ApoA-I Protects Pancreatic ß-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.

BACKGROUND: High cholesterol levels in pancreatic ß-cells cause oxidative stress and decrease insulin secretion. ß-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves ß-cell insulin secretion by reducing oxidative stress. METHODS: Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-ß-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by ß-cells was monitored by flow cytometry. The effects of apoA-I internalization on ß-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the ß-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in ß-cells and isolated islets with MitoSOX and confocal microscopy. RESULTS: An F1-ATPase ß-subunit on the ß-cell surface was identified as the main apoA-I-binding partner. ß-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase ß-subunit-dependent. ß-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase ß-subunit levels than ß-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E ß-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. CONCLUSIONS: These results establish that ß-cells are functionally heterogeneous, and apoA-I restores insulin secretion in ß-cells with elevated cholesterol levels by improving mitochondrial redox balance.

Adjustments of Ventilator Parameters during Operating Room-to-ICU Transition and 28-Day Mortality.

Rationale: Lung-protective mechanical ventilation strategies have been proven beneficial in the operating room (OR) and the ICU. However, differential practices in ventilator management persist, often resulting in adjustments of ventilator parameters when transitioning patients from the OR to the ICU. Objectives: To characterize patterns of ventilator adjustments during the transition of mechanically ventilated surgical patients from the OR to the ICU and assess their impact on 28-day mortality. Methods: Hospital registry study including patients undergoing general anesthesia with continued, controlled mechanical ventilation in the ICU between 2008 and 2022. Ventilator parameters were assessed 1 hour before and 6 hours after the transition. Measurements and Main Results: Of 2,103 patients, 212 (10.1%) died within 28 days. Upon OR-to-ICU transition, VT and driving pressure decreased (-1.1 ml/kg predicted body weight [IQR, -2.0 to -0.2]; P < 0.001; and -4.3 cm H2O [-8.2 to -1.2]; P < 0.001). Concomitantly, respiratory rates increased (+5.0 breaths/min [2.0 to 7.5]; P < 0.001), resulting overall in slightly higher mechanical power (MP) in the ICU (+0.7 J/min [-1.9 to 3.0]; P < 0.001). In adjusted analysis, increases in MP were associated with a higher 28-day mortality rate (adjusted odds ratio, 1.10; 95% confidence interval, 1.06-1.14; P < 0.001; adjusted risk difference, 0.7%; 95% confidence interval, 0.4-1.0, both per 1 J/min). Conclusion: During transition of mechanically ventilated patients from the OR to the ICU, ventilator adjustments resulting in higher MP were associated with a greater risk of 28-day mortality.

High Mechanical Power and Driving Pressures are Associated With Postoperative Respiratory Failure Independent From Patients' Respiratory System Mechanics.

OBJECTIVES: High mechanical power and driving pressure (ΔP) have been associated with postoperative respiratory failure (PRF) and may be important parameters guiding mechanical ventilation. However, it remains unclear whether high mechanical power and ΔP merely reflect patients with poor respiratory system mechanics at risk of PRF. We investigated the effect of mechanical power and ΔP on PRF in cohorts after exact matching by patients' baseline respiratory system compliance. DESIGN: Hospital registry study. SETTING: Academic hospital in New England. PATIENTS: Adult patients undergoing general anesthesia between 2008 and 2020. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was high (≥ 6.7 J/min, cohort median) versus low mechanical power and the key-secondary exposure was high (≥ 15.0 cm H 2 O) versus low ΔP. The primary endpoint was PRF (reintubation or unplanned noninvasive ventilation within seven days). Among 97,555 included patients, 4,030 (4.1%) developed PRF. In adjusted analyses, high intraoperative mechanical power and ΔP were associated with higher odds of PRF (adjusted odds ratio [aOR] 1.37 [95% CI, 1.25-1.50]; p < 0.001 and aOR 1.45 [95% CI, 1.31-1.60]; p < 0.001, respectively). There was large variability in applied ventilatory parameters, dependent on the anesthesia provider. This facilitated matching of 63,612 (mechanical power cohort) and 53,260 (ΔP cohort) patients, yielding identical baseline standardized respiratory system compliance (standardized difference [SDiff] = 0.00) with distinctly different mechanical power (9.4 [2.4] vs 4.9 [1.3] J/min; SDiff = -2.33) and ΔP (19.3 [4.1] vs 11.9 [2.1] cm H 2 O; SDiff = -2.27). After matching, high mechanical power and ΔP remained associated with higher risk of PRF (aOR 1.30 [95% CI, 1.17-1.45]; p < 0.001 and aOR 1.28 [95% CI, 1.12-1.46]; p < 0.001, respectively). CONCLUSIONS: High mechanical power and ΔP are associated with PRF independent of patient's baseline respiratory system compliance. Our findings support utilization of these parameters for titrating mechanical ventilation in the operating room and ICU.

Effects of Ketamine Infusion on Breathing and Encephalography in Spontaneously Breathing ICU Patients.

BACKGROUND: Preclinical studies suggest that ketamine stimulates breathing. We investigated whether adding a ketamine infusion at low and high doses to propofol sedation improves inspiratory flow and enhances sedation in spontaneously breathing critically ill patients. METHODS: In this prospective interventional study, twelve intubated, spontaneously breathing patients received ketamine infusions at 5 mcg/kg/min, followed by 10 mcg/kg/min for 1 h each. Airway flow, pressure, and esophageal pressure were recorded during a spontaneous breathing trial (SBT) at baseline, and during the SBT conducted at the end of each ketamine infusion regimen. SBT consisted of one-minute breathing with zero end-expiratory pressure and no pressure support. Changes in inspiratory flow at the pre-specified time points were assessed as the primary outcome. Ketamine-induced change in beta-gamma electroencephalogram power was the key secondary endpoint. We also analyzed changes in other ventilatory parameters respiratory timing, and resistive and elastic inspiratory work of breathing. RESULTS: Ketamine infusion of 5 and 10 mcg/kg/min increased inspiratory flow (median, IQR) from 0.36 (0.29-0.46) L/s at baseline to 0.47 (0.32-0.57) L/s and 0.44 (0.33-0.58) L/s, respectively (p = .013). Resistive work of breathing decreased from 0.4 (0.1-0.6) J/l at baseline to 0.2 (0.1-0.3) J/l after ketamine 10 mcg/kg/min (p = .042), while elastic work of breathing remained unchanged. Electroencephalogram beta-gamma power (19-44 Hz) increased compared to baseline (p < .01). CONCLUSIONS: In intubated, spontaneously breathing patients receiving a constant rate of propofol, ketamine increased inspiratory flow, reduced inspiratory work of breathing, and was associated with an "activated" electroencephalographic pattern. These characteristics might facilitate weaning from mechanical ventilation.

Treatment-resistant OCD: Pharmacotherapies in adults.

Serotonin reuptake inhibitor (SRI) medications are well established as first-line pharmacotherapeutic treatment for Obsessive-Compulsive Disorder (OCD). However, despite the excellent safety profile and demonstrated efficacy of these medications, a substantial proportion of individuals with OCD fail to attain sufficient benefit from SRIs. In this narrative review, we discuss clinical features of OCD that have been associated with poorer response to SRIs, and we present pharmacotherapeutic interventions that have been explored as augmenting or alternative treatments for treatment-resistant OCD. We additionally highlight non-SRI interventions for OCD that are currently under investigation. Pharmacotherapeutic interventions were identified via expert consensus. To assess the evidence base for individual pharmacotherapies, targeted searches for relevant English-language publications were performed on standard biomedical research databases, including MEDLINE. Information relevant to ongoing registered clinical trials in OCD was obtained by search of ClinicalTrials.gov. Pharmacotherapies are grouped for review in accordance with the general principles of Neuroscience-based Nomenclature (NbN). Clinical features of OCD that may suggest poorer response to SRI treatment include early age of onset, severity of illness, duration of untreated illness, and the presence of symmetry/ordering or hoarding-related symptoms. Based on evolving pathophysiologic models of OCD, diverse agents engaging serotonin, dopamine, norepinephrine, glutamate, and anti-inflammatory pathways have been explored as alternative or adjunctive therapies for treatment-resistant OCD and have at least preliminary evidence of efficacy. Medications with dopamine antagonist activity remain the most robustly evidence-based of augmenting interventions, yet dopamine antagonists benefit only a minority of those who try them and carry elevated risks of adverse effects. Interventions targeting glutamatergic and anti-inflammatory pathways are less well evidenced, but may offer more favorable benefit to risk profiles. Ongoing research should explore whether specific interventions may benefit individuals with particular features of treatment-resistant OCD.

A Machine Learning Model Ensemble for Mixed Power Load Forecasting across Multiple Time Horizons.

The increasing penetration of renewable energy sources tends to redirect the power systems community's interest from the traditional power grid model towards the smart grid framework. During this transition, load forecasting for various time horizons constitutes an essential electric utility task in network planning, operation, and management. This paper presents a novel mixed power-load forecasting scheme for multiple prediction horizons ranging from 15 min to 24 h ahead. The proposed approach makes use of a pool of models trained by several machine-learning methods with different characteristics, namely neural networks, linear regression, support vector regression, random forests, and sparse regression. The final prediction values are calculated using an online decision mechanism based on weighting the individual models according to their past performance. The proposed scheme is evaluated on real electrical load data sensed from a high voltage/medium voltage substation and is shown to be highly effective, as it results in R2 coefficient values ranging from 0.99 to 0.79 for prediction horizons ranging from 15 min to 24 h ahead, respectively. The method is compared to several state-of-the-art machine-learning approaches, as well as a different ensemble method, producing highly competitive results in terms of prediction accuracy.

5-Oxo-ETE/OXER1: A Link between Tumor Cells and Macrophages Leading to Regulation of Migration.

Chronic inflammation is an important factor in the development of cancer. Macrophages found in tumors, known as tumor associated macrophages (TAMs), are key players in this process, promoting tumor growth through humoral and cellular mechanisms. 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), an arachidonic acid metabolite, has been described to possess a potent chemoattractant activity for human white blood cells (WBCs). The biological actions of 5-oxo-ETE are mediated through the GPCR 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor (OXER1). In addition, we have previously reported OXER1 as one of the membrane androgen receptors with testosterone antagonizing 5-oxo-ETE's actions. OXER1 is highly expressed in inflammatory cells and many normal and cancer tissues and cells, including prostate and breast cancer, promoting cancer cell survival. In the present study we investigate the expression and role of OXER1 in WBCs, THP-1 monocytes, and THP-1 derived macrophages, as well as its possible role in the interaction between macrophages and cancer cells (DU-145 and T47D). We report that OXER1 is differentially expressed between WBCs and macrophages and that receptor expression is modified by LPS treatment. Our results show that testosterone and 5-oxo-ETE can act in an antagonistic way affecting Ca2+ movements, migration, and cytokines' expression in immune-related cells, in a differentiation-dependent manner. Finally, we report that 5-oxo-ETE, through OXER1, can attract macrophages to the tumor site while tumor cells' OXER1 activation in DU-145 prostate and T47D breast cancer cells, by macrophages, induces actin cytoskeletal changes and increases their migration.

Clinicopathological correlation of oral candidiasis - Our experience in a tertiary centre over two decades.

INTRODUCTION: Oral candidiasis is one of the most common fungal infections that has been widely reported around the world. In Malaysia, the available studies for this infection are scarce. MATERIALS AND METHODS: This is a 20-year retrospective study aimed to investigate the prevalence, demographic characteristics, clinical presentations, and the association of oral candidiasis with clinical parameters in oral candidiasis cases reported in the Faculty of Dentistry, Universiti Malaya from 1999 until 2019. A total of 12,964 histopathological records from the Oral Pathology Diagnostic and Research Laboratory (OPDRL) between 1999 to 2019 were retrieved. Oral candidiasis cases were selected according to the inclusion and exclusion criteria. Information of interest was obtained and analysed. RESULTS: From the total records retrieved, 378 oral candidiasis cases were recorded and 82.8% were diagnosed from smear test. This study showed that oral candidiasis was predominantly reported in female (64.2%) and Indian population (64.2%). The peak incidence was in the sixth decades of life (27.0%). The most commonly affected site was tongue and coated tongue was the most common clinical presentation. More than 50% of the cases had comorbidity and 10.6% were associated with dentures. Ethnicity and site of occurrence were significantly associated (p<0.05) with oral candidiasis. CONCLUSION: This is the first large-scale study of oral candidiasis cases in Malaysia. The findings of this study are useful for clinical assessment of patients suspected of oral candidiasis.

Anesthetics to Prevent Lung Injury in Cardiac Surgery: A Randomized Controlled Trial.

OBJECTIVES: To investigate if sevoflurane based anesthesia is superior to propofol in preventing lung inflammation and preventing postoperative pulmonary complications. DESIGN: Randomized controlled trial. SETTING: Single tertiary care university hospital. PARTICIPANTS: Forty adults undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized in a 1:1 ratio to anesthetic maintenance with sevoflurane or propofol. MEASUREMENTS AND MAIN RESULTS: Blood and bronchoalveolar lavage fluid was sampled before and after bypass to measure pulmonary inflammation using a biomarker panel. The change in bronchoalveolar lavage concentration of tumor necrosis factor alpha (TNFα) was the primary outcome. Secondary outcomes included lung inflammation defined as changes in other biomarkers and postoperative pulmonary complications. There were no significant differences between groups in the change in bronchoalveolar lavage TNFα concentration (median [IQR] change, 17.24 [1.11-536.77] v 101.51 [1.47-402.84] pg/mL, sevoflurane v propofol, p = 0.31). There was a significantly lower postbypass concentration of plasma interleukin 8 (median [IQR], 53.92 [34.5-55.91] v 66.92 [53.03-94.44] pg/mL, p = 0.04) and a significantly smaller postbypass increase in the plasma receptor for advanced glycosylation end products (median [IQR], 174.59 [73.59-446.06] v 548.22 [193.15-852.39] pg/mL, p = 0.03) in the sevoflurane group compared with propofol. The incidence of postoperative pulmonary complications was 100% in both groups, with high rates of pleural effusion (17/18 [94.44%] v 19/22 [86.36%], p = 0.39) and hypoxemia (16/18 [88.88%] v 22/22 [100%], p = 0.11). CONCLUSIONS: Sevoflurane anesthesia during cardiac surgery did not consistently prevent lung inflammation or prevent postoperative pulmonary complications compared to propofol. There were significantly lower levels of 2 plasma biomarkers specific for lung injury and inflammation in the sevoflurane group.

Endovascular treatment of a giant renal artery aneurysm associated with an arteriovenous fistula: Report of a case and review of the literature.

Renal artery aneurysm (RAA) concomitant with a renal arteriovenous fistula (RAVF) has been infrequently reported in the literature. We report a case of a 42-year-old man suffering from a giant RAA combined with a congenital high-flow RAVF. The contrast-enhanced CTA showed a 12.7-cm RAA synchronous with an RAVF between the right renal artery and a draining vein. After a comprehensive preoperative assessment, an endovascular approach was decided. Successful embolization was performed using an Amplatzer vascular Plug, and multiple coils. Completion angiogram demonstrated no flow into the RAA. The results of longterm follow-up demonstrate that endovascular techniques are safe and effective for the management of RAAs combined with high-flow RAVF.

Tuberculosis bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular Bacterial Load Assay.

In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=-0.51, 95% CI (-0.56 to -0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin-20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials.

Optimized Histological Preparation of Ovary for Ovariole Counting in Africanized Honey Bee Queens (Hymenoptera: Apidae).

Techniques for counting ovariole number in virgin and mated Apis mellifera L. queens have been described in previous studies. Having a systematic and fast way to collect this measurement can help accelerate bee breeding programs, because selection decisions can be taken faster. The aim of this work was to develop an efficient histological method to preserve ovaries that allows assessing the number of ovarioles in newly emerged virgin queens, and also in mated queens, in a shorter time than the methods already published. The proposed method resulted in images suitable for ovariole counting in both newly emerged and mated queens, and the total histological process took less than 10 h. This method provides the optimization of the histological procedure for research breeding programs that use ovariole number as selection criteria for improving reproduction and production traits.

Identification of Native and Posttranslationally Modified HLA-B*57:01-Restricted HIV Envelope Derived Epitopes Using Immunoproteomics.

The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the ER. These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here, naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv) are identified. HIVenv peptides are present at a very small percentage of the overall HLA-B*57:01 peptidome (<0.1%) and both native and posttranslationally modified forms of two distinct HIV peptides are identified. Notably, a peptide bearing a natively encoded C-terminal tryptophan residue is also present in a modified form containing a kynurenine residue. Kynurenine is a major product of tryptophan catabolism and is abundant during inflammation and infection. Binding of these peptides at a molecular level and their immunogenicity in preliminary functional studies are examined. Modest immune responses are observed to the modified HIVenv peptide, highlighting a potential role for kynurenine-modified peptides in the immune response to HIV and other viral infections.

Bilateral Endograft Limb Occlusion after Endovascular Aortic Repair: Predictive Factors of Occurrence.

BACKGROUND: Bilateral limb occlusion after endovascular aortic repair (EVAR) is relatively uncommon. The aim of this study was to investigate the incidence of bilateral endograft limb occlusion after EVAR and identify potential anatomical predictive factors of occurrence. METHODS: A total of 579 patients underwent elective EVAR for abdominal aortic aneurysm between January 2010 and December 2015. All patients presenting with unilateral and bilateral occlusions were prospectively analyzed. A group of patients who underwent EVAR but did not present with endograft limb occlusion were matched for sex, age, and commercial type of endograft and were used as controls. RESULTS: Overall, 21 (3.6%) patients were complicated with unilateral endograft limb occlusion, whereas 8 (1.4%) of them presented with sequential (in different time) bilateral limb occlusion. We found that iliac artery angulation ≥60°, iliac perimeter calcification ≥50%, and endograft oversizing in the common iliac artery of more than 15% had the same impact and could equally result in limb occlusion. We coded the variables angle, calcification, and endograft limb oversizing of the common iliac artery with a score from 0 to 2 as follows: (1) 0: angle <60° in both limbs, 1: angle ≥60° in one limb, 2: angle ≥60° in both limbs; (2) 0: calcification <50%: in both limbs, 1: calcification ≥ 50%: in one limb, 2: calcification ≥ 50%: in both limbs; and (3) 0: endograft limb oversizing <15%, 1: endograft limb oversizing ≥15% in one limb, 2: endograft limb oversizing ≥15% in both limbs. A composite variable, consisting of the sum of scoring in variables was analyzed, with a score from 0 to 6. Our study showed that it was the most probable to be in the control group when score in the composite variable was 0-3, it was the most probable to have unilateral limb occlusion when score was 4-5, and finally, it was the most probable to have bilateral limb occlusion when score in the composite variable was equal to 6. CONCLUSIONS: Our study evidenced that the highest probability for bilateral limb occlusion occurred when implantation of a more than 15% oversized endograft in iliac arteries with iliac artery angulation ≥60° and iliac perimeter calcification ≥50% was present in both iliac arteries. It is therefore clear that limb occlusion requires the synergistic effect and interaction of bilateral multiple thrombogenic components in the iliac artery before it is manifested.

Simple derivative-free method of zero extraction by phase-based enclosure for determination of complex propagation constants in planar multilayer waveguides.

A rigorous and simple way to implement a numerical method for extracting the propagation constants and modal characteristics of lossless, lossy, and active planar multilayer waveguides is presented. The method can accurately determine the complex propagation constants of both guided and leaky modes. The method does not utilize the derivative of the dispersion function nor any integrals of it. It is based on finding the estimates of the zeros of the dispersion function by a systematic successively tighter enclosure of the zeros with exclusive use of only the phase of the dispersion function along varying rectangular contours in the complex plane. The zero estimates are then refined by Müller's iterative scheme employing deflation. The method was named derivative-free zero extraction by phase-based enclosure (DFZEPE) for brevity. The DFZEPE method has been applied to lossless, lossy, active, and antiresonant reflecting optical waveguides published in the literature and analyzed with similar methods, and the results are excellent. The proposed DFZEPE method has global convergence and can be applied to a plethora of electromagnetic (and other) problems where the zeros of an analytic function are sought.

Review and accuracy comparison of various permittivity-averaging schemes for material discontinuities in the two-dimensional FDFD method: implementation using efficient computer graphics techniques.

Several known and widely used averaging techniques aiming to improve the accuracy of the two-dimensional finite-difference frequency-domain (FDFD) method, in the presence of material discontinuities, are reviewed, numerically tested, and compared with respect to their accuracies. Furthermore, all averaging techniques are rigorously and efficiently implemented using the Supercover Digital Differential Analyzer algorithm and a modified Liang-Barsky algorithm suitably adapted from computer graphics applications. The FDFD with Gaussian blurring; the FDFD with volume-polarized effective permittivity; the FDFD with volume-polarized effective permittivity on shifted cells; and the FDFD with anisotropic smoothing [FDFD (AS)] are compared with respect to their accuracies (for both TE and TM polarization), in the case of scattering by an infinite homogeneous cylinder (for which analytical solution exists) comprising a lossless dielectric, a high-index, low-loss dielectric, or a metal. Sample plots of the relative errors are presented for various field components. Absolute error norms (L2 and L∞) are also presented for both polarizations and for two grid-cell sizes for quantitative comparisons. The results show that the FDFD (AS) prevails in accuracy mainly because it satisfies the boundary conditions at the cylinder's boundary the best. However, for the high-index dielectrics and metals, even the FDFD without any averaging gives very good results for the field components parallel to the uniformity direction. However, the FDFD (AS) is always more accurate when the in-plane field components are sought.

Performance analysis of waveguide-mode resonant optical filters with stochastic design parameters.

The performance of optical filters with resonant waveguide gratings is investigated numerically in a stochastic context, assuming random fluctuations of various design variables. Specifically, we derive stochastic models based on polynomial chaos expansions, whose involved coefficients are obtained by computing spectral projections via sparse-grid quadrature. The latter exploits purely deterministic results from a rigorous coupled-wave analysis solver and requires less simulation data than standard Monte Carlo (MC) techniques. The statistical moments of the filter's spectral response are calculated reliably, as the comparison against reference results from MC analysis verifies, and the extraction of the Sobol indices reveals the structure's sensitivity with respect to specific design parameters. Moreover, the present analysis clearly points out that neglecting even small geometric variations in the filter design may produce misleading conclusions regarding the corresponding performance, with undesirable consequences in real-life applications.

Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade.

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

Why being an expert - despite xpert -remains crucial for children in high TB burden settings.

BACKGROUND: As access to Xpert expands in high TB-burden settings, its performance against clinically diagnosed TB as a reference standard provides important insight as the majority of childhood TB is bacteriologically unconfirmed. We aim to describe the characteristics and outcomes of children with presumptive TB and TB disease, and assess performance of Xpert under programmatic conditions against a clinical diagnosis of TB as a reference standard. METHODS: Retrospective review of children evaluated for presumptive TB in Mbeya, Tanzania. Baseline characteristics were compared by TB disease status and, for patients diagnosed with TB, by TB confirmation status using Wilcoxon rank sum test for continuous variables and the Chi-square test for categorical variables. Sensitivity and specificity were calculated to assess the performance of Xpert, smear, and culture against clinical TB. Kappa statistics were calculated to assess agreement between Xpert and smear to culture. RESULTS: Among children (N = 455) evaluated for presumptive TB, 70.3% (320/455) had Xpert and 62.8% (286/455) had culture performed on sputa. 34.5% (157/455) were diagnosed with TB: 80.3% (126/157) pulmonary TB, 13.4% (21/157) bacteriologically confirmed, 53.5% (84/157) HIV positive, and 48.4% (76/157) inpatients. Compared to the reference standard of clinical diagnosis, sensitivity of Xpert was 8% (95% CI 4-15), smear 6% (95% CI 3-12) and culture 16% (95% CI 9-24), and did not differ based on patient disposition, nutrition or HIV status. CONCLUSION: Despite access to Xpert, the majority of children with presumptive TB were treated based on clinical diagnosis. Reflecting the reality of clinical practice in resource limited settings, new diagnostics such as Xpert serve as important adjunctive tests but will not obviate the need for astute clinicians and comprehensive diagnostic algorithms.