Consequences of low estimated glomerular filtration rate either before or early after kidney donation.

In the general population, decreases in glomerular filtration rate (GFR) are associated with subsequent development of chronic kidney disease (CKD), cardiovascular disease (CVD), and death. It is unknown if low estimated GFR (eGFR) before or early after kidney donation was also associated with these risks. One thousand six hundred ninety-nine living donors who had both predonation and early (4-10 weeks) postdonation eGFR were included. We studied the relationships between eGFR, age at donation, and the time to sustained eGFR<45 (CKD stage 3b) and <30 mL/min/1.73m2 (CKD stage 4), hypertension, diabetes mellitus (DM), CVD, and death. Median follow-up was 12 (interquartile range, 6-21) years. Twenty-year event rates were 5.8% eGFR<45 mL/min/1.73m2; 1.2% eGFR<30 mL/min/1.73m2; 29.0% hypertension; 7.8% DM; 8.0% CVD; and 5.2% death. The median time to eGFR<45 mL/min/1.73m2 (N = 79) was 17 years, and eGFR<30 mL/min/1.73m2 (N = 22) was 25 years. Both low predonation and early postdonation eGFR were associated with eGFR<45 mL/min/1.73m2 (P < .0001) and eGFR<30 mL/min/1.73m2 (P < .006); however, the primary driver of risk for all ages was low postdonation (rather than predonation) eGFR. Predonation and postdonation eGFR were not associated with hypertension, DM, CVD, or death. Low predonation and early postdonation eGFR are risk factors for developing eGFR<45 mL/min/1.73m2 (CKD stage 3b) and <30 mL/min/1.73m2 (CKD stage 4), but not CVD, hypertension, DM, or death.

Kidney transplant outcomes in children with simultaneous versus sequential heart-kidney transplants.

BACKGROUND: Heart transplant recipients frequently require kidney transplantation for concomitant advanced chronic kidney disease. Data on simultaneous (heart and kidney transplants performed simultaneously) versus sequential (heart transplant performed before kidney) heart-kidney transplants in children are limited. Herein, we compare kidney transplant outcomes between the two groups. METHOD: We used the Scientific Registry of Transplant Recipients to identify all pediatric (age <21 years) heart transplant recipients who also received a kidney transplant within 10 years of the heart transplant. We divided the study cohort into simultaneous heart-kidney and sequential heart-kidney recipients. We compared patient and death-censored graft survival using the Cox regression, adjusting for age at kidney transplant, sex, race, pre-transplant dialysis, donor type, and prior kidney transplant. We evaluated delayed graft function (defined as dialysis within the first week posttransplant) using logistic regression. RESULTS: Our analysis cohort included 165 recipients (86 simultaneous and 79 sequential). The incidence of delayed graft function was higher in simultaneous recipients (22.4 vs. 7.7%, p=0.017), but the difference lost statistical significance on multivariable analysis. We found no difference in patient survival (aHR 0.97; 95% CI 0.39, 2.41; p=0.95) after kidney transplant but higher death-censored kidney graft survival in sequential heart-kidney recipients compared with simultaneous heart-kidney recipients (aHR 4.26; 95% CI 1.21, 14.9; p=0.02). CONCLUSION: Sequential heart-kidney transplants are associated with higher death-censored kidney allograft survival in children compared with simultaneous heart-kidney transplants.

Neurodevelopmental profile of infants and toddlers awaiting a kidney transplant.

BACKGROUND: Infants and toddlers with kidney failure are susceptible to neurodevelopmental delays due to medical comorbidities and rapid brain development in early childhood. However, research on the neuropsychological development of this patient population has been limited over the past 10 years. METHODS: We performed a retrospective study to evaluate the neurodevelopmental functioning of infants/toddlers with kidney failure who completed the Bayley Scales of Infant and Toddler Development (3rd and 4th Edition) as part of a pretransplant evaluation between 2010 and 2022 (n = 23; Mage = 18 months, SD = 8.53; 16 males) using t-tests, linear model, and Pearson correlations. RESULTS: Mean Bayley scores of participants were below normative means for cognition (M = 86.74, 95% CI = 80.53-92.94, p < 0.001), language (M = 79.20, 95% CI = 73.32-85.08, p < 0.001), and motor (M = 78.00, 95% CI = 70.15-85.85, p < 0.001) domains. After adjusting for prematurity and epilepsy, patients on dialysis had significantly lower cognitive (78.7 vs. 93.8; p = 0.001) and motor scores (67.1 vs. 85.5; p = 0.01) compared to no dialysis. Pretransplant cognitive scores were positively correlated with posttransplant Full-Scale IQ (r(8) = 0.65 p = 0.04), verbal comprehension (r(8) = 0.75 p = 0.02), and fluid reasoning (r(7) = 0.68 p = 0.045). Similarly, pretransplant language scores were positively correlated with posttransplant Full-Scale IQ (r(7) = 0.74 p = 0.03) and verbal comprehension (r(7) = 0.73 p = 0.03). Of the 16 participants who reached age > 5 years during the study period, seven were diagnosed with a neurodevelopmental disorder, including three with autism spectrum disorder. CONCLUSIONS: Infants and toddlers with kidney failure are at risk of developmental delays and later neurodevelopmental disorders. Dialysis is associated with cognitive and motor delays independent of prematurity and epilepsy.

New Morbidities During Critical Illness and Associated Risk of ICU Readmission: Virtual Pediatric Systems Cohort, 2017-2020.

OBJECTIVES: To describe change in Functional Status Scale (FSS) associated with critical illness and assess associated development of new morbidities with PICU readmission. DESIGN: Retrospective, cross-sectional cohort study using the Virtual Pediatric Systems (VPS; Los Angeles, CA) database. SETTING: One hundred twenty-six U.S. PICUs participating in VPS. SUBJECTS: Children younger than 21 years old admitted 2017-2020 and followed to December 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 40,654 patients, 86.2% were classified as having good function or mild dysfunction before illness. Most patients did not have a change in their FSS category during hospitalization. Survival with new morbidity occurred most in children with baseline good/mild dysfunction (8.7%). Hospital mortality increased across categories of baseline dysfunction. Of 39,701 survivors, 14.2% were readmitted within 1 year. Median time to readmission was 159 days. In multivariable, mixed-effects Cox modeling, time to readmission was most associated with discharge functional status (hazard ratio [HR], 5.3 [95% CI, 4.6-6.1] for those with very severe dysfunction), and associated with lower hazard in those who survived with new morbidity (HR, 0.7 [95% CI, 0.6-0.7]). CONCLUSIONS: Development of new morbidities occurs commonly in pediatric critical illness, but we failed to find an association with greater hazard of PICU readmission. Instead, patient functional status is associated with hazard of PICU readmission.

School Connectedness and Adolescent E-cigarette Susceptibility in an Urban Sample of Middle and High School Students.

Adolescent school connectedness generally protects from risk behaviors such as tobacco use; however, its relationship to e-cigarette use is unclear. This study examines the relationship between adolescent school connectedness and e-cigarette susceptibility in a diverse longitudinal sample. This secondary analysis of a school-based intervention surveyed 608 middle (66%) and high school (34%) students from 10 schools at 3 time points over 1 year. At baseline, respondents had a mean age of 14 years, 54% were female, and 71% were BIPOC (Black, Indigenous, People of Color). Logistic regression models examined unadjusted and adjusted associations between school connectedness (both baseline and concurrent) and e-cigarette susceptibility over time. E-cigarettes represented the most prevalent form of current nicotine-containing product use in spring 2019 (2.3%), and most respondents reported no e-cigarette susceptibility (69%). E-cigarette susceptibility remained relatively stable during the study. Higher baseline school connectedness levels were associated with lower odds of e-cigarette susceptibility over time. Similarly, higher concurrent school connectedness scores were associated with lower odds of e-cigarette susceptibility over time: spring 2019 (OR, 0.39; 95% CI, 0.32, 0.47), fall 2019 (OR, 0.49; 95% CI, 0.34, 0.72), and spring 2020 (OR, 0.64; 95% CI, 0.47, 0.87). Findings were similar for middle and high school students and did not differ significantly after adjusting for other covariates. Adolescents' school connectedness appears to protect from e-cigarette susceptibility over time, underscoring the importance of promoting positive school experiences to reduce adolescent risk e-cigarette use.

Invasive haemodynamics predict outcomes in paediatric pulmonary artery hypertension.

BACKGROUND: Invasive haemodynamics are often performed for initiating and guiding pulmonary artery hypertension therapy. Little is known about the predictive value of invasive haemodynamic indices for long-term outcomes in children with pulmonary artery hypertension. We aimed to evaluate invasive haemodynamic data to help predict outcomes in paediatric pulmonary artery hypertension. METHODS: Patients with pulmonary artery hypertension who underwent cardiac catheterisation (2006-2019) at a single centre were included. Invasive haemodynamic data from the first cardiac catheterisation and clinical outcomes were reviewed. The combined adverse outcome was defined as pericardial effusion (due to right ventricle failure), creation of a shunt for pulmonary artery hypertension (atrial septal defect or reverse Pott's shunt), lung transplant, or death. RESULTS: Among 46 patients with a median [interquartile range (IQR)] age of 13.2 [4.1-44.7] months, 76% had CHD. Median mean pulmonary artery pressure was 37 [28-52] mmHg and indexed pulmonary vascular resistance was 6.2 [3.6-10] Woods units × m2. Median pulmonary artery pulsatility index was 4.0 [3.0-4.7] and right ventricular stroke work index was 915 [715-1734] mmHg mL/m2. After a median follow-up of 2.4 years, nine patients had a combined adverse outcome (two had a pericardial effusion, one underwent atrial level shunt, one underwent reverse Pott's shunt, and six died). Patients with an adverse outcome had higher systolic and mean pulmonary artery pressures, higher diastolic and transpulmonary pressure gradients, higher indexed pulmonary vascular resistance, higher pulmonary artery elastance, and higher right ventricular stroke work index (p < 0.05 each). CONCLUSION: Invasive haemodynamics (especially mean pulmonary artery pressure and diastolic pressure gradient) obtained at first cardiac catheterisation in children with pulmonary artery hypertension predicts outcomes.

Evaluation of an augmented reality navigational guidance platform for percutaneous procedures in a cadaver model.

Purpose: The objective of this study is to review the accuracy of an augmented reality navigational guidance system designed to facilitate improved visualization, guidance, and accuracy during percutaneous needle-based procedures including biopsies and ablations. Approach: Using the HoloLens 2, the system registers and projects 3D CT-based models of segmented anatomy along with live ultrasound, fused with electromagnetically tracked instruments including ultrasound probes and needles, giving the operator comprehensive stereoscopic visualization for intraoperative planning and navigation during procedures.Tracked needles were guided to targets implanted in a cadaveric model using the system. Image fusion registration error, the multimodality error measured as the post-registration distance between a corresponding point measured in the stereoscopic CT and tracked ultrasound coordinate systems, and target registration error, the Euclidean distance between needle tip and target after needle placement, were measured as registration and targeting accuracy metrics. A t-distribution was used for statistical analysis. Results: Three operators performed 36 total needle passes, 18 to measure image fusion registration error and 18 to measure target registration error on four targets. The average depth of each needle pass was 8.4 cm from skin to target center. Mean IFRE was 4.4 mm (H0: µ=5 mm, P<0.05). Mean TRE was 2.3 mm (H0: µ=5 mm, P<0.00001). Conclusions: The study demonstrated high registration and targeting accuracy of this AR navigational guidance system in percutaneous, needle-based procedures. This suggests the ability to facilitate improved clinical performance in percutaneous procedures such as ablations and biopsies.

SENTRI: Single-Particle Energy Transducer for Radionuclide Injections for Personalized Targeted Radionuclide Cancer Therapy.

PURPOSE: Targeted radionuclide therapy (TRT), whereby a tumor-targeted molecule is linked to a therapeutic beta- or alpha-emitting radioactive nuclide, is a promising treatment modality for patients with metastatic cancer, delivering radiation systemically. However, patients still progress due to suboptimal dosing, driven by the large patient-to-patient variability. Therefore, the ability to continuously monitor the real-time dose deposition in tumors and organs at risk provides an additional dimension of information during clinical trials that can enable insights into better strategies to personalize TRT. METHODS AND MATERIALS: Here, we present a single beta-particle sensitive dosimeter consisting of a 0.27-mm3 monolithic silicon chiplet directly implanted into the tumor. To maximize the sensitivity and have enough detection area, minimum-size diodes (1 µm2) are arrayed in 64 × 64. Signal amplifiers, buffers, and on-chip memories are all integrated in the chip. For verification, PC3-PIP (prostate-specific membrane antigen [PSMA]+) and PC3-flu (PSMA-) cell lines are injected into the left and right flanks of the mice, respectively. The devices are inserted into each tumor and measure activities at 5 different time points (0-2 hours, 7-9 hours, 12-14 hours, 24-26 hours, and 48-50 hours) after 177Lu-PSMA-617 injections. Single-photon emission computed tomography/computed tomography scans are used to verify measured data. RESULTS: With a wide detection range from 0.013 to 8.95 MBq/mL, the system is capable of detecting high tumor uptake as well as low doses delivered to organs at risk in real time. The measurement data are highly proportional (R2 > 0.99) to the 177Lu-PSMA-617 activity. The in vivo measurement data agree well with the single-photon emission computed tomography/computed tomography results within acceptable errors (±1.5%ID/mL). CONCLUSIONS: Given the recent advances in clinical use of TRT in prostate cancer, the proposed system is verified in a prostate cancer mouse model using 177Lu-PSMA-617.

Valacyclovir or valganciclovir for cytomegalovirus prophylaxis: A randomized controlled trial in adult and pediatric kidney transplant recipients.

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.

Impact of the Reverse 2-Step Algorithm for Clostridioides difficile Testing in the Microbiology Laboratory on Hospitalized Patients.

Background: Multistep laboratory testing is recommended for the diagnosis of Clostridioides difficile infection (CDI). The aim of this study was to present the impact of multistep CDI diagnostic testing in an academic hospital system and evaluate the toxin B gene polymerase chain reaction (PCR) cycle threshold (Ct) values of PCR-positive tests. Methods: In October 2022, our system began reflex testing all PCR-positive stool samples with the C. DIFF QUIK CHEK COMPLETE (Techlab), an enzyme immunoassay-based test with results for the glutamate dehydrogenase antigen (GDH) and C difficile toxin A/B. Hospital-onset (HO) CDI and CDI antibiotic use before and after testing were tracked. Ct values were obtained from the Infectious Diseases Diagnostic Laboratory. Receiver operating curve analysis was used to examine the sensitivity and specificity for identifying GDH+/toxin+ and GDH-/toxin- at various Ct thresholds. Results: The HO-CDI rate decreased from 0.352 cases per 1000 patient-days to 0.115 cases per 1000 patient-days post-reflex testing (P < .005). Anti-CDI antibiotics use decreased, but the decrease was not commensurate with CDI rates following reflex testing. PCR+/GDH+/toxin+ samples had a lower mean Ct value than PCR+/GDH-/toxin- samples (23.3 vs 33.5, P < .0001). A Ct value of 28.65 could distinguish between those 2 groups. Fifty-four percent of PCR+/GDH+/toxin- samples had a Ct value below that cut-off, suggesting the possibility of CDI with a negative toxin test. Conclusions: Reflex testing for a laboratory diagnosis of CDI results in rapid, systemwide decreases in the rate of HO-CDI. Additional research is needed to distinguish CDI from C difficile colonization in patients with discordant testing.

Low cost, high temporal resolution optical fiber-based γ-photon sensor for real-time pre-clinical evaluation of cancer-targeting radiopharmaceuticals.

Cancer radiopharmaceutical therapies (RPTs) have demonstrated great promise in the treatment of neuroendocrine and prostate cancer, giving hope to late-stage metastatic cancer patients with currently very few treatment options. These therapies have sparked a large amount of interest in pre-clinical research due to their ability to target metastatic disease, with many research efforts focused towards developing and evaluating targeted RPTs for different cancer types in in vivo models. Here we describe a method for monitoring real-time in vivo binding kinetics for the pre-clinical evaluation of cancer RPTs. Recognizing the significant heterogeneity in biodistribution of RPTs among even genetically identical animal models, this approach offers long-term monitoring of the same in vivo organism without euthanasia in contrast to ex vivo tissue dosimetry, while providing high temporal resolution with a low-cost, easily assembled platform, that is not present in small-animal SPECT/CTs. The method utilizes the developed optical fiber-based γ-photon biosensor, characterized to have a wide linear dynamic range with Lutetium-177 (177Lu) activity (0.5-500 µCi/mL), a common radioisotope used in cancer RPT. The probe's ability to track in vivo uptake relative to SPECT/CT and ex vivo dosimetry techniques was verified by administering 177Lu-PSMA-617 to mouse models bearing human prostate cancer tumors (PC3-PIP, PC3-flu). With this method for monitoring RPT uptake, it is possible to evaluate changes in tissue uptake at temporal resolutions <1 min to determine RPT biodistribution in pre-clinical models and better understand dose relationships with tumor ablation, toxicity, and recurrence when attempting to move therapies towards clinical trial validation.

Neurocognitive Profile in Pediatric Kidney Transplant Candidates: Effects of Medical and Sociodemographic Factors.

Background: We evaluated the effects of kidney failure etiology, dialysis, and sociodemographic factors on the subdomains of intellectual functioning in pediatric kidney transplant candidates. Methods: This retrospective study included 78 pediatric kidney transplant candidates who completed a Wechsler Intelligence Scale assessment during pre-transplant neuropsychological evaluation between 1/1/2010 and 10/31/2022. Linear regression models were employed to examine the effects of kidney failure etiology, dialysis status, neighborhood area deprivation, and race on subdomains of intellectual functioning. Results: The mean scores of various intellectual functioning domains in pediatric kidney transplant candidates were significantly lower than in the general population (ps <0.001). After adjusting for covariates, patients with congenital anomalies of the kidney and urinary tract had significantly lower processing speed (M=85; 95% CI: 79-91) compared to patients with nephrotic syndrome (M=99; 95% CI: 90-107) and other etiologies (M=84; 95% CI: 78-90) (p=0.003). Patients living in high-level deprivation neighborhoods showed lower working memory performance (M=84, 95% CI: 77-91) than patients living in median-level (M=91, 95% CI: 87-95) and low-level (M=98, 95% CI: 92-104) neighborhood area deprivation (p=0.03). Patients from marginalized racial groups demonstrated lower verbal skills (M=80, 95% CI: 74-87) than White patients (M=92, 95% CI: 88-97) (p=0.02). Additionally, patients receiving dialysis showed higher reasoning skills (M=98, 95% CI: 90-104) than patients without dialysis (M= 90, 95% CI: 86-95) (p=0.04). Conclusions: Neurocognitive development in pediatric kidney transplant candidates is associated with medical and sociodemographic factors. Strategies to monitor, treat, and accommodate neurocognitive concerns need to be considered to optimize long-term medical and social outcomes.

Disparities in Documentation: Evidence of Race-Based Biases in the Electronic Medical Record.

Personal implicit biases may contribute to inequitable health outcomes, but the mechanisms of these effects are unclear at a system level. This study aimed to determine whether stigmatizing subjective terms in electronic medical records (EMR) reflect larger societal racial biases. A cross-sectional study was conducted using natural language processing software of all documentation where one or more predefined stigmatizing words were used between January 1, 2019 and June 30, 2021. EMR from emergency care and inpatient encounters in a metropolitan healthcare system were analyzed, focused on the presence or absence of race-based differences in word usage, either by specific terms or by groupings of negative or positive terms based on the common perceptions of the words. The persistence ("stickiness") of negative and/or positive characterizations in subsequent encounters for an individual was also evaluated. Final analyses included 12,238 encounters for 9135 patients, ranging from newborn to 104 years old. White (68%) vs Black/African American (17%) were the analyzed groups. Several negative terms (e.g., noncompliant, disrespectful, and curse words) were significantly more frequent in encounters with Black/African American patients. In contrast, positive terms (e.g., compliant, polite) were statistically more likely to be in White patients' documentation. Independent of race, negative characterizations were twice as likely to persist compared with positive ones in subsequent encounters. The use of stigmatizing language in documentation mirrors the same race-based inequities seen in medical outcomes and larger sociodemographic trends. This may contribute to observed healthcare outcome differences by disseminating one's implicit biases to unknown future healthcare providers.

Risk of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) Among Patients with Type 2 Diabetes Mellitus on Anti-Hyperglycemic Medications.

Background: Observed activity of metformin in reducing the risk of severe COVID-19 suggests a potential use of the anti-hyperglycemic in the prevention of post-acute sequelae of SARS-CoV-2 infection (PASC). We assessed the 3-month and 6-month risk of PASC among patients with type 2 diabetes mellitus (T2DM) comparing metformin users to sulfonylureas (SU) or dipeptidyl peptidase-4 inhibitors (DPP4i) users. Methods: We used de-identified patient level electronic health record data from the National Covid Cohort Collaborative (N3C) between October 2021 and April 2023. Participants were adults ≥ 18 years with T2DM who had at least one outpatient healthcare encounter in health institutions in the United States prior to COVID-19 diagnosis. The outcome of PASC was defined based on the presence of a diagnosis code for the illness or using a predicted probability based on a machine learning algorithm. We estimated the 3-month and 6-month risk of PASC and calculated crude and weighted risk ratios (RR), risk differences (RD), and differences in mean predicted probability. Results: We identified 5596 (mean age: 61.1 years; SD: 12.6) and 1451 (mean age: 64.9 years; SD 12.5) eligible prevalent users of metformin and SU/DPP4i respectively. We did not find a significant difference in risk of PASC at 3 months (RR = 0.86 [0.56; 1.32], RD = -3.06 per 1000 [-12.14; 6.01]), or at 6 months (RR = 0.81 [0.55; 1.20], RD = -4.91 per 1000 [-14.75, 4.93]) comparing prevalent users of metformin to prevalent users of SU/ DPP4i. Similar observations were made for the outcome definition using the ML algorithm. Conclusion: The observed estimates in our study are consistent with a reduced risk of PASC among prevalent users of metformin, however the uncertainty of our confidence intervals warrants cautious interpretations of the results. A standardized clinical definition of PASC is warranted for thorough evaluation of the effectiveness of therapies under assessment for the prevention of PASC.

Previous research suggests that metformin, due to its anti-viral, anti-inflammatory, and anti-thrombotic properties may reduce the risk of severe COVID-19. Given the shared etiology of COVID-19 and the post-acute sequelae of SARS-CoV-2 (PASC), and the proposed inflammatory processes of PASC, metformin may also be a beneficial preventive option. We investigated the benefit of metformin for PASC prevention in a population of type 2 diabetes mellitus patients with a COVID-19 diagnosis who were on metformin or two other anti-hyperglycemic medications prior to infection with SARS-CoV-2. Our results were consistent with a reduction in the risk of PASC with the use of metformin, however, the imprecise confidence intervals obtained warrants further investigation of this association of the potential beneficial effect of metformin for preventing PASC in patients with medication-managed diabetes.

Imaging the Granzyme Mediated Host Immune Response to Viral and Bacterial Pathogens In Vivo Using Positron Emission Tomography.

Understanding how the host immune system engages complex pathogens is essential to developing therapeutic strategies to overcome their virulence. While granzymes are well understood to trigger apoptosis in infected host cells or bacteria, less is known about how the immune system mobilizes individual granzyme species in vivo to combat diverse pathogens. Toward the goal of studying individual granzyme function directly in vivo, we previously developed a new class of radiopharmaceuticals termed "restricted interaction peptides (RIPs)" that detect biochemically active endoproteases using positron emission tomography (PET). In this study, we showed that secreted granzyme B proteolysis in response to diverse viral and bacterial pathogens could be imaged with [64Cu]Cu-GRIP B, a RIP that specifically targets granzyme B. Wild-type or germline granzyme B knockout mice were instilled intranasally with the A/PR/8/34 H1N1 influenza A strain to generate pneumonia, and granzyme B production within the lungs was measured using [64Cu]Cu-GRIP B PET/CT. Murine myositis models of acute bacterial (E. coli, P. aeruginosa, K. pneumoniae, and L. monocytogenes) infection were also developed and imaged using [64Cu]Cu-GRIP B. In all cases, the mice were studied in vivo using mPET/CT and ex vivo via tissue-harvesting, gamma counting, and immunohistochemistry. [64Cu]Cu-GRIP B uptake was significantly higher in the lungs of wild-type mice that received A/PR/8/34 H1N1 influenza A strain compared to mice that received sham or granzyme B knockout mice that received either treatment. In wild-type mice, [64Cu]Cu-GRIP B uptake was significantly higher in the infected triceps muscle versus normal muscle and the contralateral triceps inoculated with heat killed bacteria. In granzyme B knockout mice, [64Cu]Cu-GRIP B uptake above the background was not observed in the infected triceps muscle. Interestingly, live L. monocytogenes did not induce detectable granzyme B on PET, despite prior in vitro data, suggesting a role for granzyme B in suppressing their pathogenicity. In summary, these data show that the granzyme response elicited by diverse human pathogens can be imaged using PET. These results and data generated via additional RIPs specific for other granzyme proteases will allow for a deeper mechanistic study analysis of their complex in vivo biology.

A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.

Pilot trial results of D-HOMES: a behavioral-activation based intervention for diabetes medication adherence and psychological wellness among people who have been homeless.

Introduction: People living with type 2 diabetes who experience homelessness face a myriad of barriers to engaging in diabetes self-care behaviors that lead to premature complications and death. This is exacerbated by high rates of comorbid mental illness, substance use disorder, and other physical health problems. Despite strong evidence to support lay health coach and behavioral activation, little research has effectively engaged people living with type 2 diabetes who had experienced homelessness (DH). Methods: We used community engaged research and incremental behavioral treatment development to design the Diabetes HOmeless MEdication Support (D-HOMES) program, a one-on-one, 3 month, coaching intervention to improve medication adherence and psychological wellness for DH. We present results of our pilot randomized trial (with baseline, 3 mo., 6 mo. assessments) comparing D-HOMES to enhanced usual care (EUC; brief diabetes education session and routine care; NCT05258630). Participants were English-speaking adults with type 2 diabetes, current/recent (<24 mo.) homelessness, and an HbA1c_7.5%. We focused on feasibility (recruitment, retention, engagement) and acceptability (Client Satisfaction Questionnaire, CSQ-8). Our primary clinical outcome was glycemic control (HbA1c) and primary behavioral outcome was medication adherence. Secondary outcomes included psychological wellness and diabetes self-care. Results: Thirty-six eligible participants enrolled, 18 in each arm. Most participants identified as Black males, had high rates of co-morbidities, and lived in subsidized housing. We retained 100% of participants at 3-months, and 94% at 6-months. Participants reported high satisfaction (mean CSQ-8 scores=28.64 [SD 3.94] of 32). HbA1c reduced to clinically significant levels in both groups, but we found no between group differences. Mean blood pressure improved more in D-HOMES than EUC between baseline and 6 mo. with between group mean differences of systolic -19.5 mmHg (p=0.030) and diastolic blood pressure -11.1 mmHg (p=0.049). We found no significant between group differences in other secondary outcomes. Conclusion: We effectively recruited and retained DH over 6 months. Data support that the D-HOMES intervention was acceptable and feasible. We observe preliminary blood pressure improvement favoring D-HOMES that were statistically and clinically significant. D-HOMES warrants testing in a fully powered trial which could inform future high quality behavioral trials to promote health equity. Clinical trial registration: https://clinicaltrials.gov/study/NCT05258630?term=D-HOMES&rank=1, identifier NCT05258630.

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura.

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. Results: In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.