunction at 12 months, with results that are favorable compared to outcomes reported for an FDA-cleared lateral approach.

Pacific Spine and Pain Society (PSPS) Evidence Review of Surgical Treatments for Lumbar Degenerative Spinal Disease: A Narrative Review.

INTRODUCTION: Interventional treatment options for the lumbar degenerative spine have undergone a significant amount of innovation over the last decade. As new technologies emerge, along with the surgical specialty expansion, there is no manuscript that utilizes a review of surgical treatments with evidence rankings from multiple specialties, namely, the interventional pain and spine communities. Through the Pacific Spine and Pain Society (PSPS), the purpose of this manuscript is to provide a balanced evidence review of available surgical treatments. METHODS: The PSPS Research Committee created a working group that performed a comprehensive literature search on available surgical technologies for the treatment of the degenerative spine, utilizing the ranking assessment based on USPSTF (United States Preventative Services Taskforce) and NASS (North American Spine Society) criteria. RESULTS: The surgical treatments were separated based on disease process, including treatments for degenerative disc disease, spondylolisthesis, and spinal stenosis. CONCLUSIONS: There is emerging and significant evidence to support multiple approaches to treat the symptomatic lumbar degenerative spine. As new technologies become available, training, education, credentialing, and peer review are essential for optimizing patient safety and successful outcomes.

Contrast-free dynamic susceptibility contrast using sinusoidal and bolus oxygenation challenges.

Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO2. High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.

Data on chemical composition of coffee husks and lignin microparticles as their extracted product.

Coffee husks are an abundant and underutilized biomass waste released from coffee production. Experimental analysis showed that coffee husks consisted of 39.2 ± 0.2 wt% cellulose, 12.6 ± 0.1 wt% hemicellulose, 23.3 ± 0.1 wt% Klason lignin, 2.9 ± 0.4 wt% acid-soluble lignin, 8.7 ± 0.2 wt% extractives, and 9.5 ± 0.2 wt% ash. Moreover, different minor elements, including K, Ca, Mg, Al, Fe, Ti, S, and Si, were found. Subsequently, coffee husks were used for the extraction of lignin using an alkaline treatment. As a result, lignin microparticles were formed with a relatively uniform size of 0.55 ± 0.11 mm. Altogether, the current article provided useful data for the valorization of coffee husks and the primary properties of lignin microparticles for further use.

Improved cerebrovascular reactivity mapping using coherence weighted general linear model in the frequency domain.

Cerebrovascular reactivity (CVR) is a prognostic indicator of cerebrovascular health. Estimating CVR from endogenous end-tidal carbon dioxide (CO2) fluctuation and MRI signal recorded under resting state can be difficult due to the poor signal-to-noise ratio (SNR) of signals. Thus, we aimed to improve the method of estimating CVR from end-tidal CO2 and MRI signals. We proposed a coherence weighted general linear model (CW-GLM) to estimate CVR from the Fourier coefficients weighted by the signal coherence in frequency domain, which confers two advantages. First, it requires no signal alignment in time domain, which simplifies experimental methods. Second, it limits the GLM analysis within the frequency band where CO2 and MRI signals are highly correlated, which automatically suppresses noise and nuisance signals. We compared the performance of our method with time-domain GLM (TD-GLM) and frequency-domain GLM (FD-GLM) in both synthetic and in-vivo data; wherein we calculated CVR from signals recorded under both resting state and sinusoidal stimulus. In synthetic data, CW-GLM has a remarkable performance on CVR estimation from narrow band signals with a mean-absolute error of 0.7 % (gray matter) and 1.2 % (white matter), which was lower than all the other methods. Meanwhile, CW-GLM maintains a comparable performance on CVR estimation from resting signals, with a mean-absolute error of 4.1 % (gray matter) and 8 % (white matter). The superior performance was maintained across the 36 in-vivo measurements, with CW-GLM exhibiting limits of agreement of -16.7 % - 9.5 % between CVR calculated from the resting and sinusoidal CO2 paradigms which was 12 % - 209 % better than current time-domain methods. Evaluating of the cross-coherence spectrum revealed highest signal coherence within the frequency band from 0.01 Hz to 0.05 Hz, which overlaps with previously recommended frequency band (0.02 Hz to 0.04 Hz) for CVR analysis. Our data demonstrates that CW-GLM can work as a self-adaptive band-pass filter to improve CVR robustness, while also avoiding the need for signal temporal alignment.

Pain Education and Knowledge (PEAK) Consensus Guidelines for Neuromodulation: A Proposal for Standardization in Fellowship and Training Programs.

The need to be competent in neuromodulation is and should be a prerequisite prior to completing a fellowship in interventional pain medicine. Unfortunately, many programs lack acceptable candidates for these advanced therapies, and fellows may not receive adequate exposure to neuromodulation procedures. The American Society of Pain and Neuroscience (ASPN) desires to create a consensus of experts to set a minimum standard of competence for neurostimulation procedures, including spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), and peripheral nerve stimulation (PNS). The executive board of ASPN accepted nominations for colleagues with excellence in the subject matter of neuromodulation and physician education. This diverse group used peer-reviewed literature and, based on grading of evidence and expert opinion, developed critical consensus guides for training that all accredited fellowship programs should adopt. For each consensus point, transparency and recusal were used to eliminate bias, and an author was nominated for evidence grading oversight and bias control. Pain Education and Knowledge (PEAK) Consensus Guidelines for Neuromodulation sets a standard for neuromodulation training in pain fellowship training programs. The consensus panel has determined several recommendations to improve care in the United States for patients undergoing neuromodulation. As neuromodulation training in the United States has evolved dramatically, these therapies have become ubiquitous in pain medicine. Unfortunately, fellowship programs and the Accreditation Council for Graduate Medical Education (ACGME) pain program requirements have not progressed training to match the demands of modern advancements. PEAK sets a new standard for fellowship training and presents thirteen practice areas vital for physician competence in neuromodulation.

Venous Blood Oxygenation Measurements Using TRUST and T2-TRIR MRI During Hypoxic and Hypercapnic Gas Challenges.

BACKGROUND: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv ) levels, which in turn can be calculated from venous blood T2 values (T2b ). T2b can be measured using different MRI sequences, including T2-relaxation-under-spin-tagging (TRUST) and T2-prepared-blood-relaxation-imaging-with-inversion-recovery (T2-TRIR). The latter measures both T2b and T1 (T1b ) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. PURPOSE: To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. STUDY TYPE: Prospective. POPULATION: Twelve healthy volunteers (four female, age 36 ± 10 years). FIELD STRENGTH/SEQUENCE: A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). ASSESSMENT: TRUST- and T2-TRIR-derived T2b , Yv , OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2-TRIR was used to estimate Hct (HctTRIR ) and compared with venipuncture (HctVP ). STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, Friedman test, Bland-Altman, and correlation analysis. Bonferroni multiple-comparison correction was performed. Significance level was 0.05. RESULTS: A significant bias was observed between TRUST- and T2-TRIR-derived T2b , Yv , and OEF values (-13 ± 11 msec, -5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). DATA CONCLUSION: Given the constant bias, TRUST- and T2-TRIR-derived venous T2b values can be used interchangeably to estimate Yv , OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2-TRIR-derived T1-values only weakly correlated with Hct from venipuncture. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Brain BOLD and NIRS response to hyperoxic challenge in sickle cell disease and chronic anemias.

PURPOSE: Congenital anemias, including sickle cell anemia and thalassemia, are associated with cerebral tissue hypoxia and heightened stroke risks. Recent works in sickle cell disease mouse models have suggested that hyperoxia respiratory challenges can identify regions of the brain having chronic tissue hypoxia. Therefore, this work investigated differences in hyperoxic response and regional cerebral oxygenation between anemic and healthy subjects. METHODS: A cohort of 38 sickle cell disease subjects (age 22 ± 8 years, female 39%), 25 non-sickle anemic subjects (age 25 ± 11 years, female 52%), and 31 healthy controls (age 25 ± 10 years, female 68%) were examined. A hyperoxic gas challenge was performed with concurrent acquisition of blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS). In addition to hyperoxia-induced changes in BOLD and NIRS, global measurements of cerebral blood flow, oxygen delivery, and cerebral metabolic rate of oxygen were obtained and compared between the three groups. RESULTS: Regional BOLD changes were not able to identify brain regions of flow limitation in chronically anemic patients. Higher blood oxygen content and tissue oxygenation were observed during hyperoxia gas challenge. Both control and anemic groups demonstrated lower blood flow, oxygen delivery, and metabolic rate compared to baseline, but the oxygen metabolism in anemic subjects were abnormally low during hyperoxic exposure. CONCLUSION: These results indicated that hyperoxic respiratory challenge could not be used to identify chronically ischemic brain. Furthermore, the low hyperoxia-induced metabolic rate suggested potential negative effects of prolonged oxygen therapy and required further studies to evaluate the risk for hyperoxia-induced oxygen toxicity and cerebral dysfunction.

Sinusoidal CO2 respiratory challenge for concurrent perfusion and cerebrovascular reactivity MRI.

Introduction: Deoxygenation-based dynamic susceptibility contrast (dDSC) has previously leveraged respiratory challenges to modulate blood oxygen content as an endogenous source of contrast alternative to gadolinium injection in perfusion-weighted MRI. This work proposed the use of sinusoidal modulation of end-tidal CO2 pressures (SineCO 2 ), which has previously been used to measure cerebrovascular reactivity, to induce susceptibility-weighted gradient-echo signal loss to measure brain perfusion. Methods: SineCO 2 was performed in 10 healthy volunteers (age 37 ± 11, 60% female), and tracer kinetics model was applied in the frequency domain to calculate cerebral blood flow, cerebral blood volume, mean transit time, and temporal delay. These perfusion estimates were compared against reference techniques, including gadolinium-based DSC, arterial spin labeling, and phase contrast. Results: Our results showed regional agreement between SineCO 2 and the clinical comparators. SineCO 2 was able to generate robust CVR maps in conjunction to baseline perfusion estimates. Discussion: Overall, this work demonstrated feasibility of using sinusoidal CO2 respiratory paradigm to simultaneously acquire both cerebral perfusion and cerebrovascular reactivity maps in one imaging sequence.

Bimatoprost promotes satiety and attenuates body weight gain in rats fed standard or obesity-promoting diets.

Bimatoprost is a synthetic prostamide F2α analog that down-regulates adipogenesis in vitro. This effect has been attributed to participation in a negative feedback loop that regulates anandamide-induced adipogenesis. A follow-on investigation has now been conducted into the broader metabolic effects of bimatoprost using rats under both normal state and obesity-inducing conditions. Chronic bimatoprost administration attenuated weight gain in a dose dependent-manner in rats fed either standard [max effect -7%] or obesity-promoting diets [max effect -23%] over a 9-10 week period. Consistent with these findings, bimatoprost promoted satiety as measured by decreased food intake [max effect, -7%], gastric emptying [max effect, -33-50%] and decreased circulating concentrations of the gut hormones, ghrelin and GLP-1 [max effect, -33-50%]. Additionally, subcutaneous, and visceral fat mass were distinctly affected by treatment [-30% diet independent]. Taken together, these results suggest that bimatoprost regulates energy homeostasis through promoting satiety and a decrease in food intake. These newly reported activities of bimatoprost reveal an additional method of metabolic disease intervention for potential therapeutic exploitation.

Caring for the whole person: transgender-competent HIV pre-exposure prophylaxis as part of integrated primary healthcare services in Vietnam.

INTRODUCTION: Although HIV prevalence among transgender women who have sex with men in Vietnam is high (16-18%), uptake of pre-exposure prophylaxis (PrEP) is low compared to other populations. When PrEP was initiated in 2017, gender-affirming healthcare was largely unavailable. Lack of access to competent, stigma-free healthcare is a well-documented barrier to transgender women's uptake of PrEP and primary healthcare (PHC). We aimed to demonstrate the utility of a PrEP quality improvement intervention in pinpointing and addressing barriers to PrEP use among transgender women in Vietnam. METHODS: We applied a real-world participatory continuous quality improvement (CQI) and Plan-Do-Study-Act (PDSA) methodology to ascertain barriers to PrEP uptake among transgender women and determine priority actions for quality improvement. A CQI team representing transgender women leaders, key population (KP)-clinic staff, public-sector HIV managers and project staff applied PDSA to test solutions to identified barriers that addressed the primary quality improvement outcome of the monthly change in PrEP uptake among transgender women and secondary outcomes, including month-3 PrEP continuation, the impact of offering PHC on PrEP uptake and unmet PrEP need. We utilized routine programmatic data and a descriptive cross-sectional study enrolling 124 transgender women to measure these outcomes from October 2018 to September 2021. RESULTS: Five key barriers to PrEP uptake among transgender women were identified and corresponding solutions were put in place: (1) offering gender-affirming care training to KP-clinics and community-based organizations; (2) integrating gender-affirming services into 10 KP-clinics; (3) offering PHC through five one-stop shop (OSS) clinics; (4) implementing a campaign addressing concerns related to hormone use and PrEP interactions; and (5) developing national HIV and transgender healthcare guidelines. New PrEP enrolment and month-3 PrEP continuation increased significantly among transgender women. Of 235 transgender women who initially sought healthcare other than PrEP at OSS clinics, 26.4% subsequently enrolled in PrEP. About one-third of transgender women reported unmet PrEP need, while two-thirds indicated an interest in long-acting cabotegravir. CONCLUSIONS: Offering gender-competent, integrated PHC can increase PrEP enrolment and continuation, and can be an entry-point for PrEP among those seeking care within PHC clinics. More work is needed to expand access to transgender women-led and -competent healthcare in Vietnam.

Chronic anemia: The effects on the connectivity of white matter.

Chronic anemia is commonly observed in patients with hemoglobinopathies, mainly represented by disorders of altered hemoglobin (Hb) structure (sickle cell disease, SCD) and impaired Hb synthesis (e.g. thalassemia syndromes, non-SCD anemia). Both hemoglobinopathies have been associated with white matter (WM) alterations. Novel structural MRI research in our laboratory demonstrated that WM volume was diffusely lower in deep, watershed areas proportional to anemia severity. Furthermore, diffusion tensor imaging analysis has provided evidence that WM microstructure is disrupted proportionally to Hb level and oxygen saturation. SCD patients have been widely studied and demonstrate lower fractional anisotropy (FA) in the corticospinal tract and cerebellum across the internal capsule and corpus callosum. In the present study, we compared 19 SCD and 15 non-SCD anemia patients with a wide range of Hb values allowing the characterization of the effects of chronic anemia in isolation of sickle Hb. We performed a tensor analysis to quantify FA changes in WM connectivity in chronic anemic patients. We calculated the volumetric mean of FA along the pathway of tracks connecting two regions of interest defined by BrainSuite's BCI-DNI atlas. In general, we found lower FA values in anemic patients; indicating the loss of coherence in the main diffusion direction that potentially indicates WM injury. We saw a positive correlation between FA and hemoglobin in these same regions, suggesting that decreased WM microstructural integrity FA is highly driven by chronic hypoxia. The only connection that did not follow this pattern was the connectivity within the left middle-inferior temporal gyrus. Interestingly, more reductions in FA were observed in non-SCD patients (mainly along with intrahemispheric WM bundles and watershed areas) than the SCD patients (mainly interhemispheric).

Anemia Increases Oxygen Extraction Fraction in Deep Brain Structures but Not in the Cerebral Cortex.

Sickle cell disease (SCD) is caused by a single amino acid mutation in hemoglobin, causing chronic anemia and neurovascular complications. However, the effects of chronic anemia on oxygen extraction fraction (OEF), especially in deep brain structures, are less well understood. Conflicting OEF values have been reported in SCD patients, but have largely attributed to different measurement techniques, faulty calibration, and different locations of measurement. Thus, in this study, we investigated the reliability and agreement of two susceptibility-based methods, quantitative susceptibility mapping (QSM) and complex image summation around a spherical or a cylindrical object (CISSCO), for OEF measurements in internal cerebral vein (ICV), reflecting oxygen saturation in deep brain structures. Both methods revealed that SCD patients and non-sickle anemia patients (ACTL) have increased OEF in ICV (42.6% ± 5.6% and 30.5% ± 3.6% in SCD by CISSCO and QSM respectively, 37.0% ± 4.1% and 28.5% ± 2.3% in ACTL) compared with controls (33.0% ± 2.3% and 26.8% ± 1.8%). OEF in ICV varied reciprocally with hematocrit (r 2 = 0.92, 0.53) and oxygen content (r 2 = 0.86, 0.53) respectively. However, an opposite relationship was observed for OEF measurements in sagittal sinus (SS) with the widely used T2-based oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST), in the same cohorts (31.2% ± 6.6% in SCD, 33.3% ± 5.9% in ACTL and 36.8% ± 5.6% in CTL). Importantly, we demonstrated that hemoglobin F and other fast moving hemoglobins decreased OEF by TRUST and explained group differences in sagittal sinus OEF between anemic and control subjects. These data demonstrate that anemia causes deep brain hypoxia in anemia subjects with concomitant preservation of cortical oxygenation, as well as the key interaction of the hemoglobin dissociation curve and cortical oxygen extraction.

Six Month Interim Outcomes from SECURE: A Single arm, Multicenter, Prospective, Clinical Study on a Novel Minimally Invasive Posterior Sacroiliac Fusion Device.

INTRODUCTION: Sacroiliac joint disease is a prominent diagnosis across the world. A novel fixation technique employing a posterior approach, single point, bone allograft transfixation has proven to be helpful anecdotally. The purpose of this is study is to investigate prospectively the safety and efficacy of this approach. METHODS: A multicenter, prospective, single arm study was performed after patient identification and treatment with the novel posterior fusion, single-point transfixation system and followed for 24 months. Target enrollment is 100 patients. Interim results on the first 69 consecutive patients at 6 months is presented. Primary endpoint at 6-month analysis was Pain Intensity reduction by visual analogue scale and functional improvement by Oswestry Disability Index. Adverse events were assessed for safety analysis. RESULTS: In total, 69 patients were identified for this analysis. At 6 months, a mean improvement of 34.9 was identified by a reduction in VAS and functional improvement was demonstrated by a mean reduction in ODI of 17.7. There were three adverse events, all unrelated to the device. CONCLUSION: The posterior single point transfixation is safe and efficacious for the treatment of sacroiliac joint dysfunction with statistical improvements in pain and function.

IonicRF™: a novel step in technology for radiofrequency ablation treatments.

Radiofrequency ablation (RFA) has been utilized since the 1970s to treat various painful conditions. The technology has evolved from its initial use to treat lumbar facet mediated pain with monopolar lesioning to now treat a plethora of chronic pain conditions. This article reviews Abbott Corporation's (IL, USA) IonicRF™ generator. The IonicRF generator utilizes an intelligent power algorithm that improves efficiency and reduces procedure time. The generator also carries a wide range of RFA therapies such as monopolar, bipolar, pulsed or pulsed dose radiofrequency. Additionally, the IonicRF RFA generator is compatible with the Simplicity™ RF probe (Abbott) which allows for efficient and effective denervation of the sacroiliac joint.

Lay abstract Radiofrequency ablation (RFA) has been utilized since the 1970s to treat many different painful conditions. The technique was originally developed to treat common low back pain because of arthritis. Since that time, RFA has evolved to treat other painful areas of the body such as the face, knees, shoulders, hips and buttocks. RFA is a safe, convenient, and non-surgical option to treat pain in these different areas of the body. This technique is reserved for patients who have already tried physical therapy and over the counter pain medications such as ibuprofen and acetaminophen.

Alteration of macrophage immune phenotype in a murine sepsis model is associated with susceptibility to secondary fungal infection.

BACKGROUND: Secondary fungal infection is a major complication in patients with sepsis-associated immunosuppression. However, sepsis-induced immune alterations related to fungal susceptibility have not been well characterized. OBJECTIVES: To determine kinetic changes in the immune phenotype by determining the proportion of T cells, B cells and macrophages, and especially the expression of an immune exhaustion marker PD-1, in murine sepsis. In addition, sepsis -induced alterations of these immune cells were assessed in relation to susceptibility to secondary fungal infection. METHODS: Cecal ligation and puncture (CLP) was used as a mouse sepsis model, with Candida albicans as the secondary systemic fungal infection. Splenic T cells, B cells and macrophages were assessed by flow cytometry. RESULTS: Alterations in T cell and B cell numbers and the proportion of PD-1 expressing T cells and B cells in CLP mice were not clearly related to susceptibility to secondary Candida infection. By contrast, changes in levels of CD86+-activated macrophages, and the proportion of the PD-1+ population among the CD86+ macrophages in CLP mice were found to be related to secondary fungal infection susceptibility. CONCLUSIONS: Macrophage activation and exhaustion might be a significant determinant in susceptibility to fungal infection, and outcomes of infection. This study provided more comprehensive knowledge pertinent to patient evaluation and therapeutics design in restoring host defenses against secondary fungal infection in those with sepsis.

Perfusion MRI using endogenous deoxyhemoglobin as a contrast agent: Preliminary data.

PURPOSE: To demonstrate the feasibility of mapping cerebral perfusion metrics with BOLD MRI during modulation of pulmonary venous oxygen saturation. METHODS: A gas blender with a sequential gas delivery breathing circuit was used to implement rapid isocapnic changes in the partial pressure of oxygen of the arterial blood. Partial pressure of oxygen was initially lowered to a baseline of 40 mmHg. It was then rapidly raised to 95 mmHg for 20 s before rapidly returning to baseline. The induced cerebral changes in deoxyhemoglobin concentration were tracked over time using BOLD MRI in 6 healthy subjects and 1 patient with cerebral steno-occlusive disease. BOLD signal change, contrast-to-noise ratio, and time delay metrics were calculated. Perfusion metrics such as mean transit time, relative cerebral blood volume, and relative cerebral blood flow were calculated using a parametrized method with a mono-exponential residue function. An arterial input function from within the middle cerebral artery was used to scale relative cerebral blood volume and calculate absolute cerebral blood volume and cerebral blood flow. RESULTS: In normal subjects, average gray and white matter were: BOLD change = 6.3 ± 1.2% and 2.5 ± 0.6%, contrast-to-noise ratio = 4.3 ± 1.3 and 2.6 ± 0.7, time delay = 2.3 ± 0.6 s and 3.6 ± 0.7 s, mean transit time = 3.9 ± 0.6 s and 5.5 ± 0.6 s, relative cerebral blood volume = 3.7 ± 0.9 and 1.6 ± 0.4, relative cerebral blood flow = 70.1 ± 8.3 and 20.6 ± 4.0, cerebral blood flow volume = 4.1 ± 0.9 mL/100 g and 1.8 ± 0.5 mL/100 g, and cerebral blood flow = 97.2 ± 18.7 mL/100 g/min and 28.7 ± 5.9 mL/100 g/min. CONCLUSION: This study demonstrates that induced abrupt changes in deoxyhemoglobin can function as a noninvasive vascular contrast agent that may be used for cerebral perfusion imaging.

Reduced global cerebral oxygen metabolic rate in sickle cell disease and chronic anemias.

Anemia is the most common blood disorder in the world. In patients with chronic anemia, such as sickle cell disease or major thalassemia, cerebral blood flow increases to compensate for decreased oxygen content. However, the effects of chronic anemia on oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) are less well understood. In this study, we examined 47 sickle-cell anemia subjects (age 21.7 ± 7.1, female 45%), 27 non-sickle anemic subjects (age 25.0 ± 10.4, female 52%) and 44 healthy controls (age 26.4 ± 10.6, female 71%) using MRI metrics of brain oxygenation and flow. Phase contrast MRI was used to measure resting cerebral blood flow, while T2 -relaxation-under-spin-tagging (TRUST) MRI with disease appropriate calibrations were used to measure OEF and CMRO2 . We observed that patients with sickle cell disease and other chronic anemias have decreased OEF and CMRO2 (respectively 27.4 ± 4.1% and 3.39 ± 0.71 ml O2 /100 g/min in sickle cell disease, 30.8 ± 5.2% and 3.53 ± 0.64 ml O2 /100 g/min in other anemias) compared to controls (36.7 ± 6.0% and 4.00 ± 0.65 ml O2 /100 g/min). Impaired CMRO2 was proportional to the degree of anemia severity. We further demonstrate striking concordance of the present work with pooled historical data from patients having broad etiologies for their anemia. The reduced cerebral oxygen extraction and metabolism are consistent with emerging data demonstrating increased non-nutritive flow, or physiological shunting, in sickle cell disease patients.

Calibration of T2 oximetry MRI for subjects with sickle cell disease.

PURPOSE: Cerebral T2 oximetry is a non-invasive imaging method to measure blood T2 and cerebral venous oxygenation. Measured T2 values are converted to oximetry estimates using carefully validated and potentially disease-specific calibrations. In sickle cell disease, red blood cells have abnormal cell shape and membrane properties that alter T2 oximetry calibration relationships in clinically meaningful ways. Previous in vitro works by two independent groups established potentially competing calibration models. METHODS: This study analyzed pooled datasets from these two studies to establish a unified and more robust sickle-specific calibration to serve as a reference standard in the field. RESULTS: Even though the combined calibration did not demonstrate statistical superiority compared to previous models, the calibration was unbiased compared to blood-gas co-oximetry and yielded limits of agreement of (-10.1%, 11.6%) in non-transfused subjects with sickle cell disease. In transfused patients, this study proposed a simple correction method based on individual hemoglobin S percentage that demonstrated reduced bias in saturation measurement compared to previous uncorrected sickle calibrations. CONCLUSION: The combined calibration is based on a larger range of hematocrit, providing greater confidence in the hematocrit-dependent model parameters, and yielded unbiased estimates to blood-gas co-oximetry measurements from both sites. Additionally, this work also demonstrated the need to correct for transfusion in T2 oximetry measurements for hyper-transfused sickle cell disease patients and proposes a correction method based on patient-specific hemoglobin S concentration.

Tract-specific analysis and neurocognitive functioning in sickle cell patients without history of overt stroke.

INTRODUCTION: Sickle cell disease (SCD) is a hereditary blood disorder in which the oxygen-carrying hemoglobin molecule in red blood cells is abnormal. SCD patients are at increased risks for strokes and neurocognitive deficit, even though neurovascular screening and treatments have lowered the rate of overt strokes. Tract-specific analysis (TSA) is a statistical method to evaluate microstructural WM damage in neurodegenerative disorders, using diffusion tensor imaging (DTI). METHODS: We utilized TSA and compared 11 major brain WM tracts between SCD patients with no history of overt stroke, anemic controls, and healthy controls. We additionally examined the relationship between the most commonly used DTI metric of WM tracts and neurocognitive performance in the SCD patients and healthy controls. RESULTS: Disruption of WM microstructure orientation-dependent metrics for the SCD patients was found in the genu of the corpus callosum (CC), cortico-spinal tract, inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculus, and left uncinate fasciculus. Neurocognitive performance indicated slower processing speed and lower response inhibition skills in SCD patients compared to controls. TSA abnormalities in the CC were significantly associated with measures of processing speed, working memory, and executive functions. CONCLUSION: Decreased DTI-derived metrics were observed on six tracts in chronically anemic patients, regardless of anemia subtype, while two tracks with decreased measures were unique to SCD patients. Patients with WMHs had more significant FA abnormalities. Decreased FA values in the CC significantly correlated with all nine neurocognitive tests, suggesting a critical importance for CC in core neurocognitive processes.