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Introduction A disproportionate increase in ventilation relative to carbon dioxide output (V E /VCO 2 ) slope is a strong prognostic indicator in heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) patients. Similarly, secondary pulmonary hypertension also poses a profound mortality risk in these patients. Exaggerated ventilation and pulmonary pressures appear to parallel one another during exercise in HF. However, an underlying pathophysiologic mechanism relating these two outcomes remains incompletely understood. Thus, the aim of this study was to determine associations between anatomical and physiologic metrics of ventilatory control and pulmonary pressures during exercise in HFrEF and HFpEF. Methods 32 HFpEF and 33 HFrEF (EF: 62±2 vs 22±1%; male: 17 and 31; age: 70±2 and 55±2 yrs; BMI: 34±1 and 28±1 kg/m 2 ; weight: 98±4 and 86±3 (all P <0.05), respectively, participated in cardiopulmonary exercise testing during right heart catheterization. Measures of pulmonary pressures included: systolic (PASP); diastolic (PADP); mean (mPAP); wedge (PCWP); pulse (PP); transpulmonary gradient (TPG). Partial pressure of arterial oxygen (PaO 2 ) and carbon dioxide (PaCO 2 ) were measured via radial arterial catheterization. Ventilation was measured continuously using a breath by breath metabolic measurement system. We calculated dead space to tidal volume [Vd/Vt=(V E ×PaCO 2 )‐(863×VCO 2 )/(V E ×PaCO 2 )] and Alveolar‐arterial oxygen gradient (A‐a)=PAO 2 ‐PaO 2 ; V E /VCO 2 slope=rest to peak exercise. Results At rest, pulmonary pressures did not differ between groups ( P >0.05); whereas Vd/Vt was lower in HFpEF vs HFrEF (0.42±0.02 vs 0.48±0.01, respectively, P =0.03). At peak exercise, HFpEF had higher PCWP (34.8±1.2 vs 30.2±1.5 mm Hg, P =0.02) and PADP (35.4±1.3 vs 29.8±1.6 mm Hg, P =0.02), but lower Vd/Vt (0.32±0.02 vs 0.38±0.01, P =0.03) and V E /VCO 2 slope (35.3±1.6 vs 43.5±2.0, P <0.01) vs HFrEF. At peak in HFpEF, Vd/Vt was related to PASP (r=0.40, P =0.03), PP (r=0.44, P =0.01), and TPG (r=0.53, P <0.01), and A‐a was related to PASP (r=0.43, P =0.01), PP (r=0.44, P =0.01), and TPG (r=0.46, P <0.01). At peak in HFrEF, Vd/Vt was related to PADP (r=0.41, P =0.02), and A‐a was related to PASP (r=0.43, P <0.01), PADP (r=0.42, P =0.01), and mPAP (r=0.44, P <0.01). There were no significant relationships between measures of pulmonary pressures and PaCO 2 . Remaining correlations between pulmonary pressures and anatomical or physiologic metrics of ventilatory control were negligible in both groups ( P >0.05). Conclusion These data suggest pulmonary pressures play a role in dead space ventilation during exercise in HF. Moreover, as suggested by the A‐a gradient, augmented pulmonary pressures may contribute to an exacerbation of ventilation/perfusion mismatch during exercise in both HFrEF and HFpEF patients. Support or Funding Information None

Background SCN5A ‐encoded Na V 1.5 is a mechanosensitive voltage‐gated sodium channel expressed in human gastrointestinal smooth muscle cells. In the gastrointestinal tract, alterations in Na V 1.5 current density by naturally occurring mutations or by pharmaceutical block of channel function are associated with constipation. In the heart loss of Na V 1.5 current is associated with cardiac contractility disorders such as dilated cardiomyopathy. Ion channel expression level is regulated by miRNAs, and Na V 1.5 is known to be regulated by miRNA in heart. However , it is not known if miRNAs regulate Na V 1.5 expression in GI smooth muscle. Aim To identify miRNAs that regulate Na V 1.5 expression in gastrointestinal smooth muscle in health and disease. Methods A qPCR array was used to screen for differential expression of 372 of the most common miRNAs in the miRBase database to test the differential expression of miRNA between control tissue and tissues from patients with slow transit constipation. qRT‐PCR was done to determine expression levels of SCN5A mRNA. A cell line (HuJej) was derived from human jejunum smooth muscle cells by immortalization using the SV40 large T antigen. Whole cell voltage clamp experiments were done by standard patch clamp techniques. Results SCN5A mRNA expression was reduced by 66±0.08% in patients with slow transit constipation (57.5±1.8 years) compared to age matched controls (53±1.7 years). qPCR array screening showed that 12 miRNAs were significantly upregulated in colonic muscularis externa from patients with STC compared to controls. Let‐7f miRNA was increased 6.46‐fold in slow transit constipation compared to controls and was the only miRNA with strong negative correlation to SCN5A mRNA expression in the same tissues. HuJej cells express Na V 1.5; therefore, we investigated the effect of let‐7f on Na V 1.5 currents by transfection with a stable miRNA mimic. 48 hours after transfection with let‐7f mimic, Na V 1.5 currents were significantly decreased compared to untransfected cells or to cells transfected with non‐targeting miRNA (let‐7f, −0.6±0.1 pA/pF versus untransfected, −3.9±0.6 pA/pF or non‐targeting, −2.3±0.6 pA/pF). Summary and Conclusions SCN5A mRNA is decreased in slow transit constipation. Expression levels of let‐7f and Na V 1.5 RNA are negatively correlated in human colonic smooth muscle. miRNA let‐7f regulates Na V 1.5 current density. Regulation of Na V 1.5 current density may have relevance in health and disease. Support or Funding Information This work was supported by grant DK52766.

Introduction Several common and functional genes are known to contribute to renal, blood vessel, and cardiac functional characteristics associated with sodium (Na + ) handling, vascular reactivity, and cardiac output, respectively. Many of these same genes are suggested to contribute to differential responsiveness to blood pressure (BP) therapy. Few studies have explored the simultaneous phenotypic consequence of multiple genes critical for BP control. Despite a significant impulse of the medical community towards personalized medicine, BP therapy is typically guided by algorithms that do not include a patient's genetic information. Purpose The purpose of this study was to determine the impact of 14 genes on time to BP control in response to common BP therapy, with a specific focus on genes associated with drug metabolism and protein function in the kidney, the blood vessels, and the heart. Methods Eighty‐six patients completed one study visit consisting of a buccal swab for DNA extraction and genotyping, measurement of ambulatory BP, and a medical chart review for objective BP history. Genes in the analysis included those that encode for one drug metabolizing enzyme (CYP2D6), renal Na + handling (SCNN1A, WNK1, SLC12A3, and Alpha Adducin), vascular function (angiotensin, ACE, angiotensin‐II receptor type‐I, and renin), and cardiac function (the β 1 and β 2 adrenergic receptors ADRB1 and ADRB2, respectively). Results Genetic variation of WNK1 (rs1159744) demonstrated differential responses to diuretic therapy (determined as those with blood pressure under 140/90 vs. those above 140/90 according to genotype)(WNK1=GG>CG/CC, P<0.05). Genes that encode ADRB1 (rs1801252), ADRB2 (rs1042713), and CYP2D6 (rs3892097) demonstrated differential response to β‐blocker therapy (ADRB1=Ser/Ser>SerThr/ThrThr, ADRB2=GG>AG/AA, CYP2D6=CC>CT/TT, P<0.05). Genes that encode angiotensin (rs699), ACE (rs1799752), and renin (rs12750834) demonstrated differential response to ACE‐inhibition and angiotensin receptor blockade (angiotensin=CT/TT>CC, ACE=Ins/Ins>InsDel/DelDel, renin=AG/AA>GG, p<0.05). Conclusion These results demonstrate that genetic variants encoding proteins involved in renal Na + handling, vascular function, and cardiac output influence response to BP therapy for their respective drug classes. Support or Funding Information Funded by Geneticure

Introduction Hypertension is one of the most important preventable contributors to disease and death worldwide and represents the most common condition seen in the primary care setting. Approximately one in three adults living in the US has hypertension. Despite the prevalence and impact of hypertension, little data exists on the average time to blood pressure (BP) control in US patients and time to control according to common BP medication classes. Purpose Therefore, the purpose of this study was to assess the average time to BP control in adults with controlled hypertension, according to drug class. Methods For this study we assessed how long (in months) and how many clinic visits were needed in order to control BP according to common medication classes in patients with existing hypertension. The study was performed at two clinical sites where patients came in for one visit for an in‐clinic assessment of BP and for completion of a patient survey regarding their history of BP. The primary care physician performed a chart review for a detailed objective BP history. Results Ninety‐nine patients completed all aspects of the study (age=58±0.8yrs., %female=46, height=169±1.0cm, weight=86±1.4kg, BMI=29.9±0.4m/kg 2 ). The average initial BP was 151±2mmHg systolic (SBP), 91±1mmHg diastolic, and 111±1mmHg mean arterial (MAP). Patients demonstrated a significant drop in BP with therapy (SBP=16mmHg, DBP=10mmHg, MAP=12mmHg). Patients were prescribed an average of 1.8 BP medications (62% on ACE‐inhibitor, 42% on diuretic, 33% on β‐blocker, 27% on angiotensin receptor blocker, and 16% on Ca + channel blocker). The average time to BP control was 14.9 months or 3.6 clinic visits. Patients on a diuretic had the longest time to BP control, while patients on a Ca + channel blocker had the shortest time to control (diuretic=19.5±10.4, angiotensin receptor blocker=22.8±13.1, ACE‐inhibitor=22.2±11.4, β‐blocker=24.5±16.9, Ca + channel blocker=9.9±4.5 months, pANOVA<0.05). In contrast, patients on a Ca + channel blocker had significantly more clinic visits to attain BP control (diuretic=4.5±0.6, ACE‐inhibitor=3.1±0.4, angiotensin receptor blocker=3.9±0.6, β‐blocker=4.9±0.7, Ca + channel blocker=5.1±0.7 visits). Conclusion These results suggest important differences in the time to BP control, and the number of office visits necessary for BP control according to common classes of hypertension therapies. Funding was provided by Geneticure, LLC Support or Funding Information Funded by Geneticure

Diffusion measurements in the kidney are affected not only by renal microstructure but also by physiological processes (i.e., glomerular filtration, water reabsorption, and urine formation). Because of the superposition of passive tissue diffusion, blood perfusion, and tubular pre‐urine flow, the limitations of the monoexponential apparent diffusion coefficient (ADC) model in assessing pathophysiological changes in renal tissue are becoming apparent and motivate the development of more advanced diffusion‐weighted imaging (DWI) variants. These approaches take advantage of the fact that the length scale probed in DWI measurements can be adjusted by experimental parameters, including diffusion‐weighting, diffusion gradient directions and diffusion time. This forms the basis by which advanced DWI models can be used to capture not only passive diffusion effects, but also microcirculation, compartmentalization, tissue anisotropy. In this review, we provide a comprehensive overview of the recent advancements in the field of renal DWI. Following a short introduction on renal structure and physiology, we present the key methodological approaches for the acquisition and analysis of renal DWI data, including intravoxel incoherent motion (IVIM), diffusion tensor imaging (DTI), non‐Gaussian diffusion, and hybrid IVIM‐DTI. We then briefly summarize the applications of these methods in chronic kidney disease and renal allograft dysfunction. Finally, we discuss the challenges and potential avenues for further development of renal DWI.Level of Evidence5Technical EfficacyStage 2

Background Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. Methods We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. Conclusions We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

Positron emission tomography (PET) imaging in prostate cancer has advanced significantly in the past decade with prostate cancer targeted radiopharmaceuticals now playing a growing role in diagnosis, staging, and treatment. This narrative review focuses on the most commonly used PET radiopharmaceuticals in the USA: prostate-specific membrane antigen (PSMA), fluciclovine, and choline. 18F-fluorodeoxyglucose (FDG) is used in many other malignancies, but rarely in prostate cancer. Previous literature is discussed regarding each radiopharmaceutical’s utility in the settings of screening/diagnosis, initial staging, biochemical recurrence, advanced disease, and evaluation prior to targeted radiopharmaceutical therapy and radiation therapy. PET imaging has demonstrated utility over traditional imaging in various scenarios; however, there are few head-to-head studies comparing PET radiopharmaceuticals. PSMA radiopharmaceuticals are the newest tracers developed and have unique properties and uses, especially at low prostate-specific antigen (PSA) levels. However, each PET radiopharmaceutical has different properties which can affect image interpretation. Choline and fluciclovine have minimal urinary activity, whereas PSMA agents can have high urinary activity which may affect locoregional disease evaluation. Of the three radiopharmaceuticals, only PSMA is approved for both diagnostic and therapeutic indications with 177 Lu-PSMA. A variety of diagnostic PET radiotracers for prostate cancer allows for increased flexibility, especially in the setting of supply chain and medication shortages. For the time being, keeping a diverse group of PET radiopharmaceuticals for prostate cancer is justifiable.

Abstract Although the majority of HPV (+) oropharyngeal squamous cell carcinoma (OPSCC) patients exhibit a favorable prognosis, approximately 20% face recurrent or metastatic disease, posing management challenges. Therefore, the identification of robust prognostic markers for risk stratification is essential. Our study focused on the comprehensive characterization of intratumor heterogeneity within the tumor immune microenvironment (TME) in both primary tumors and metastatic lymph nodes. Utilizing computational approaches, we integrated hematoxylin and eosin (H&E) and 11 adjacent immunohistochemistry (IHC)-stained slides to investigate the cellular composition and functional characteristics across different regions within the TME. Based on these detailed immune characteristics, we classified patients into specific immune subtypes. Our integrative TME analysis indicated that patients with high tumor-infiltrating lymphocytes (TIL), increased CD8 + levels, and reduced CD163 + cell counts within their primary tumors were likely to have a more favorable progression-free survival outcome. The integration of H&E and IHC data enhances the functional characterization of immune phenotypes of the TME with biological interpretability and improves patient stratification in HPV(+) OPSCC.

Background: Severe adolescent idiopathic scoliosis (AIS) can be treated with instrumented fusion, but the number of anchors needed for optimal correction is controversial. Methods: We conducted a multicenter, randomized study that included patients undergoing spinal fusion for single thoracic curves between 45° and 65°, the most common form of operatively treated AIS. Of the 211 patients randomized, 108 were assigned to a high-density screw pattern and 103, to a low-density screw pattern. Surgeons were instructed to use ≥1.8 implants per spinal level fused for patients in the high-implant-density group or ≤1.4 implants per spinal level fused for patients in the low-implant-density group. The primary outcome measure was the percent correction of the coronal curve at the 2-year follow-up. The power analysis for this trial required 174 patients to show equivalence, defined as a 95% confidence interval (CI) within a ±10% correction margin with a probability of 90%. Results: In the intention-to-treat analysis, the mean percent correction of the coronal curve was equivalent between the high-density and low-density groups at the 2-year follow-up (67.6% versus 65.7%; difference, −1.9% [95% CI: −6.1%, 2.2%]). In the per-protocol cohorts, the mean percent correction of the coronal curve was also equivalent between the 2 groups at the 2-year follow-up (65.0% versus 66.1%; difference, 1.1% [95% CI: −3.0%, 5.2%]). A total of 6 patients in the low-density group and 5 patients in the high-density group required reoperation (p = 1.0). Conclusions: In the setting of spinal fusion for primary thoracic AIS curves between 45° and 65°, the percent coronal curve correction obtained with use of a low-implant-density construct and that obtained with use of a high-implant-density construct were equivalent. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.