Quantification of Collateral Supply with Local-AIF Dynamic Susceptibility Contrast MRI Predicts Infarct Growth.

BACKGROUND AND PURPOSE: In ischemic stroke, leptomeningeal collaterals can provide delayed and dispersed compensatory blood flow to tissue-at-risk despite an occlusion and can impact treatment response and infarct growth. The purpose of this work is to test the hypothesis that inclusion of this delayed and dispersed flow with an appropriately calculated Local Arterial Input Function (Local-AIF) is needed to quantify the degree of collateral blood supply in tissue distal to an occlusion. MATERIALS AND METHODS: Seven experiments were conducted in a pre-clinical middle cerebral artery occlusion model. Dynamic susceptibility contrast MRI was imaged and post-processed to yield quantitative cerebral blood flow (qCBF) maps with both a traditionally chosen single arterial input function applied globally to the whole brain (i.e. "Global-AIF") and a delay and dispersion corrected AIF (i.e. "Local-AIF") that is sensitive to retrograde flow. Leptomeningeal collateral arterial recruitment was quantified with a pial collateral score from x-ray angiograms, and infarct growth calculated from serially acquired diffusion weighted MRI scans. RESULTS: The degree of collateralization at x-ray correlated more strongly with qCBF using the Local-AIF in the ischemic penumbra (R2=0.81) than traditionally chosen Global-AIF (R2=0.05). qCBF using a Local-AIF was negatively correlated (less infarct progression as perfusion increased) with infarct growth (R2 = 0.79) more strongly than a Global-AIF (R2=0.02). CONCLUSIONS: In acute stroke, qCBF calculated with a Local-AIF is more accurate for assessing tissue status and collateral supply than traditionally chosen Global-AIFs. These findings support use of a Local-AIF that corrects for delayed and dispersed retrograde flow in determining quantitative tissue perfusion with collateral supply in occlusive disease. ABBREVIATIONS: MRI = magnetic resonance imaging; DSC = dynamic susceptibility contrast; PCS = pial collateral score; MCAO = middle cerebral artery occlusion; MCA = middle cerebral artery; AIF = arterial input function; rCBF = relative cerebral blood flow; qCBF = quantitative cerebral blood flow.

Impact of pathogenic variants of the Ras-mitogen-activated protein kinase pathway on major white matter tracts in the human brain.

Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras-mitogen-activated protein kinase pathway.

Quantification of Multi-Compartment Flow with Spectral Diffusion MRI.

Purpose: Estimation of multi-compartment intravoxel 'flow' in fD in ml/100g/min with multi-b-value diffusion weighted imaging and a multi-Gaussian model in the kidneys. Theory and Methods: A multi-Gaussian model of intravoxel flow using water transport time to quantify f D (ml/100g/min) is presented and simulated. Multi-compartment anisotropic DWI signal is simulated with Rician noise and SNR=50 and analyzed with a rigid bi-exponential, a rigid tri-exponential and diffusion spectrum imaging model of intravoxel incoherent motion (spectral diffusion) to study extraction of multi-compartment flow. The regularization parameter for spectral diffusion is varied to study the impact on the resulting spectrum and computation speed. The application is demonstrated in a two-center study of 54 kidney allografts with 9 b-value advanced DWI that were split by function (CKD-EPI 2021 eGFR<45ml/min/1.73m2) and fibrosis (Banff 2017 interstitial fibrosis and tubular atrophy score 0-6) to demonstrate multi-compartment flow of various kidney pathologies. Results: Simulation of anisotropic multi-compartment flow from spectral diffusion demonstrated strong correlation to truth for both three-compartment anisotropic diffusion ( y = 1.08 x + 0.1 , R 2 = 0.71 ) and two-compartment anisotropic diffusion ( y = 0.91 + 0.6 , R 2 = 0.74 ), outperforming rigid models in cases of variable compartment number. Use of a fixed regularization parameter set to λ = 0.1 increased computation up to 208-fold and agreed with voxel-wise cross-validated regularization (concordance correlation coefficient=0.99). Spectral diffusion of renal allografts showed decreasing trend of tubular and vascular flow with higher levels of fibrosis, and significant increase in tissue parenchyma flow (f-stat=3.86, p=0.02). Tubular f D was significantly decreased in allografts with impaired function (eGFR<45ml/min/1.73m2)(Mann-Whitney U t-stat=-2.14, p=0.04). Conclusions: Quantitative multi-compartment intravoxel 'flow' can be estimated in ml/100g/min with f D from multi-Gaussian diffusion with water transport time, even with moderate anisotropy such as in kidneys. The use of spectral diffusion with a multi-Gaussian model and a fixed regularization parameter is particularly promising in organs such as the kidney with variable numbers of physiologic compartments.

Association of systemic and demographic risk factors with prevalence of retinopathy in US adults with prediabetes.

BACKGROUND/OBJECTIVES: To investigate the relative contribution of systemic risk factors to retinopathy in prediabetes using a nationally representative cohort in the US. SUBJECTS/METHODS: A group of 2098 participants aged ≥40 years with available HbA1c and gradable retinal images from the National Health and Nutrition Examination Survey 2005-2008 were included in this retrospective cross-sectional analysis. Participants were stratified into control, prediabetes, and diabetes groups based on HbA1c and anti-hyperglycaemic medication use. Logistic regression was used to assess the contribution of potential systemic risk factors to retinopathy prevalence. RESULTS: The prevalence of retinopathy in the prediabetes group was 7.69%. Multivariable logistic regression revealed an inverse association of female sex (OR, 0.25; 95% CI, 0.08-0.74; p = 0.02), eGFR (OR, 0.98; 95% CI, 0.96-1.00; p = 0.04), and fasting glucose levels (OR, 0.92; 95% CI 0.87-0.98; p = 0.02) with retinopathy in individuals with prediabetes and a positive association with a Race/Ethnicity classification of "Other" (OR, 6.05; 95% CI, 1.65-22.1; p = 0.01). Comparison of ORs between groups indicated differential associations of "Other" race, fasting glucose, and C-reactive protein (CRP) with retinopathy in prediabetes compared with diabetes. CONCLUSIONS: The prevalence of retinopathy among individuals with prediabetes in the NHANES database is similar to other studies. Our findings suggest that nonglycemic metabolic risk factors may be especially relevant to the risk of retinopathy in prediabetes and extend the previously suggested protective effect of female sex on retinopathy in diabetes to prediabetes. The increased odds of retinopathy in underrepresented racial/ethnic groups in the setting of prediabetes also have implications for risk assessment in this population.

Quantification of Collateral Supply with Local-AIF Dynamic Susceptibility Contrast MRI Predicts Infarct Growth.

Background and purpose: In ischemic stroke, leptomeningeal collaterals can provide compensatory blood flow to tissue at risk despite an occlusion, and impact treatment response and infarct growth. The purpose of this work is to test the hypothesis that local perfusion with an appropriate Local Arterial Input Function (AIF) is needed to quantify the degree of collateral blood supply in tissue distal to an occlusion. Materials and methods: Seven experiments were conducted in a pre-clinical middle cerebral artery occlusion model. Magnetic resonance dynamic susceptibility contrast (DSC) was imaged and post-processed as cerebral blood flow maps with both a traditionally chosen single arterial input function (AIF) applied globally to the whole brain (i.e. "Global-AIF") and a novel automatic delay and dispersion corrected AIF (i.e. "Local AIF") that is sensitive to retrograde flow. Pial collateral recruitment was assessed from x-ray angiograms and infarct growth via serially acquired diffusion weighted MRI scans both blinded to DSC. Results: The degree of collateralization at x-ray correlated strongly with quantitative perfusion determined using the Local AIF in the ischemic penumbra (R2=0.81) compared to a traditionally chosen Global-AIF (R2=0.05). Quantitative perfusion calculated using a Local-AIF was negatively correlated (less infarct progression as local perfusion increased) with infarct growth (R2 = 0.79) compared to Global-AIF (R2=0.02). Conclusions: Local DSC perfusion with a Local-AIF is more accurate for assessing tissue status and degree of leptomeningeal collateralization than traditionally chosen AIFs. These findings support use of a Local-AIF in determining quantitative tissue perfusion with collateral supply in occlusive disease.

A Student Teaching Assistant Program for Diversity, Equity, Inclusion, and Antiracism Curricular Enhancement.

PROBLEM: In the United States, physician bias is exhibited early in medical training and contributes to systemic inequities within the field of medicine. A lack of diversity, equity, inclusion, and antiracism (DEI-AR) content within medical curricula drives critical gaps in knowledge and deficiencies when preparing medical students to serve patients of diverse backgrounds. At the Mayo Clinic Alix School of Medicine (MCASOM), student-led curricular reviews between 2017 to 2018 and 2020 to 2021 revealed opportunities to improve DEI-AR content within preclinical courses. Course directors expressed concern of limited expertise and time to enact effective changes. APPROACH: The MCASOM DEI-AR teaching assistant (TA) program aims to curate a collaborative partnership between course directors and compensated student TAs to facilitate course enhancements responsive to the prior preclinical course review while centering standardized DEI-AR best practices. OUTCOMES: As of January 2024, the program has engaged 14 TAs and partnered with 24 preclinical courses. Postcourse student evaluation responses were collected from 8 courses for 2021 to 2022 (before enhancements) and 2022 to 2023 (after enhancements). Student satisfaction with DEI-AR content is tracked through postcourse evaluations, with preliminary data demonstrating improvement after DEI-AR curricular integration (improvement of mean preenhancement and postenhancement scores of 3.81 to 4.05; t12 = 1.79, P = .21). Qualitative student comments were sorted into general categories of positive, negative, or neutral, showing a 6.25% median increase in positive perception of DEI. NEXT STEPS: Plans for the MCASOM DEI-AR TA program include application of quality improvement strategies to improve program processes and outcomes. Development of a centralized dashboard that integrates course enhancement progress and ongoing feedback from evaluations is anticipated to facilitate this effort. The program additionally aims to develop partnerships with clinical clerkships, which would allow for a more comprehensive enhancement of the overall medical education experience related to DEI-AR.

[Translated article] In vitro elution of local anaesthetics from PMMA bone cement.

BACKGROUND AND AIM: Currently, we do not have a gold standard for pain management after total knee arthroplasty. We may use one of more drug delivery systems, none of which are ideal. An ideal depot delivery system would provide therapeutic, nontoxic, doses of drug at the surgical side, especially during 72h postoperatively. The bone cement used in arthroplasties has been used as a drug delivery system, especially antibiotics, since 1970. Based on this principle, we developed this study with the aim to characterize the elution profile of two local anaesthetics (lidocaine hydrochloride and bupivacaine hydrochloride) from PMMA (polymethilmethacrylate) bone cement. MATERIAL AND METHODS: Palacos® R+G bone cement and lidocaine hydrochloride or bupivacaine hydrochloride specimens were obtained depending on the study group. These specimens were immersed in PBS (phosphate buffered saline) and removed from the solution at different set times. Subsequently, the concentration of local anaesthetic in the liquid was analyzed by liquid chromatography. RESULTS: The percentage of lidocaine eluted from PMMA bone cement in this study was 9.74% of the total lidocaine content per specimen at 72h and 18.73% at 336h (14 days). In case of bupivacaine, the elution percentage was 2.71% of the total bupivacaine content per specimen at 72h and 2.70% at 336h (14 days). CONCLUSIONS: Local anaesthetics elute in vitro from PMMA bone cement, reaching doses at 72h close to the doses used in anaesthetic blocks.

Investigating major trauma in Maori youth at Te Whatu Ora Counties Manukau.

BACKGROUND: The Ninth Perioperative Mortality Review Committee (POMRC) report found the likelihood of death was over three times higher in Maori youth compared to non-Maori (age: 15-18 years) in the 30-days following major trauma. The aim of our study is to investigate variations in care provided to Maori youth presenting to Te Whatu Ora Counties Manukau (TWO-CM) with major trauma, to inform policies and improve care. METHODS: This was a retrospective, observational study of 15-18-year-olds admitted to Middlemore Hospital from January 2018 to December 2021 following major trauma (Injury Severity Score (ISS) >12 or with (ISS) <12 who died). Data were obtained from the New Zealand Trauma Registry (NZTR). Six key performance indicators were studied against hospital guidelines/international consensus: Deaths, Cause-of-death, trauma call, RedBlanket activations, time-to-computed tomography (CT), and time-to-operating theatre (OT). RESULTS: Of 77 patients, five deaths occurred, four non-Maori, and one Maori (P = 0.645). Five trauma calls were not activated (P = 0.642). There was no statistically significant difference for both median time to CT (P = 0.917) and time to CT for patients with GCS >13 (P = 0.778) between Maori and non-Maori. Five patients did not meet guidelines for time-to-OT (three non-Maori and two Maori) (P = 0.377). CONCLUSION: No statistically significant variations in care were present for Maori youth presenting with major trauma, these findings did not match the national trend.

Tandem Mass Tag LC-MS/MS of Aqueous Humor From Individuals With Type 2 Diabetes Without Retinopathy Reveals Early Dysregulation of Synaptic Proteins.

Purpose: An early neurodegenerative component of diabetic retinal disease (DRD) that precedes the vascular findings of clinically diagnosed diabetic retinopathy (DR) is increasingly being recognized. However, the relevant molecular mechanisms and biomarkers for early DRD are poorly defined. The purpose of this study was to uncover novel potential mediators of early diabetic retinal neuronal dysfunction through analysis of the aqueous fluid proteome in preclinical DR. Methods: Aqueous fluid was collected from subjects with type 2 diabetes mellitus (DM) but no clinical DR and from nondiabetic controls undergoing routine cataract surgery. Preoperative spectral-domain optical coherence tomography of the macula was obtained. Tandem mass tag LC-MS/MS was performed to identify proteins differentially present in diabetic and control aqueous fluid, and proteins with >50% change and P < 0.05 were considered significant. Selected results were validated with western blot of human aqueous fluid samples. Results: We identified decreased levels of proteins implicated in neuronal synapse formation and increased levels of inflammatory proteins in the aqueous fluid from patients with type 2 DM but no DR compared with controls. Of the differentially present synaptic proteins that we identified and confirmed with western blot, the majority have not previously been linked with DRD. Conclusions: The proteomic profile of aqueous fluid from individuals with type 2 DM but no DR suggests that retinal neuronal dysfunction and inflammation represent very early events in the pathophysiology of DRD. These findings support the concept that diabetic retinal neurodegeneration precedes vascular pathology and reveal novel potential mediators and/or biomarkers warranting further investigation.

Oncolytic vaccinia virus immunotherapy antagonizes image-guided radiotherapy in mouse mammary tumor models.

Ionizing radiation (IR) and oncolytic viruses are both used to treat cancer, and the effectiveness of both agents depends upon stimulating an immune response against the tumor. In this study we tested whether combining image guided ionizing radiation (IG-IR) with an oncolytic vaccinia virus (VACV) could yield a better therapeutic response than either treatment alone. ΔF4LΔJ2R VACV grew well on irradiated human and mouse breast cancer cells, and the virus can be combined with 4 or 8 Gy of IR to kill cells in an additive or weakly synergistic manner. To test efficacy in vivo we used immune competent mice bearing orthotopic TUBO mammary tumors. IG-IR worked well with 10 Gy producing 80% complete responses, but this was halved when the tumors were treated with VACV starting 2 days after IG-IR. VACV monotherapy was ineffective in this model. The antagonism was time dependent as waiting for 21 days after IG-IR eliminated the inhibitory effect but without yielding any further benefits over IR alone. In irradiated tumors, VACV replication was also lower, suggesting that irradiation created an environment that did not support infection as well in vivo as in vitro. A study of how four different treatment regimens affected the immune composition of the tumor microenvironment showed that treating irradiated tumors with VACV altered the immunological profiles in tumors exposed to IR or VACV alone. We detected more PD-1 and PD-L1 expression in tumors exposed to IR+VACV but adding an αPD-1 antibody to the protocol did not change the way VACV interferes with IG-IR therapy. VACV encodes many immunosuppressive gene products that may interfere with the ability of radiotherapy to induce an effective anti-tumor immune response through the release of danger-associated molecular patterns. These data suggest that infecting irradiated tumors with VACV, too soon after exposure, may interfere in the innate and linked adaptive immune responses that are triggered by radiotherapy to achieve a beneficial impact.

Assessment of lifestyle changes related to quarantine among Saudi population during the early COVID-19 pandemic: pre- and post-analysis.

BACKGROUND: The escalating emergence of the COVID-19 pandemic interrupted human life due to the ever-increasing morbidity, containment measures, and the associated emotional distress. This study examined the influence of COVID-19-related measures on the lifestyle behaviors of adults living in the Kingdom of Saudi Arabia (KSA). METHODS: The study recruited 638 participants through convenience sampling in Jeddah and Taif cities, Saudi Arabia. Demographic characteristics and COVID-19-related information were collected through an anonymous self-reported electronic questionnaire. Lifestyle behaviors were assessed before and during the quarantine using the Healthy Dietary Habits Index (HDHI)-A and the International Physical Activity Questionnaire (IPAQ-SF). RESULTS: The study revealed significant changes in the dietary pattern: a reduction in fish intake and increased consumption of French fries and candies. Vegetables and fruit intake increased significantly. Sedentary time > 6 h per day increased from 36.7% pre to 60.8% during the pandemic. Healthy dietary index score and physical activity MET-minutes/week values were respectively 3.5% and 37.9% significantly higher before compared to the full quarantine period. CONCLUSION: The pandemic detrimentally influenced eating habits and physical activity levels that led to weight gain, and hence higher vulnerability to COVID-19 infection and negative outcomes. This analysis provides public health agencies with data to tailor nutrition interventions that mitigate the observed adverse lifestyle behaviors.

Considerations for Colorectal Neoplasia Detection in Inflammatory Bowel Disease Clinical Trials.

BACKGROUND: High-quality colonoscopic surveillance can lead to earlier and increased detection of colorectal neoplasia in patients with inflammatory bowel disease (IBD). In IBD clinical trials, endoscopy is used to assess mucosal disease activity before and after treatment but also provides an opportunity to surveil for colorectal neoplasia during follow-up. SUMMARY: Best practices for colorectal cancer identification in IBD clinical trials require engagement and collaboration between the clinical trial sponsor, site endoscopist and/or principal investigator, and central read team. Each team member has unique responsibilities for maximizing dysplasia detection in IBD trials. KEY MESSAGES: Sponsors should work in accordance with scientific guidelines to standardize imaging procedures, design the protocol to ensure the trial population is safeguarded, and oversee trial conduct. The site endoscopist should remain updated on best practices to tailor sponsor protocol-required procedures to patient needs, examine the mucosa for disease activity and potential dysplasia during all procedures, and provide optimal procedure videos for central read analysis. Central readers may detect dysplasia or colorectal cancer and a framework to report these findings to trial sponsors is essential. Synergistic relationships between all team members in IBD clinical trials provide an important opportunity for extended endoscopic evaluation and colorectal neoplasia identification.

Retinal characteristics in eyes with pathologic myopia among individuals self-identifying as Black.

OBJECTIVE: Investigate retinal characteristics of pathologic myopia (PM) among patients self-identifying as Black. DESIGN: Retrospective cohort single-institution retrospective medical record review. METHODS: Adult patients between January 2005 and December 2014 with International Classification of Diseases (ICD) codes consistent with PM and given 5-year follow-up were evaluated. The Study Group consisted of patients self-identifying as Black, and the Comparison Group consisted of those not self-identifying as Black. Ocular features at study baseline and 5-year follow-up visit were evaluated. RESULTS: Among 428 patients with PM, 60 (14%) self-identified as Black and 18 (30%) had baseline and 5-year follow-up visits. Of the remaining 368 patients, 63 were in the Comparison Group. For the study (n = 18) and Comparison Group (n = 29), median (25th percentile, 75th percentile) baseline visual acuity was 20/40 (20/25, 20/50) and 20/32 (20/25, 20/50) in the better-seeing eye and 20/70 (20/50, 20/1400) and 20/100 (20/50, 20/200), respectively, in the worse-seeing eye. In the eyes that did not have choroidal neovascularization (CNV) in the study and Comparison Group, median study baseline optical coherence tomography central subfield thickness was 196 µm (169, 306 µm) and 225 µm (191, 280 µm), respectively, in the better-seeing eye and 208 µm (181, 260 µm) and 194 µm (171, 248 µm), respectively, in the worse-seeing eye. Baseline prevalence of CNV was 1 Study Group eye (3%) and 20 Comparison Group eyes (34%). By the 5-year visit, zero (0%) and 4 (15%) additional eyes had CNV in the study and Comparison Group, respectively. CONCLUSION: These findings suggest that the prevalence and incidence of CNV may be lower in patients with PM self-identifying as Black when compared with individuals of other races.

Variable Practice, Variable Results: Impact of Postinterview Communication Practices Among Critical Care Medicine/Pulmonary and Critical Care Medicine Fellowship Applicants and Program Directors.

BACKGROUND: Although postinterview communication (PIC) guidelines exist, adherence is voluntary. There are no studies of PIC practices in critical care medicine (CCM) and pulmonary and critical care medicine (PCCM) fellowship recruitment. RESEARCH QUESTION: What is the frequency, format, goals, and content of PIC between CCM/PCCM applicants and program directors? What is the impact of PIC on applicant and program rank order lists (ROLs)? STUDY DESIGN AND METHODS: CCM/PCCM applicants and program directors were separately surveyed after the 2022-2023 National Resident Matching Program Specialty Match. Surveys included multiple-choice, Likert-scale, and two free text questions. Thematic content analysis of free text responses was performed. RESULTS: One-third of eligible participants responded (applicants: n = 373 [34%]; program directors: n = 86 [32%]). Applicant respondents applied to CCM (19%), PCCM (69%), or both (12%). Program directors represented CCM (17%), PCCM (57%), or both (26%) programs. Applicant (66%) and program director (49%) respondents reported initiating PIC. PIC did not impact ROL decision for most applicants (73%) or program directors (83%), though 21% of applicants and 17% of program directors moved programs or applicants up on their ROL in response to PIC. One-quarter (23%) of applicants strongly agreed or agreed that PIC was helpful in creating their ROL, 27% strongly disagreed or disagreed, and 29% were neutral. PIC challenges identified by both groups included time; lack of uniformity; peer pressure; misleading language; and uncertainty about motives, rules, and response protocols. INTERPRETATION: PIC is common among CCM/PCCM applicants and program directors. About 50% of applicants and 20% of program directors share ranking intentions via PIC. Although PIC did not impact ROL for most applicants and program directors, a minority of applicants and program directors moved programs up on their ROL after receiving PIC from the other party. Applicants have mixed perspectives on PIC value. Applicants and program directors alike desire clear guidance on PIC to minimize ambiguous and misleading communication.

Cryopreservation of mouse thymus depletes thymocytes but supports immune reconstitution on transplantation.

Cryopreservation of mouse thymus depletes donor thymocytes but preserves thymus function when transplanted after thawing into athymic mice. No differences in immune reconstitution were observed between fresh and frozen/thawed transplants suggesting that donor thymocyte depletion does not affect outcome. Thus, cryopreservation of thymus may improve outcomes in thymus transplant patients.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

[Translated article] In vitro elution of local anaesthetics from PMMA bone cement.

BACKGROUND AND AIM: Currently, we do not have a gold standard for pain management after total knee arthroplasty. We may use one of more drug delivery systems, none of which are ideal. An ideal depot delivery system would provide therapeutic, nontoxic, doses of drug at the surgical side, especially during 72h postoperatively. The bone cement used in arthroplasties has been used as a drug delivery system, especially antibiotics, since 1970. Based on this principle, we developed this study with the aim to characterise the elution profile of two local anaesthetics (lidocaine hydrochloride and bupivacaine hydrochloride) from PMMA (polymethilmethacrylate) bone cement. MATERIAL AND METHODS: Palacos® R+G bone cement and lidocaine hydrochloride or bupivacaine hydrochloride specimens were obtained depending on the study group. These specimens were immersed in PBS (phosphate buffered saline) and removed from the solution at different set times. Subsequently, the concentration of local anaesthetic in the liquid was analysed by liquid chromatography. RESULTS: The percentage of lidocaine eluted from PMMA bone cement in this study was 9.74% of the total lidocaine content per specimen at 72h and 18.73% at 336h (14 days). In case of bupivacaine, the elution percentage was 2.71% of the total bupivacaine content per specimen at 72h and 2.70% at 336h (14 days). CONCLUSIONS: Local anaesthetics elute in vitro from PMMA bone cement, reaching doses at 72h close to the doses used in anaesthetic blocks.

Effect of nurse-led intervention on knowledge and preventive behavior of diabetic pregnant women regarding COVID-19 associated mucromycosis infection in mid-delta region of Egypt.

BACKGROUND: Black fungus (mycoses) is an opportunistic invasive infection that predominantly occurred among immunosuppressed persons. It has been recently detected in COVID-19 patients. The pregnant diabetic woman is susceptible to such infections and needs recognition for protection. This study aimed to evaluate the effect of the nurse-led intervention on the knowledge and preventive practice of diabetic pregnant women regarding fungal mycosis during the COVID-19 pandemic. METHOD: This quasi-experimental study was conducted at maternal health care centers in Shebin El-Kom, Menoufia Governorate, Egypt. The study recruited 73 diabetic pregnant women through a systematic random sampling of pregnant women attending the maternity clinic during the period of the study. A structured interview questionnaire was used to measure their knowledge regarding Mucormycosis and COVID-19 manifestations. The preventive practices were assessed through an observational checklist of hygienic practice, insulin administration, and blood glucose monitoring for the prevention of Mucormycosis infection. RESULTS: The study revealed a statistically significant increment in the participants' knowledge, preventive practice, personal hygiene, and diabetes self-care scores (9.56 ± 1.75 ,3.6 ± 1.18, 3.18 ± 1.29 post-intervention) comparable to (6.19 ± 1.66, 1.97 ± 1.35, 0.89 ± 1.38 pre-intervention) respectively. There was a significant improvement in the overall COVID-19 protective score against Mucormycosis (from 2.66 ± 1.74 to 4.53 ± 1.43). CONCLUSION: Nursing educational sessions had a positive effect on pregnant women's awareness and preventive behavior. Hence, it is recommended to integrate nurse-led intervention targeting the preventive practice against COVID-19-associated Mucormycosis infection (CAM) as routine services for diabetic pregnant women during antenatal care.

In vitro elution of local anesthetics from PMMA bone cement. / Estudio in vitro de elución de anestésicos locales en cemento óseo de PMMA.

BACKGROUND AND AIM: Currently, we do not have a gold standard for pain management after total knee arthroplasty. We may use one of more drug delivery systems, none of which are ideal. An ideal depot delivery system would provide therapeutic, nontoxic, doses of drug at the surgical side, especially during 72h postoperatively. The bone cement used in arthroplasties has been used as a drug delivery system, especially antibiotics, since 1970. Based on this principle, we developed this study with the aim to characterize the elution profile of two local anesthetics (lidocaine hydrochloride and bupivacaine hydrochloride) from PMMA (polymethilmethacrylate) bone cement. MATERIAL AND METHODS: Palacos® R+G bone cement and lidocaine hydrochloride or bupivacaine hydrochloride specimens were obtained depending on the study group. These specimens were immersed in PBS (phosphate buffered saline) and removed from the solution at different set times. Subsequently, the concentration of local anesthetic in the liquid was analyzed by liquid chromatography. RESULTS: The percentage of lidocaine eluted from PMMA bone cement in this study was 9.74% of the total lidocaine content per specimen at 72h and 18.73% at 336h (14 days). In case of bupivacaine, the elution percentage was 2.71% of the total bupivacaine content per specimen at 72h and 2.70% at 336h (14 days). CONCLUSIONS: Local anesthetics elute in vitro from PMMA bone cement, reaching doses at 72h close to the doses used in anesthetic blocks.