Chronic Deltoid Insufficiency in Stage IV Adult Acquired Flatfoot Deformity: Do We Have a Good Answer?

Stage IV adult acquired flatfoot deformity (AAFD) with secondary chronic deltoid ligament insufficiency is a challenging deformity to treat, with minimal consensus in the literature concerning its surgical management. Many surgical treatment options have been described, including joint-sparing techniques, fusions, osteotomies, and even arthroplasties. However, questions remain as to what, if any, treatment is optimal. This contribution reviews studies on surgical treatments for stage IV AAFD with deltoid ligament failure and provides a critical analysis regarding the quality of outcomes reported for those different treatment options. PubMed and Google Scholar databases were searched between June 1, 2022, and August 15, 2022, for studies published between 1990 and 2022 that describe the treatment of stage IV AAFD with deltoid ligament insufficiency. Articles included in the study focused on subjects with stage IV AAFD and associated deltoid ligament insufficiency undergoing surgical correction. Exclusion criteria included stage I, II, and III AAFD, as well as deltoid ligament repair following acute injury/rupture. Nine studies covering five different treatment options for patients with stage IV AAFD and chronic deltoid insufficiency were included, with minimal overlap in outcome measures used to assess the efficacy of the procedure. Triple arthrodesis with deltoid ligament reconstruction resulted in a 62.5% (5/8) success rate with a residual tibiotalar (TT) angulation of 2° (success defined as <3°). Tibiotalar arthrodesis of four patients resulted in an average post-operative tibiotalar angulation of 4.8° with all patients showing progressive destabilization of the hindfoot complex at 12-18 year follow-ups. Deltoid arthroscopic laminoplasty (Brostrom) resulted in an increased American Orthopaedic Foot and Ankle Society (AOFAS) score from 49.7 pre-op to 91.9 post-op. There was no long-term follow-up of these patients. Deltoid ligament reconstruction using autografts of the peroneus longus resulted in a post-operative valgus of 2.1° in one study and <5° in another. Deltoid ligament reconstruction using an anterior tibial tendon autograft resulted in a gain of 126.4 + 40.2% in stiffness compared to an intact ligament. Twinfix suture anchors resulted in a post-operative hindfoot angle averaging 5.3°. Combined deltoid and spring ligament reconstruction resulted in a 5.1° valgus angulation. There is currently no standard of care or clinical consensus regarding surgical treatment for stage IV AAFD with deltoid insufficiency. Several studies imply that mild valgus malalignment around the tibiotalar joint can result in satisfactory outcomes. A few studies even deemed <5° of valgus tilt post-operatively successful. However, it has been described that any imbalance in tibiotalar tilt is a significant risk factor for progressive arthritis and future ligamentous failure. No treatment option was able to correct valgus tilt to an anatomical standard (i.e., to normal anatomy). These varied findings, along with the lack of consensus on post-surgical measures to assess efficacy, are worrisome and emphasize the need for better surgical options. Moreover, there is a critical need for additional research on the long-term outcomes following stage IV AAFD and deltoid insufficiency repair, particularly, as over five million people in the United States and 10% of the geriatric population are affected by AAFD with a risk of progressing to stage IV.

Influence of Regular Physical Activity on Sleep.

Good sleep and adequate physical activity are essential to health. Yet, large numbers of people are chronically deficient in sleep and physical activity. About 1 in 3 Americans get less than 7 h of sleep per night and only 1 of 4 adults regularly complete weekly physical activity in amounts recommended for good health. This chapter reviews research that has examined relationships between regular physical activity and sleep. The overall weight of evidence supports that regular physical activity is associated with better sleep quality among healthy adults, with epidemiological studies showing moderate-sized effects and more well-controlled randomized controlled trial experiments often showing larger effects. Large epidemiology studies suggest that the relationship between regular physical activity and better sleep quality may partially mediate the well-established associations between physical activity and reduced risk of mortality, cardiovascular diseases, and dementia. There is evidence that the completion of regular physical activity also is associated with better sleep quality among those with certain sleep disorders (i.e., insomnia, obstructive sleep apnea, and restless legs syndrome), mental health disorders (i.e., depression and posttraumatic stress disorder), and medical illnesses (i.e., breast cancer survivors). The evidence is inadequate to support that regular physical activity substantially improves sleep quality either (i) in children, adolescents, and older adults, (ii) in those with cancers except for breast cancer, (iii) in those with fibromyalgia, or (iv) among those with chronic kidney disease. Also, there is inadequate evidence to conclude that sleep quality is disrupted during weeks when competitive athletes engage in periods of overtraining.

Tuning the photophysical properties of cyanine by barbiturate functionalization and nanoformulation for efficient optoacoustics- guided phototherapy.

Cyanine derivatives are organic dyes widely used for optical imaging. However, their potential in longitudinal optoacoustic imaging and photothermal therapy remains limited due to challenges such as poor chemical stability, poor photostability, and low photothermal conversion. In this study, we present a new structural modification for cyanine dyes by introducing a strongly electron-withdrawing group (barbiturate), resulting in a new series of barbiturate-cyanine dyes (BC810, BC885, and BC1010) with suppressed fluorescence and enhanced stability. Furthermore, the introduction of BC1010 into block copolymers (PEG114-b-PCL60) induces aggregation-caused quenching, further boosting the photothermal performance. The photophysical properties of nanoparticles (BC1010-NPs) include their remarkably broad absorption range from 900 to 1200 nm for optoacoustic imaging, allowing imaging applications in NIR-I and NIR-II windows. The combined effect of these strategies, including improved photostability, enhanced nonradiative relaxation, and aggregation-caused quenching, enables the detection of optoacoustic signals with high sensitivity and effective photothermal treatment of in vivo tumor models when BC1010-NPs are administered before irradiation with a 1064 nm laser. This research introduces a barbiturate-functionalized cyanine derivative with optimal properties for efficient optoacoustics-guided theranostic applications. This new compound holds significant potential for biomedical use, facilitating advancements in optoacoustic-guided diagnostic and therapeutic approaches.

Genetic interaction between TTG2 and AtPLC1 reveals a role for phosphoinositide signaling in a co-regulated suite of Arabidopsis epidermal pathways.

The TTG2 transcription factor of Arabidopsis regulates a set of epidermal traits, including the differentiation of leaf trichomes, flavonoid pigment production in cells of the inner testa (or seed coat) layer and mucilage production in specialized cells of the outer testa layer. Despite the fact that TTG2 has been known for over twenty years as an important regulator of multiple developmental pathways, little has been discovered about the downstream mechanisms by which TTG2 co-regulates these epidermal features. In this study, we present evidence of phosphoinositide lipid signaling as a mechanism for the regulation of TTG2-dependent epidermal pathways. Overexpression of the AtPLC1 gene rescues the trichome and seed coat phenotypes of the ttg2-1 mutant plant. Moreover, in the case of seed coat color rescue, AtPLC1 overexpression restored expression of the TTG2 flavonoid pathway target genes, TT12 and TT13/AHA10. Consistent with these observations, a dominant AtPLC1 T-DNA insertion allele (plc1-1D) promotes trichome development in both wild-type and ttg2-3 plants. Also, AtPLC1 promoter:GUS analysis shows expression in trichomes and this expression appears dependent on TTG2. Taken together, the discovery of a genetic interaction between TTG2 and AtPLC1 suggests a role for phosphoinositide signaling in the regulation of trichome development, flavonoid pigment biosynthesis and the differentiation of mucilage-producing cells of the seed coat. This finding provides new avenues for future research at the intersection of the TTG2-dependent developmental pathways and the numerous molecular and cellular phenomena influenced by phospholipid signaling.

Radiotherapy dose escalation using pre-treatment diffusion-weighted imaging in locally advanced rectal cancer: a planning study.

Objectives: Diffusion-weighted MRI (DWI) may provide biologically relevant target volumes for dose-escalated radiotherapy in locally advanced rectal cancer (LARC). This planning study assessed the dosimetric feasibility of delivering hypofractionated boost treatment to intra-tumoural regions of restricted diffusion prior to conventional long-course radiotherapy. Methods: Ten patients previously treated with curative-intent standard long-course radiotherapy (50 Gy/25#) were re-planned. Boost target volumes (BTVs) were delineated semi-automatically using 40th centile intra-tumoural apparent diffusion coefficient value with expansions (anteroposterior 11 mm, transverse 7 mm, craniocaudal 13 mm). Biased-dosed combined plans consisted of a single-fraction volumetric modulated arc therapy flattening-filter-free (VMAT-FFF) boost (phase 1) of 5, 7, or 10 Gy before long-course VMAT (phase 2). Phase 1 plans were assessed with reference to stereotactic conformality and deliverability measures. Combined plans were evaluated with reference to standard long-course therapy dose constraints. Results: Phase 1 BTV dose targets at 5/7/10 Gy were met in all instances. Conformality constraints were met with only 1 minor violation at 5 and 7 Gy. All phase 1 and combined phase 1 + 2 plans passed patient-specific quality assurance. Combined phase 1 + 2 plans generally met organ-at-risk dose constraints. Exceptions included high-dose spillage to bladder and large bowel, predominantly in cases where previously administered, clinically acceptable non-boosted plans also could not meet constraints. Conclusions: Targeted upfront LARC radiotherapy dose escalation to DWI-defined is feasible with appropriate patient selection and preparation. Advances in knowledge: This is the first study to evaluate the feasibility of DWI-targeted upfront radiotherapy boost in LARC. This work will inform an upcoming clinical feasibility study.

Utilization of In-Hospital Orthopaedic Spine Consultations: Evaluating the Impact of Health Care Policy.

Access to specialty and private practice providers has been a divisive policy issue over the last decade, complicated by the conflict between a reduction in government-funded health care reimbursement and the need for health care providers to sustain a financially sound practice. This study evaluates the orthopedic spine consult service at an academic tertiary care center at 2 separate time points over a 5-year period to better understand the impact of decreasing orthopedic reimbursement rates and the increasing prevalence of federally supported medical insurance on the access to specialty care. In total 500 patients in 2017 and 480 patients in 2021 were included for the final analysis. A higher percentage of consults in 2021 came from the emergency department (74.0% versus 60.4%, P < 0.001); however, the emergency department saw fewer spinal cord injuries (11.9% versus 21.4%, P < 0.001), and the spinal cord injuries were less severe (3.1% versus 6.2% Association Impairment Scale A or B, P = 0.034). A smaller percentage of patients in 2021 went on to receive orthopedic spine surgery following consultation (35.2% versus 43.8%, P = 0.007), and those receiving surgery had an operation performed farther out from the initial consultation (4.73 versus 4.09 days, P < 0.001). Additionally, fewer patients with Medicare insurance (23.5% versus 30.8%) and more patients with Medicaid insurance (20.2% versus 12.4%) were seen in 2021 compared with 2017 (P = 0.003). Overall, this study found an increased proportion of Medicaid patients seen by the spine consult service but a decrease in the acuity of consults. Measures to improve access to health insurance under the Affordable Care Act have revealed the complexity of this issue in health care. This study's findings have demonstrated that while more patients did have insurance coverage following the Affordable Care Act, they still face a barrier to accessing outpatient orthopedic spine providers.

Multilevel ossification of the posterior longitudinal ligament causing cervical myelopathy: An observational series of North American patients.

Background: Few studies regarding ossification of the posterior longitudinal ligament (OPLL) outside of Asia currently exist in the literature. A set of patients with multilevel cervical OPLL causing symptomatic myelopathy or radiculopathy from a North American sample is analyzed. Objective: The objective of this study was to describe the demographics, radiographic findings, and surgical outcomes of a cohort of North American patients with degenerative spondylosis presenting for operative management of multilevel (>3 segments) cervical OPLL. Materials and Methods: Forty-three patients diagnosed with multilevel cervical OPLL and degenerative spondylosis presenting with symptomatic cervical myelopathy or radiculopathy were surgically treated over a 9-year period at a single tertiary care academic medical center. Radiographic measurements were performed on preoperative computed tomography and magnetic resonance imaging images of the cervical spine. Clinical outcomes included pre- and postoperative Nurick scores, 90-day readmission, complication, and revision surgery rates. Results: The mean age was 66.1 ± 10.9 years with a mean latest follow-up time of 32.7 ± 16.4 months. Most patients had previous diagnoses of obesity (70.7%) and hypertension (55.8%). At least one-quarter of patients were diagnosed with type 2 diabetes (34.9%), hyperlipidemia (41.9%), cardiovascular disease (25.6%), or chronic kidney disease (25.3%). The most common OPLL subtype was segmental (39.5%) and spanned a mean of 3.54 ± 1.48 segments. Myelopathic symptoms were present in 88.4% of patients. All patients experienced significant neurologic improvement at 3-week and latest follow-up (P < 0.001 for both). Conclusions: Obesity, diabetes, and other metabolic derangements in patients with existing cervical spondylosis may be risk factors for a particularly aggressive form of multilevel OPLL. Various operative approaches may be employed to achieve adequate neurologic recovery. Further workup for OPLL in patients with these risk factors may prove beneficial to ensure appropriate operative management.

Does Clinical Decision Support Increase Appropriate Medication Prescribing for Cardiovascular Risk Reduction?

PURPOSE: To assess the impact of a clinical decision support (CDS) system's recommendations on prescribing patterns targeting cardiovascular disease (CVD) when the recommendations are prioritized in order from greatest to least benefit toward overall CVD risk reduction. METHODS: Secondary analysis of trial data from September 20, 2018, to March 15, 2020, where 70 community health center clinics were cluster-randomized to the CDS intervention (42 clinics; 8 organizations) or control group (28 clinics; 7 organizations). Included patients were medication-naïve and aged 40 to 75 years with ≥1 uncontrolled cardiovascular disease risk factor, with known diabetes or cardiovascular disease, or ≥10% 10-year reversible CVD risk. RESULTS: Among eligible encounters with 29,771 patients, the probability of prescribing a medication targeting hypertension was greater at intervention clinic encounters when CDS was used (34.9% [95% CI, 31.5 to 38.3]) versus dismissed (29.6% [95% CI, 26.7 to 32.6]; P < .001), but not when compared with control clinic encounters (34.9% [95% CI, 31.1 to 38.7]; P = .998). Prescribing for dyslipidemia was significantly higher at intervention encounters where the CDS system was used (11.3% [95% CI, 9.3 to 13.3]) compared with dismissed (7.7% [95% CI, 6.1 to 9.3]; P = .003) and to control encounters (8.7% [95% CI, 7.0 to 10.4]; P = .044); smoking cessation medication showed a similar pattern. Except for dyslipidemia, prescribing rates increased according to their prioritization. CONCLUSIONS: Use of this CDS system was associated with significantly higher prescribing targeting most cardiovascular risk factors. These results highlight how displaying prioritized actions to reduce reversible CVD risk could improve risk management. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03001713, https://clinicaltrials.gov/.

Differential Effects of an Intervention to Reduce Cardiovascular Risk for Patients With Bipolar Disorder, Schizoaffective Disorder, or Schizophrenia: A Randomized Clinical Trial.

Objective: To measure the impact of a clinical decision support (CDS) tool on total modifiable cardiovascular risk at 12 months separately for outpatients with 3 subtypes of serious mental illness (SMI) identified via ICD-9 and ICD-10 codes: bipolar disorder, schizoaffective disorder, and schizophrenia.Methods: This cluster-randomized pragmatic clinical trial was active from March 2016 to September 2018; data were analyzed from April 2021 to September 2022. Clinicians and patients from 78 primary care clinics participated. All 8,922 adult patients aged 18-75 years with diagnosed SMI, at least 1 cardiovascular risk factor not at goal, and an index and follow-up visit during the study period were included. The CDS tool provided a summary of modifiable cardiovascular risk and personalized treatment recommendations.Results: Intervention patients had 4% relative reduction in total modifiable cardiovascular risk at 12 months compared to controls (relative risk ratio = 0.96; 95% CI, 0.94 to 0.98), with similar intervention benefits for all 3 SMI subtypes. At index, 10-year cardiovascular risk was higher for patients with schizophrenia (mean [SD] = 11.3% [9.2%]) than for patients with bipolar disorder (8.5% [8.9%]) or schizoaffective disorder (9.4% [8.1%]), while 30-year cardiovascular risk was highest for patients with schizoaffective disorder (44% with 2 or more major cardiovascular risk factors, compared to 40% for patients with schizophrenia and 37% for patients with bipolar disorder). Smoking was highly prevalent (47%), and mean (SD) BMI was 32.7 (7.9).Conclusions: This CDS intervention produced a clinically and statistically significant 4% relative reduction in total modifiable cardiovascular risk for intervention patients versus controls at 12 months, an effect observed across all 3 SMI subtypes and attributable to the aggregate impact of small changes in multiple cardiovascular risk factors.Trial Registration: ClinicalTrials.gov Identifier: NCT02451670.

Implementation of a retrofit MRI simulator for radiation therapy planning.

Magnetic resonance imaging (MRI) is being integrated into routine radiation therapy (RT) planning workflows. To reap the benefits of this imaging modality, patient positioning, image acquisition parameters and a quality assurance programme must be considered for accurate use. This paper will report on the implementation of a retrofit MRI Simulator for RT planning, demonstrating an economical, resource efficient solution to improve the accuracy of MRI in this setting.

30-year Cardiovascular Disease Risk for Young Adults with Serious Mental Illness.

Objective: To estimate 30-year CVD risk and modifiable risk factors in young adults with serious mental illness (SMI) versus those without, and assess variations in CVD risk by race, ethnicity, and sex. Method: In this cross-sectional study, we estimated and compared the Framingham 30-year CVD risk score and individual modifiable CVD risk factors in young adult (20-39 years) primary care patients with and without SMI at two US healthcare systems (January 2016-Septemeber 2018). Interaction terms assessed whether the SMI-risk association differed across demographic groups. Results: Covariate-adjusted 30-year CVD risk was significantly higher for those with (n=4228) versus those without (n=155,363) SMI (RR 1.28, 95% CI [1.26, 1.30]). Patients with SMI had higher rates of hypertension (OR 2.02 [1.7, 2.39]), diabetes (OR 3.14 [2.59, 3.82]), obesity (OR 1.93 [1.8, 2.07]), and smoking (OR 4.94 [4.6, 5.36]). The increased 30-year CVD risk associated with SMI varied significantly by race and sex: there was an 8% higher risk in Black compared to White patients (RR 1.08, [1.04, 1.12]) and a 9% lower risk in men compared to women (RR 0.91 [0.88, 0.94]). Conclusions: Young adults with SMI are at increased 30-year risk of CVD, and further disparities exist for Black individuals and women.

Bolstering the Business Case for Adoption of Shared Decision-Making Systems in Primary Care: Randomized Controlled Trial.

BACKGROUND: Limited budgets may often constrain the ability of health care delivery systems to adopt shared decision-making (SDM) systems designed to improve clinical encounters with patients and quality of care. OBJECTIVE: This study aimed to assess the impact of an SDM system shown to improve diabetes and cardiovascular patient outcomes on factors affecting revenue generation in primary care clinics. METHODS: As part of a large multisite clinic randomized controlled trial (RCT), we explored the differences in 1 care system between clinics randomized to use an SDM intervention (n=8) versus control clinics (n=9) regarding the (1) likelihood of diagnostic coding for cardiometabolic conditions using the 10th Revision of the International Classification of Diseases (ICD-10) and (2) current procedural terminology (CPT) billing codes. RESULTS: At all 24,138 encounters with care gaps targeted by the SDM system, the proportion assigned high-complexity CPT codes for level of service 5 was significantly higher at the intervention clinics (6.1%) compared to that in the control clinics (2.9%), with P<.001 and adjusted odds ratio (OR) 1.64 (95% CI 1.02-2.61). This was consistently observed across the following specific care gaps: diabetes with glycated hemoglobin A1c (HbA1c)>8% (n=8463), 7.2% vs 3.4%, P<.001, and adjusted OR 1.93 (95% CI 1.01-3.67); blood pressure above goal (n=8515), 6.5% vs 3.7%, P<.001, and adjusted OR 1.42 (95% CI 0.72-2.79); suboptimal statin management (n=17,765), 5.8% vs 3%, P<.001, and adjusted OR 1.41 (95% CI 0.76-2.61); tobacco dependency (n=7449), 7.5% vs. 3.4%, P<.001, and adjusted OR 2.14 (95% CI 1.31-3.51); BMI >30 kg/m2 (n=19,838), 6.2% vs 2.9%, P<.001, and adjusted OR 1.45 (95% CI 0.75-2.8). Compared to control clinics, intervention clinics assigned ICD-10 diagnosis codes more often for observed cardiometabolic conditions with care gaps, although the difference did not reach statistical significance. CONCLUSIONS: In this randomized study, use of a clinically effective SDM system at encounters with care gaps significantly increased the proportion of encounters assigned high-complexity (level 5) CPT codes, and it was associated with a nonsignificant increase in assigning ICD-10 codes for observed cardiometabolic conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02451670; https://clinicaltrials.gov/ct2/show/NCT02451670.

Patients From Socioeconomically Distressed Communities Experience Similar Clinical Improvements Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: The aim was to compare patient-reported outcome measures (PROMs) following anterior cervical discectomy and fusion (ACDF) when categorizing patients based on socioeconomic status. Secondarily, we sought to compare PROMs based on race. SUMMARY OF BACKGROUND DATA: Social determinants of health are believed to affect outcomes following spine surgery, but there is limited literature on how combined socioeconomic status metrics affect PROMs following ACDF. MATERIALS AND METHODS: The authors identified patients who underwent primary elective one-level to four-level ACDF from 2014 to 2020. Patients were grouped based on their distressed community index (DCI) quintile (Distressed, At-Risk, Mid-tier, Comfortable, and Prosperous) and then race (White or Black). Multivariate regression for ∆PROMs was performed based on DCI group and race while controlling for baseline demographics and surgical characteristics. RESULTS: Of 1204 patients included in the study, all DCI groups improved across all PROMs, except mental health component score (MCS-12) for the Mid-tier group ( P =0.091). Patients in the Distressed/At-Risk group had worse baseline MCS-12, visual analog scale (VAS) Neck, and neck disability index (NDI). There were no differences in magnitude of improvement between DCI groups. Black patients had significantly worse baseline VAS Neck ( P =0.002) and Arm ( P =0.012) as well as worse postoperative MCS-12 ( P =0.016), PCS-12 ( P =0.03), VAS Neck ( P <0.001), VAS Arm ( P =0.004), and NDI ( P <0.001). Multivariable regression analysis did not identify any of the DCI groupings to be significant independent predictors of ∆PROMs, but being White was an independent predictor of greater improvement in ∆PCS-12 (ß=3.09, P =0.036) and ∆NDI (ß=-7.32, P =0.003). CONCLUSIONS: All patients experienced clinical improvements regardless of DCI or race despite patients in Distressed communities and Black patients having worse preoperative PROMs. Being from a distressed community was not an independent predictor of worse improvement in any PROMs, but Black patients had worse improvement in NDI compared with White patients. LEVEL OF EVIDENCE: 3.

Impact of cannabidiol-rich hemp extract oil on reconsolidation disruption of naturalistic interoceptive aversive memory in humans: Protocol for a randomized clinical trial.

BACKGROUND: Preclinical experiments with rodents demonstrate that cannabidiol (CBD), the non-psychotomimetic constituent of the Cannabis sativa plant, disrupts reconsolidation of aversive memories conditioned in the laboratory when administered within the memory reconsolidation window (< 6 h. post-retrieval) by indirectly activating cannabinoid type-1 (CB1) receptors in the dorsal anterior cingulate cortex (dACC). Based on these findings, we aim to test whether administration of 300 mg CBD-rich hemp extract oil following fear reactivation of an aversive interoceptive threat memory can disrupt reconsolidation of naturalistic aversive memories in humans. More specifically, naturalistic interoceptive aversive memories, a form of transdiagnostic fear memory that contributes to the pathogenesis of fear-related disorders such as panic disorder, posttraumatic stress disorder (PTSD), and illness anxiety disorder. METHODS: For this proof-of-concept, placebo-controlled double-blind trial, volunteers (n = 99) reporting elevated fears of somatic sensations will be stratified on biological sex and randomized to one of three intervention arms: (a). CBD-rich oil administered within the reconsolidation window, (b) Placebo oil administered within the reconsolidation window; or (c) CBD-rich oil administered outside of the reconsolidation window. Change in emotional reactivity to a 35% CO2 challenge from baseline to two-week follow-up will serve as our primary outcome. CONCLUSION: Study findings may contribute towards the development of a novel brief transdiagnostic intervention guided by reconsolidation theory for individuals prone to fear-related psychiatric disorders. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04726475.

Preclinical Activity and Pharmacokinetic/Pharmacodynamic Relationship for a Series of Novel Benzenesulfonamide Perforin Inhibitors.

Perforin is a key effector of lymphocyte-mediated cell death pathways and contributes to transplant rejection of immunologically mismatched grafts. We have developed a novel series of benzenesulfonamide (BZS) inhibitors of perforin that can mitigate graft rejection during allogeneic bone marrow/stem cell transplantation. Eight such perforin inhibitors were tested for their murine pharmacokinetics, plasma protein binding, and their ability to block perforin-mediated lysis in vitro and to block the rejection of major histocompatibility complex (MHC)-mismatched mouse bone marrow cells. All compounds showed >99% binding to plasma proteins and demonstrated perforin inhibitory activity in vitro and in vivo. A lead compound, compound 1, that showed significant increases in allogeneic bone marrow preservation was evaluated for its plasma pharmacokinetics and in vivo efficacy at multiple dosing regimens to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The strongest PK/PD correlation was observed between perforin inhibition in vivo and time that total plasma concentrations remained above 900 µM, which correlates to unbound concentrations similar to 3× the unbound in vitro IC90 of compound 1. This PK/PD relationship will inform future dosing strategies of BZS perforin inhibitors to maintain concentrations above 3× the unbound IC90 for as long as possible to maximize efficacy and enhance progression toward clinical evaluation.

Embedded Health Risk from Arsenic in Globally Traded Rice.

International food trade is fundamental to global food security but with often negative consequences in the producing country. We propose a method of quantifying flows of inorganic arsenic (iAs) and embedded increased lifetime cancer risks (EHR) at a global scale, where negative impacts are felt on the importing country. Computations were made for 153 countries. Vietnam exports the most iAs embedded in rice (796 kg/year) followed by India (788 kg/year), Thailand (485 kg/year), and the United States (323 kg/year). We show that continental China, Indonesia, and Malaysia have the highest imports of iAs (292, 174, and 123 kg/year, respectively). Bangladesh ranks highest in EHR followed by Vietnam and Cambodia (150, 141, and 111 per 100,000, respectively). Countries that depend exclusively on imported rice are importing a substantial amount of risk, as, e.g., Kiribati and Solomon Islands (57 and 53 per 100,000, respectively). We discuss the potential policy options for reducing population dietary health risks by well-balanced apportioning of rice sources. This study targets policy design solutions based on health gains, rather than on safe levels of the risk factor alone.

Depression and cardiovascular risk in primary care patients.

OBJECTIVE: This study assessed the relationship of both depression diagnosis and clinically significant depressive symptoms with individual cardiovascular risk factors and estimated total cardiovascular risk in primary care patients. METHODS: This study used a cross-sectional and retrospective design. Patients who had a primary care encounter between January 2016 and September 2018 and completed depression screening (PHQ-9) during the year prior to their appointment (N = 70,980) were included in this study. Data examining estimated total cardiovascular risk, specific cardiovascular risk factors, and relevant clinical diagnoses (including depression diagnosis) were extracted from the electronic health record. Patients were categorized into three groups: no depression (PHQ-9 < 10 and no depression diagnosis), controlled depression (PHQ-9 < 10 with previous depression diagnosis), and current depression (PHQ-9 ≥ 10). Groups were compared on estimated total risk and specific cardiovascular risk factors (e.g., body mass index [BMI], smoking status, lipids, blood pressure, and glucose). RESULTS: In adjusted analyses, patients with current depression (n = 18,267) demonstrated significantly higher 10-year and 30-year cardiovascular risk compared to patients with controlled depression (n = 33,383; 10-year: b = 0.59 [95% CI = 0.44,0.74]; 30-year: OR = 1.32 [95% CI = 1.26,1.39]) and patients without depression (n = 19,330; 10-year: b = 0.55 [95% CI = 0.37,0.73]; 30-year: OR = 1.56 [95% CI = 1.48,1.65]). Except for low-density lipoprotein (LDL), patients with current depression had the greatest cardiovascular risk across specific risk factors. CONCLUSIONS: Individuals who had a depression diagnosis and clinically significant depressive symptoms had the greatest cardiovascular risk. Pathways to prevent cardiovascular disease in those with depression might focus on treating depressive symptoms as well as specific uncontrolled cardiovascular risk factors.

Human Papillomavirus vaccination clinical decision support for young adults in an upper midwestern healthcare system: a clinic cluster-randomized control trial.

INTRODUCTION: Human papillomavirus (HPV) vaccination rates are low in young adults. Clinical decision support (CDS) in primary care may increase HPV vaccination. We tested the treatment effect of algorithm-driven, web-based, and electronic health record-linked CDS with or without shared decision-making tools (SDMT) on HPV vaccination rates compared to usual care (UC). METHODS: In a clinic cluster-randomized control trial conducted in a healthcare system serving a largely rural population, we randomized 34 primary care clinic clusters (with three clinics sharing clinicians randomized together) to: CDS; CDS+SDMT; UC. The sample included young adults aged 18-26 due for HPV vaccination with a study index visit from 08/01/2018-03/15/2019 in a study clinic. Generalized linear mixed models tested differences in HPV vaccination status 12 months after index visits by study arm. RESULTS: Among 10,253 patients, 6,876 (65.2%) were due for HPV vaccination, and 5,054 met study eligibility criteria. In adjusted analyses, the HPV vaccination series was completed by 12 months in 2.3% (95% CI: 1.6%-3.2%) of CDS, 1.6% (95% CI: 1.1%-2.3%) of CDS+SDMT, and 2.2% (95% CI: 1.6%-3.0%) of UC patients, and at least one HPV vaccine was received by 12 months in 13.1% (95% CI: 10.6%-16.1%) of CDS, 9.2% (95% CI: 7.3%-11.6%) of CDS+SDMT, and 11.2% (95% CI: 9.1%-13.7%) of UC patients. Differences were not significant between arms. Females, those with prior HPV vaccinations, and those seen at urban clinics had significantly higher odds of HPV vaccination in adjusted models. DISCUSSION: CDS may require optimization for young adults to significantly impact HPV vaccination. TRIAL REGISTRATION: clinicaltrials.gov NCT02986230, 12/6/2016.

Effect of Clinical Decision Support on Cardiovascular Risk Among Adults With Bipolar Disorder, Schizoaffective Disorder, or Schizophrenia: A Cluster Randomized Clinical Trial.

IMPORTANCE: Adults with schizophrenia, schizoaffective disorder, or bipolar disorder, collectively termed serious mental illness (SMI), have shortened life spans compared with people without SMI. The leading cause of death is cardiovascular (CV) disease. OBJECTIVE: To assess whether a clinical decision support (CDS) system aimed at primary care clinicians improves CV health for adult primary care patients with SMI. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial conducted from March 2, 2016, to September 19, 2018, restricted randomization assigned 76 primary care clinics in 3 Midwestern health care systems to receive or not receive a CDS system aimed at improving CV health among patients with SMI. Eligible clinics had at least 20 patients with SMI; clinicians and their adult patients with SMI with at least 1 modifiable CV risk factor not at the goal set by the American College of Cardiology/American Heart Association guidelines were included. Statistical analysis was conducted on an intention-to-treat basis from January 10, 2019, to December 29, 2021. INTERVENTION: The CDS system assessed modifiable CV risk factors and provided personalized treatment recommendations to clinicians and patients. MAIN OUTCOMES AND MEASURES: Patient-level change in total modifiable CV risk over 12 months, summed from individual modifiable risk factors (smoking, body mass index, low-density lipoprotein cholesterol level, systolic blood pressure, and hemoglobin A1c level). RESULTS: A total of 80 clinics were randomized; 4 clinics were excluded for having fewer than 20 eligible patients, leaving 42 intervention clinics and 34 control clinics. A total of 8937 patients with SMI (4922 women [55.1%]; mean [SD] age, 48.4 [13.5] years) were enrolled. There was a 4% lower rate of increase in total modifiable CV risk among intervention patients relative to control patients (relative rate ratio [RR], 0.96; 95% CI, 0.94-0.98). The intervention favored patients who were 18 to 29 years of age (RR, 0.89; 95% CI, 0.81-0.98) or 50 to 59 years of age (RR, 0.93; 95% CI, 0.90-0.96), Black (RR, 0.93; 95% CI, 0.88-0.98), or White (RR, 0.96; 95% CI, 0.94-0.98). Men (RR, 0.96; 95% CI, 0.94-0.99) and women (RR, 0.95; 95% CI, 0.92-0.97), as well as patients with any SMI subtype (bipolar disorder: RR, 0.96; 95% CI, 0.94-0.99; schizoaffective disorder: RR, 0.94; 95% CI, 0.90-0.98; schizophrenia: RR, 0.92; 95% CI, 0.85-0.99) also benefited from the intervention. Despite treatment effects favoring the intervention, there were no significant differences in individual modifiable risk factors. CONCLUSIONS AND RELEVANCE: This CDS intervention resulted in a rate of change in total modifiable CV risk that was 4% lower among intervention patients compared with control patients. Results were driven by the cumulative effects of incremental and mostly nonsignificant changes in individual modifiable risk factors. These findings emphasize the value of using CDS to prompt early primary care intervention for adults with SMI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02451670.

Cardiovascular Risk for Patients With and Without Schizophrenia, Schizoaffective Disorder, or Bipolar Disorder.

Background To compare estimated 10-year and 30-year cardiovascular risk in primary care patients with and without serious mental illness (SMI; bipolar disorder, schizophrenia, or schizoaffective disorder). Methods and Results All patients aged 18 to 75 years with a primary care visit in January 2016 to September 2018 were included and were grouped into those with and without SMI using diagnosis codes. Ten-year cardiovascular risk was estimated using atherosclerotic cardiovascular disease scores for patients aged 40 to 75 years without cardiovascular disease; 30-year cardiovascular risk was estimated using Framingham risk scores for patients aged 18 to 59 years without cardiovascular disease. Demographic, vital sign, medication, diagnosis, and health insurance data were collected from the electronic health record by a clinical decision support system. Descriptive statistics examined unadjusted differences, while general linear models examined differences for continuous variables and logistic regression models for categorical variables. Models were then adjusted for age, sex, race, ethnicity, and insurance type. A total of 11 333 patients with SMI and 579 924 patients without SMI were included. After covariate adjustment, 10-year cardiovascular risk was significantly higher in patients with SMI (mean, 9.44%; 95% CI, 9.29%-9.60%) compared with patients without SMI (mean, 7.99%; 95% CI, 7.97-8.02). Similarly, 30-year cardiovascular risk was significantly higher in those with SMI (25% of patients with SMI in the highest-risk group compared with 11% of patients without SMI; P<0.001). The individual cardiovascular risk factors contributing most to increased risk for those with SMI were elevated body mass index and smoking. Among SMI subtypes, patients with bipolar disorder had the highest 10-year cardiovascular risk, while patients with schizoaffective disorder had the highest 30-year cardiovascular risk. Conclusions The significantly increased cardiovascular risk associated with SMI is evident even in young adults. This suggests the importance of addressing uncontrolled major cardiovascular risk factors in those with SMI at as early an age as possible. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02451670.