Taurolidine and Heparin as Catheter Lock Solution for Central Venous Catheters in Hemodialysis.

BACKGROUND: Chronic kidney disease can lead to end-stage renal disease, and the prevalence is increasing. Many patients starting hemodialysis require central venous catheters (CVCs). Catheter-related bloodstream infections (CRBSIs) are a common complication and lead to significant morbidity and mortality. Interventions to prevent CRBSI include antimicrobial lock therapy but concern for the development of antimicrobial resistance and adverse effects. Nonantimicrobial antiseptics as catheter lock solutions have also been used. Taurolidine and heparin catheter lock solution is first approved by the Food and Drug Administration for the prevention of CRBSI in patients on hemodialysis. Taurolidine has a unique mechanism of action and favorable safety profile. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Taurolidine and heparin catheter lock solution have both antimicrobial and anticoagulant properties. Taurolidine is derivative of the amino acid taurine, and heparin is derived from porcine intestinal mucosa. Taurolidine not only damages microbial cell walls but also prevents the adherence of microorganisms to biological surfaces, preventing biofilm formation. Taurolidine and heparin catheter lock solution is intended to be used intraluminally within the catheter and should be aspirated. Because it is used locally, limited pharmacokinetic and pharmacodynamic data are available. CLINICAL TRIALS: The LOCK-IT-100 trial is a randomized, double-blind, phase 3 study, which included 795 end-stage renal disease patients on hemodialysis with CVC. Taurolidine and heparin was compared with the control heparin alone. The results of the study showed a 71% risk reduction in CRBSI for taurolidine and heparin arm (95% confident interval, 38%-86%, P = 0.0006). Other studies have also shown that taurolidine lock solution leads to decreased CRBSI episodes. Several systematic reviews and meta-analysis consisted of taurolidine in adult, and pediatric populations also showed reduction in the incidence of CRBSIs. THERAPEUTIC ADVANCE: Taurolidine and heparin lock solution represents a novel preventive strategy for those undergoing hemodialysis through a CVC by reducing the risk of CRBSI. This is significant progress because there are no other similar options available for patients for whom catheters are the only options for their life-saving treatment.

Quality of life analysis in patients with retinitis pigmentosa.

INTRODUCTION: Retinitis pigmentosa (RP) is a chronic progressive disease causing loss of visual acuity and ultimately blindness. This visual impairment can contribute to psychiatric comorbidity and worse overall quality of life (QOL). Our goal was to assess the relationship between the severity of disease for people with RP and QOL as it pertains to mental health, social support, disability resources, and financial factors. METHODS: This was a survey study conducted from June 2021 to February 2022 including 38 people with RP. Quality of life was assessed through a survey questionnaire focusing specifically on demographics, visual function, family, employment, social support, and mental health/well-being. Statistical analysis was conducted using a Chi-squared test for significance. RESULTS: A best-corrected visual acuity (BCVA) of less than 20/200 (p= 0.0285) and living alone (p=0.0358) were both statistically significant independent risk factors for experiencing depressive symptoms. Highest education level attained and unemployment rate were not found to be related to the development of depressive symptoms. Subjects had a higher unemployment rate (64% vs. US rate of 3.6%) and a high likelihood of reporting depressive symptoms (47.4%). CONCLUSIONS: People with RP are more likely to be unemployed and to develop depressive symptoms when compared to the general population. Similar to previous studies' findings, those with a BCVA of less than 20/200 were statistically more likely to experience depressive symptoms; living alone is a novel risk factor that is also associated with the presence of depressive symptoms. Contrary to prior findings, highest education level and unemployment status were found not to be related to the development of depressive symptoms. These patients may benefit from regular depression screenings and optional establishment of care with a psychiatrist or psychologist if they live alone or their BCVA is 20/200 or worse.

Diagnostic CT-Enabled Planning (DART): Results of a Randomized Trial in Palliative Radiation Therapy.

PURPOSE: Using diagnostic computed tomography (dCT) scans instead of CT simulation (CTsim) scans can increase departmental efficiency and reduce patient burden. The goal of the DART trial was to assess the efficacy and acceptability of dCT-based planning workflows with a focus on patient experiences, plan deliverability and adequacy of target coverage, and workflows. METHODS AND MATERIALS: Patients undergoing same-day CTsim and treatment for palliative radiation therapy to thoracic, abdominopelvic, or proximal limb targets with a recent dCT (within 28 days) in a reproducible position were eligible. After stratifying by target type (bone or soft tissue vs. visceral), participants were randomized (1:2 ratio) between CTsim-based (CTsim arm) vs. dCT-based planning (dCT arm). The primary endpoint was time in center (TIC), defined as total time spent in the cancer center on first day of treatment, from first radiation department appointment to first fraction completion. Secondary endpoints included plan deliverability, adequacy of target coverage, and stakeholder acceptability. RESULTS: Thirty-three patients (42 treatment sites) were enrolled between June 2022 and April 2023. The median age was 72 (interquartile range [IQR]: 67-78), 73% were male, and the most common primary cancers were lung (33%), prostate (24%), and breast (12%). The most common dose and fractionations were 8 Gy in 1 and 20 Gy in 5 fractions (50% and 43% of plans, respectively). TIC was 4.7 ± 1.1 hours (mean ± SD) in the CTsim arm vs. 0.41 ± 0.14 hours in the dCT arm (P < .001). All dCT plans were deliverable. All plans in both arms were rated as "acceptable" (80% CTsim; 81% dCT) or "acceptable with minor deviation" (20% CTsim; 19% dCT). Patient perception of acceptability was similar in both arms with the exception of time burden, which was rated as "acceptable" by 50% in the CTsim arm vs. 90% in the dCT arm (P = .025). CONCLUSION: dCT-based radiation planning substantially reduced TIC without detriment in plan deliverability or quality and had a tangible impact on patient experience with reduced patient-reported time burden.

TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway.

Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underlies facial shape variation, yet how those networks in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest, even during the late migratory phase, results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both TFAP2 family members dysregulates numerous midface GRN components involved in midface morphogenesis, patterning and differentiation. Notably, Alx1, Alx3 and Alx4 (ALX) transcript levels are reduced, whereas ChIP-seq analyses suggest TFAP2 family members directly and positively regulate ALX gene expression. Tfap2a, Tfap2b and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish implies conservation of this regulatory axis across vertebrates. Consistent with this notion, tfap2a zebrafish mutants present with abnormal alx3 expression patterns, Tfap2a binds ALX loci and tfap2a-alx3 genetic interactions are observed. Together, these data demonstrate TFAP2 paralogs regulate vertebrate midfacial development in part by activating expression of ALX transcription factor genes.

Proton Pump Inhibitors and Kidney Disease: An Intertwined Relationship.

Many patients with kidney disease are taking proton pump inhibitors (PPIs) for various gastrointestinal conditions. There are concerns about inappropriate usage of PPIs with unknown consequences, which include worsening kidney function. PPI use has been associated with kidney damage; however, a clear etiology of the association is uncertain. Potential mechanisms theorized for PPI-induced kidney damage include hypersensitivity, hypomagnesemia, gut microbiota alterations, uremic toxins, gastrointestinal hormones, and oxidative stress. Patients with kidney disease who are taking long-term PPI therapy require close monitoring for any signs and symptoms of kidney disease. Improper use of PPIs should also be reassessed and de-prescribed as indicated.

Conventional Fossil Fuel Extraction, Associated Biogeochemical Processes, and Topography Influence Methane Groundwater Concentrations in Appalachia.

The production of fossil fuels, including oil, gas, and coal, retains a dominant share in US energy production and serves as a major anthropogenic source of methane, a greenhouse gas with a high warming potential. In addition to directly emitting methane into the air, fossil fuel production can release methane into groundwater, and that methane may eventually reach the atmosphere. In this study, we collected 311 water samples from an unconventional oil and gas (UOG) production region in Pennsylvania and an oil and gas (O&G) and coal production region across Ohio and West Virginia. Methane concentration was negatively correlated to distance to the nearest O&G well in the second region, but such a correlation was shown to be driven by topography as a confounding variable. Furthermore, sulfate concentration was negatively correlated with methane concentration and with distance to coal mining in the second region, and these correlations were robust even when considering topography. We hypothesized that coal mining enriched sulfate in groundwater, which in turn inhibited methanogenesis and enhanced microbial methane oxidation. Thus, this study highlights the complex interplay of multiple factors in shaping groundwater methane concentrations, including biogeochemical conversion, topography, and conventional fossil extraction.

A Cancer Care Ontario Consensus-Based Organizational Guideline for the Planning and Delivery of Spine Stereotactic Body Radiation Therapy Treatment in Ontario.

The proposed recommendations are primarily based on the consensus opinion and in-field experience of the Ontario Health/Cancer Care Ontario stereotactic body radiation therapy (SBRT) for Spine Metastasis Guideline Development Group and published literature when available. Primary consideration was given to the perceived benefits for patients and the small likelihood of harm arising from recommendation implementation. Apart from the magnetic resonance imaging (MRI) follow-up strategy, all evidence was considered indirect and was provided by the working group in conjunction with their collective expertise in the field of SBRT. The application of an SBRT program requires a multidisciplinary team consisting of a radiation oncologist, spine surgeon, neuroradiologist, medical physicist, medical dosimetrist, and radiation therapist. In Canada, linear accelerators are the most used treatment delivery units and should follow technology-specific quality assurance procedures. Immobilization technique is location dependant. Treatment planning MRI sequences should be acquired no more than 14 days from the date of treatment. In the case of epidural disease, simulation MRI should be completed no more than 7 days from the date of treatment. After treatment, patients should be followed with routine clinical visits every 3 months for the first year, every 3 to 6 months during years 2 and 3, and every 4 to 6 months thereafter. The recommendations enclosed provide a framework for the minimum requirements for a cancer center in Ontario, Canada to offer SBRT for spine metastases.

TFAP2 paralogs regulate midfacial development in part through a conserved ALX genetic pathway.

Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underly facial shape variation, yet how those in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest even during the late migratory phase results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both Tfap2 members dysregulated numerous midface GRN components involved in midface fusion, patterning, and differentiation. Notably, Alx1/3/4 (Alx) transcript levels are reduced, while ChIP-seq analyses suggest TFAP2 directly and positively regulates Alx gene expression. TFAP2 and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish further implies conservation of this regulatory axis across vertebrates. Consistent with this notion, tfap2a mutant zebrafish present abnormal alx3 expression patterns, and the two genes display a genetic interaction in this species. Together, these data demonstrate a critical role for TFAP2 in regulating vertebrate midfacial development in part through ALX transcription factor gene expression.

Predictors of pathologic fracture and local recurrence following stereotactic body radiation therapy to 505 non-spine bone metastases.

PURPOSE: Stereotactic Body Radiation Therapy (SBRT) is increasingly applied to treat non-spine bone metastases (NSBM) though data remains limited on this approach. In this retrospective study, we report outcomes and predictors of local failure (LF) and pathological fracture (PF) post-SBRT for NSBM using a mature single-institution database. METHODS: Patients with NSBM treated with SBRT between 2011 and 2021 were identified. The primary objective was to assess the rates of radiographic LF. Secondary objectives were to assess the rates of in-field PF, overall survival (OS), and late grade ≥ 3 toxicity. Competing risks analysis was used to assess rates of LF and PF. Univariable regression and multivariable regression (MVR) were performed to investigate predictors of LF and PF. RESULTS: A total of 373 patients with 505 NSBM were included in this study. Median follow-up was 26.5 months. The cumulative incidence of LF at 6, 12, and 24 months were 5.7%, 7.9%, and 12.6%, respectively. The cumulative incidence of PF at 6, 12, and 24 months were 3.8%, 6.1%, and 10.9%, respectively. Lytic NSBM (HR = 2.18; p < 0.01), a lower biologically effective dose (HR = 1.11 per 5 Gy10 decrease; p = 0.04), and a PTV ≥ 54 cc (HR = 4.32; p < 0.01) predicted for a higher risk of LF on MVR. Lytic NSBM (HR = 3.43; p < 0.01), mixed (lytic/sclerotic) lesions (HR = 2.70; p = 0.04), and rib metastases (HR = 2.68; p < 0.01) predicted for a higher risk of PF on MVR. CONCLUSION: SBRT is an effective modality to treat NSBM with high rates of radiographic local control with an acceptable rate of PF. We identify predictors of both LF and PF that can serve to inform practice and trial design.

The Role of Post-Operative Radiotherapy for Non-Spine Bone Metastases (NSBMs).

Non-spine bone metastases (NSBMs) can cause significant morbidity and deterioration in the quality of life of cancer patients. This paper reviews the role of post-operative radiotherapy (PORT) in the management of NSBMs and provides suggestions for clinical practice based on the best available evidence. We identified six retrospective studies and several reviews that examined PORT for NSBMs. These studies suggest that PORT reduces local recurrence rates and provides effective pain relief. Based on the literature, PORT was typically delivered as 20 Gy in 5 fractions or 30 Gy in 10 fractions within 5 weeks of surgery. Complete coverage of the surgical hardware is an important consideration when designing an appropriate radiation plan and leads to improved local control. Furthermore, the integration of PORT in a multidisciplinary team with input from radiation oncologists and orthopedic surgeons is beneficial. A multimodal approach including PORT should be considered for an NSBM that requires surgery. However, phase III studies are needed to answer many remaining questions and optimize the management of NSBMs.

Evaluating the Efficacy and Pharmacoeconomics of Semaglutide and Tirzepatide in the Setting of Obesity.

BACKGROUND: Obesity is a major and growing public health concern. The associated cost for obesity and its related comorbidities is approximately 30% of US health care expenditures annually. As additional pharmacotherapeutic options join the market to combat obesity, it is important to understand the financial impact it may have on overall health care costs. This article explores the efficacy and pharmacoeconomics of incretin mimetics, semaglutide and tirzepatide, in the setting of obesity. AREA OF UNCERTAINTY: The cost of incretin mimetics (semaglutide and tirzepatide) and its overall impact on obesity management within the health care arena is being explored. The cost comparison of these medications is to be determined; however, it may represent an added cost to the total US health care expenditures. DATA SOURCES: A PubMed and Google Scholar search was conducted using various search terms (eg, semaglutide, tirzepatide, pharmacoeconomics, and obesity). THERAPEUTIC ADVANCES: Based on the data reviewed, both semaglutide and tirzepatide are effective medication options for obesity management. Obesity-related management expenditures exceed $173 billion for the US health care system annually. The cost needed to treat for 1% of weight loss with semaglutide and tirzepatide was reported as $1845 and $985, respectively. More than 40% of adults (60 years or older) experience obesity. If 1%, 5%, or 10% of this population is treated with semaglutide, the annual Medicare costs will translate to excess of $2.6 billion, $13.3 billion, and $26.8 billion, respectively. Tirzepatide is not yet approved in the United States for obesity and its financial impact remains to be seen. CONCLUSIONS: Obesity is associated with burdensome health complications and costs. Semaglutide and tirzepatide are effective drug options for the management of obesity. The cost of these medications will no doubt present a challenge to the total health care expenditures, although the cost-benefit ratio may ultimately be favorable.

Advances in neonatal cell therapies: Proceedings of the First Neonatal Cell Therapies Symposium (2022).

Despite considerable advances, there is a need to improve the outcomes of newborn infants, especially related to prematurity, encephalopathy and other conditions. In principle, cell therapies have the potential to protect, repair, or sometimes regenerate vital tissues; and improve or sustain organ function. In this review, we present highlights from the First Neonatal Cell Therapies Symposium (2022). Cells tested in preclinical and clinical studies include mesenchymal stromal cells from various sources, umbilical cord blood and cord tissue derived cells, and placental tissue and membrane derived cells. Overall, most preclinical studies suggest potential for benefit, but many of the cells tested were not adequately defined, and the optimal cell type, timing, frequency, cell dose or the most effective protocols for the targeted conditions is not known. There is as yet no clinical evidence for benefit, but several early phase clinical trials are now assessing safety in newborn babies. We discuss parental perspectives on their involvement in these trials, and lessons learnt from previous translational work of promising neonatal therapies. Finally, we make a call to the many research groups around the world working in this exciting yet complex field, to work together to make substantial and timely progress to address the knowledge gaps and move the field forward. IMPACT: Survival of preterm and sick newborn infants is improving, but they continue to be at high risk of many systemic and organ-specific complications. Cell therapies show promising results in preclinical models of various neonatal conditions and early phase clinical trials have been completed or underway. Progress on the potential utility of cell therapies for neonatal conditions, parental perspectives and translational aspects are discussed in this paper.

Expanding the Role of SGLT2 Inhibitors Beyond Diabetes: A Case-Based Approach.

Sodium glucose co-transporter-2 (SGLT2) inhibitors have been of substantial interest to clinicians, initially in connection to diabetes management. Beyond its expected antihyperglycemic effects, this drug class is associated with properties such as promoting diuresis, improving cardiac remodeling, and decreasing albuminuria. Considering these beneficial outcomes, the potential roles for SGLT2 inhibitors have evolved to include other therapeutic areas. This review uses a case-based approach to showcase the expanded indications of SGLT2 inhibitors in the setting of heart failure and chronic kidney disease for patients without diabetes.