How I diagnose and treat organizing pneumonia in hematopoietic cell transplant recipients.

Organizing pneumonia (OP) is a known non-infectious pulmonary complication following allogeneic hematopoietic cell transplant (HCT) and represents a significant risk factor for non-relapse mortality in HCT recipients. Unlike bronchiolitis obliterans syndrome, it is not universally acknowledged as a distinctive pulmonary manifestation of chronic-graft-versus-host disease (cGVHD) and therefore, its diagnostic criteria and management approach is lacking. Given it shared similar clinical features, radiological and histological findings to OP in non-HCT population, the diagnostic approach and treatment strategy for OP in HCT recipient is largely adapted from the non-HCT population. In this paper, we aim to enhance the understanding of OP within the context of cGVHD following HCT, distinguish its clinical features and treatment strategy from non-HCT counterpart, thereby reinforcing its recognition as a pulmonary manifestation of GVHD. We will propose the diagnostic criteria and outline our approach in diagnosis and treatment strategy, highlighting the potential challenges that may arise in each process. Finally, we will discuss knowledge gaps in this field and identify the area of need for future research.

Cytosolic and mitochondrial NADPH fluxes are independently regulated.

Although nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity.

Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine.

The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as 'silent' ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.

Impact of C-reactive Protein on Anticoagulation Monitoring in Extracorporeal Membrane Oxygenation.

OBJECTIVE: To evaluate the impact of inflammation on anticoagulation monitoring for patients supported with extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective single-center cohort study. SETTING: University-affiliated tertiary care academic medical center. PARTICIPANTS: Adult venovenous and venoarterial ECMO patients anticoagulated with heparin/ MEASUREMENTS AND MAIN RESULTS: C-Reactive protein (CRP) was used as a surrogate for overall inflammation. The relationship between CRP and the partial thromboplastin time (PTT, seconds) was evaluated using a CRP-insensitive PTT assay (PTT-CRP) in addition to measurement using a routine PTT assay. Data from 30 patients anticoagulated with heparin over 371 ECMO days was included. CRP levels (mg/dL) were significantly elevated (median, 17.2; interquartile range [IQR], 9.2-26.1) and 93% of patients had a CRP of ≥5. The median PTT (median 58.9; IQR, 46.9-73.3) was prolonged by 11.3 seconds compared with simultaneously measured PTT-CRP (median, 47.6; IQR, 40.1-55.5; p < 0.001). The difference between PTT and PTT-CRP generally increased with CRP elevation from 2.7 for a CRP of <5.0 to 13.0 for a CRP between 5 and 10, 17.7 for a CRP between 10 and 15, and 15.1 for a CRP of >15 (p < 0.001). In a subgroup of patients, heparin was transitioned to argatroban, and a similar effect was observed (median PTT, 62.1 seconds [IQR, 53.0-78.5 seconds] vs median PTT-CRP, 47.6 seconds [IQR, 41.3-57.7 seconds]; p < 0.001). CONCLUSIONS: Elevations in CRP are common during ECMO and can falsely prolong PTT measured by commonly used assays. The discrepancy due to CRP-interference is important clinically given narrow PTT targets and may contribute to hematological complications.

A Chiral-LC-MS Method for the Simultaneous Quantification of Short-Chain Fatty Acids and D/L-Lactate in the Ruminal Fluid of Dairy Cows.

Short-chain fatty acids (SCFA) and lactate in ruminal fluid are products resulting from the microbial fermentation of substrates and can be used to reflect the composition and activity of the ruminal microbiome. Determination of SCFA and D-/L-lactate in ruminal fluid currently requires two separate protocols, which is time-consuming and costly. In this study, we have optimised and validated a simple and unified 3-nitrophenylhydrazine (3-NPH) derivatisation protocol and a 20 min chiral-LC-MS method for the simultaneous quantification of all SCFA and D- and L-lactate in ruminal fluid. This method, which requires no sample pretreatment or purification shows adequate sensitivity (limit of detection (LOD): 0.01 µg/mL), satisfactory accuracy (recovery: 88-103%), and excellent reproducibility (relative standard deviation (RSD) for repeated analyses < 3% for most analytes). The application of this method to a cohort of 24 animals allowed us to reveal a large inter-cow variation in ruminal SCFA and lactate level, the concentration range for each species, the widespread correlation between different SCFA, and the strong correlation between D- and L-lactate.

A value-based approach to optimize red blood cell transfusion in patients receiving extracorporeal membrane oxygenation.

INTRODUCTION: The risk, cost, and adverse outcomes associated with packed red blood cell (RBC) transfusions in patients with cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO) have raised concerns regarding the overutilization of RBC products. It is, therefore, necessary to establish optimal transfusion criteria and protocols for patients supported with ECMO. The goal of this study was to establish specific criteria for RBC transfusions in patients undergoing ECMO. METHODS: This was a retrospective cohort study conducted at Stanford University Hospital. Data on RBC utilization during the entire hospital stay were obtained, which included patients aged ≥18 years who received ECMO support between 1 January 2017, and 30 June 2020 (n = 281). The primary outcome was in-hospital mortality. RESULTS: Hemoglobin (HGB) levels >10 g/dL before transfusion did not improve in-hospital survival. Therefore, we revised the HGB threshold to ≤10 g/dL to guide transfusion in patients undergoing ECMO. To validate this intervention, we prospectively compared the pre- and post-intervention cohorts for in-hospital mortality. Post-intervention analyses found 100% compliance for all eligible records and a decrease in the requirement for RBC transfusion by 1.2 units per patient without affecting the mortality. CONCLUSIONS: As an institution-driven value-based approach to guide transfusion in patients undergoing ECMO, we lowered the threshold HGB level. Validation of this revised intervention demonstrated excellent compliance and reduced the need for RBC transfusion while maintaining the clinical outcome. Our findings can help reform value-based healthcare in this cohort while maintaining the outcome.

Deep Venous Stenting Improves Healing of Lower Extremity Venous Ulcers.

BACKGROUND: Long standing, recalcitrant venous ulcers fail to heal despite standard compression therapy and wound care. Stenting of central veins has been reported to assist in venous ulcer healing. This study reports outcomes of deep venous stenting for central venous obstruction in patients with recalcitrant venous ulcers at a single comprehensive wound care center. METHODS: A single center retrospective analysis was conducted of patients with CEAP (Clinical, Etiology, Anatomy, and Pathophysiology) 6 disease that had undergone deep venous stenting in addition to wound care and compression therapy. Intra-operative details, wound healing, and stent patency rates were recorded. Stent patency and intra-operative details were compared between the healed and unhealed groups. RESULTS: Between 2010 and 2019, 15 patients met inclusion criteria (mean age: 63 years old, 12 males). Pre-operative mean wound area was 14.1 cm2 with mean wound duration of 30 months. 93% of patients healed the ulcers at mean healing time of 10.6 months. Wound recurrence rate was 57% with mean recurrence time of 14.8 months. Ten patients presented with an inferior vena cava (IVC) filter, 4 in the healed group and 6 in the unhealed group. The common iliac vein was stented in all patients. Extension into the IVC was required in 4, the common femoral vein in 11, and femoral vein in 2 patients. The average stent length was 190cm. During the follow-up period, primary patency rates in healed patients (mean follow-up time: 19.2 months) was 83% and 59% in the unhealed group (mean follow-up time: 36.6 months); secondary patency rates were 83% and 89%, respectively. CONCLUSIONS: In patients with recalcitrant venous ulcers with central venous obstruction, deep venous stenting resulted in a high rate of healing. However, a prolonged 10 month healing time was observed and despite high stent patency, wound recurrence rate was high.

A Single Institution 30-Year Review of Abnormal First Rib Resection for Thoracic Outlet Syndrome.

OBJECTIVES: Congenital abnormalities of the first rib (ABNFR) are a rare cause of thoracic outlet syndrome (TOS). The range of abnormalities have not been clearly documented in the literature. Surgical decompression in these patients presents with increased complexity secondary to anomalous anatomy. Our goal is to review an institutional experience of first rib resection (FRR) performed for ABNFRs, to present a novel classification system, and to analyze outcomes according to clinical presentation. METHODS: A prospectively collected database was used to identify individuals with ABNFRs who underwent FRR for TOS between 1990-2021. These individuals were identified both by preoperative imaging and intraoperative descriptions of the first rib after resection. Demographic, clinical, perioperative and pathological data were reviewed. ABNFRs were classified into 3 categories according to anatomical criteria: (I) Hypoplastic, (II) Fused, and (III) Hyperplastic. Outcomes were rated using the standardized Quick Disability of Arm Shoulder and Hand Scores (QDS), Somatic Pain Scores (SPS) and Derkash Scores (DkS). RESULTS: Among the 2200 cases of TOS, there were 19 patients (0.8%) with ABNFR who underwent FRR. Average age at surgery was 30.5 (range 11-74), including 13 men and 6 women. Presentations included 9 arterial (ATOS), 6 neurogenic (NTOS), and 4 venous (VTOS) cases. There were 6 class I, 6 class II, and 7 class III ABNFRs. Among 6 NTOS patients there were 4 abnormal nerve conduction tests and 5 positive anterior scalene muscle blocks. Among the 9 patients with ATOS, thrombolysis was attempted in 5 patients, and of these, 3 ultimately required surgical thrombectomy. Of 4 VTOS cases, 2 were managed with thrombolysis, and 2 with anticoagulation alone. The approach for FRR was transaxillary in all patients. Secondary procedures included 1 pectoralis minor tenotomy, 1 scalenectomy, and 1 contralateral rib resection. No major neurological or vascular complications occurred. There was 1 patient who required surgical evacuation of a hematoma. Intraoperative chest tube placement was required in 5 patients secondary to pleural entry during dissection. There was an overall improvement in symptoms over an average follow-up of 7.4 months. QDS reduced from 49.7 pre-op to 22.1 (P < 0.05). SPS improved from 3.4 pre-op to 1.8. DkS scores were good to excellent in 79% of patients. Residual symptoms were noted in 7, and ATOS accounted for 5 (70%) of these. All patients were able to return to work. CONCLUSIONS: Despite increased complexity, ABNFRs may be safely resected via transaxillary approach with low incidence of complications, very good symptom relief, and excellent outcomes. Congenital ABNFRs may by classified into 3 categories (hypoplastic, fused, and hyperplastic) with a variety of presentations, including ATOS, NTOS, and VTOS. Classification of ABNFRs allows concise description of abnormal anatomy which facilitates comparison between series and provides direction for surgical management to ultimately optimize patient outcomes.

The Impact of Plant Phytochemicals on the Gut Microbiota of Humans for a Balanced Life.

The gastrointestinal tract of humans is a complex microbial ecosystem known as gut microbiota. The microbiota is involved in several critical physiological processes such as digestion, absorption, and related physiological functions and plays a crucial role in determining the host's health. The habitual consumption of specific dietary components can impact beyond their nutritional benefits, altering gut microbiota diversity and function and could manipulate health. Phytochemicals are non-nutrient biologically active plant components that can modify the composition of gut microflora through selective stimulation of proliferation or inhibition of certain microbial communities in the intestine. Plants secrete these components, and they accumulate in the cell wall and cell sap compartments (body) for their development and survival. These compounds have low bioavailability and long time-retention in the intestine due to their poor absorption, resulting in beneficial impacts on gut microbiota population. Feeding diets containing phytochemicals to humans and animals may offer a path to improve the gut microbiome resulting in improved performance and/or health and wellbeing. This review discusses the effects of phytochemicals on the modulation of the gut microbiota environment and the resultant benefits to humans; however, the effect of phytochemicals on the gut microbiota of animals is also covered, in brief.

DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras.

Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.

A 10% Tomato Diet Selectively Reduces Radiation-Induced Damage in TRAMP Mice.

BACKGROUND: Tomatoes contain carotenoids that have the potential to alter the effects of external beam radiation therapy (EBRT). OBJECTIVES: We hypothesized that dietary lyophilized tomato paste (TP) would reduce apoptosis within carotenoid-containing nonneoplastic tissues in EBRT-treated TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. METHODS: Male TRAMP mice (n = 73) were provided an AIN-93G diet or a modified AIN-93G diet containing 10% TP (wt:wt) at 4 wk of age. Prostate tumor growth was monitored by ultrasound. The caudal half of the mouse was irradiated with 7.5 Gy (Rad) or 0 Gy (sham) at 24 wk of age or after the tumor volume exceeded 1000 mm3 with a Cobalt-60 source. Mice were euthanized 24 h postradiation. Carotenoids and α-tocopherol were measured by HPLC and compared by a t test. Tissues were assessed for radiation-induced changes (hematoxylin and eosin) and apoptosis [cleaved caspase-3 (CC3)] and compared by Kruskal-Wallis test or Freedman-Lane's permutation test. RESULTS: Serum concentrations of lycopene (52% lower), phytoene (26% lower), and α-tocopherol (22% lower) were decreased in TP-fed irradiated mice (TP-Rad) compared with TP-fed sham mice (P < 0.05). CC3 scores increased within the prostate tumor with radiation treatments (P < 0.05), but were not affected by tomato consumption. In nonneoplastic tissues, TP-Rad had a lower percentage of CC3-positive cells within the cranial (67% lower) and caudal (75% lower) duodenum than irradiated mice on the control diet (Rad) (P < 0.005). Likewise, CC3 scores within the dorsolateral prostate of TP-Rad trended toward lower scores than for Rad (P = 0.07). CONCLUSIONS: TP selectively reduces radiation-induced apoptosis in extratumoral tissues without decreasing radiation-induced apoptosis within the prostate tumor in TRAMP mice. Additional studies are needed to confirm and expand upon these findings.

Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Ldlr-/- Mice.

OBJECTIVE: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr-/- mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr-/- mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c+ foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin-coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c+ macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. CONCLUSIONS: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr-/- mice.

Trainee Experience in Simulation-Based Education of Open Vascular Surgery.

BACKGROUND: Simulation continues to be an important adjunct to vascular surgery training, yet the optimal implementation of simulation to complement conventional surgical training continues to evolve. This study aims to find areas for improvement in current simulation-based training of open vascular skills by characterizing the experience of vascular trainees attending a national simulation-based course. METHOD: This was a survey study conducted at the simulation course of the Annual UCLA/SVS Symposium: A Comprehensive Review and Update of What's New in Vascular and Endovascular Surgery, a national vascular surgery meeting. The survey consisted of 17 questions and was administered on paper or electronically via the Audience Response System, before the start of the course. The survey assessed the participants' experience in formal training, simulation training, and comfort with open surgical procedures. RESULTS: Between 2013 and 2018, the survey was completed by 150 participants of which 65% were vascular fellows. Only 48% of the participants had formal training in suturing and surgical instruments. Most participants had formal training in basic vascular techniques and advanced vascular operations. In 71%, simulation was incorporated into basic technique training and 60% in open surgical training. Simulation training was most commonly utilized in learning anastomotic techniques and open abdominal aortic aneurysm repair. Simulation skills were deemed translatable to the operating room by 59% of participants. Most participants were comfortable performing open vascular procedures. However, 68% of participants were uncomfortable performing an abdominal aortic aneurysm repair. CONCLUSIONS: There continues to be a significant portion of trainees who do not undergo a simulation-based education. Current simulation training is being targeted to meet trainee needs in open vascular surgery, specifically open aneurysm repair. Nonetheless, trainees continue to have doubts regarding applicability of simulation-based skills to the operating theater. Further studies investigating access to simulation education as well as its translatability are needed.

Elective Resection of Symptomatic Arteriovenous Fistulae and Grafts in Patients with Functioning Renal Allografts at A High Volume Transplant Hospital.

OBJECTIVE: Patients with functioning renal allografts may need ligation of pre-existing hemodialysis conduits. Chronic immunosuppression for renal allografts may adversely affect wound healing and perioperative complications following these procedures. We sought to analyze outcomes following elective ligation and resection of symptomatic arteriovenous (AV) access in immunosuppressed patients with renal allografts no longer requiring dialysis at a high-volume renal transplant hospital. METHODS: We retrospectively reviewed procedure codes for hemodialysis access resection and revision from 2014-2020 at a single academic tertiary care hospital. Patients who underwent complete or subtotal dialysis access resection with a functioning renal allograft were included for analysis of preoperative, operative, and postoperative outcomes. We performed descriptive statistics, and student's t-test using Microsoft Excel. RESULTS: Thirty-four patients met inclusion criteria. The majority were male, 56%, and the most common causes of renal failure were hypertension and diabetes, respectively. Ligation and resection of proximal upper extremity access was performed in 68%. The mean operative time was 126 minutes with pain being the most common indication for intervention. Four patients required arterial reconstruction. Mean postoperative follow-up was 13 months. Arm pain and swelling resolved in 100% and 88% of patients following AV access resection, respectively. No impairment in mean postoperative glomerular filtration rates were noted. One patient required hemodialysis and died three months after fistula resection following complications from treatment of a newly diagnosed neuroendocrine tumor and subsequent fungemia, CONCLUSION: Elective operative resection of symptomatic AV access may be performed safely in immunosuppressed patients with functioning renal transplants. The risk of allograft impairment and/or failure as a result of AV access resection in our series was low. Elective ligation and resection can be achieved with low mortality, excellent symptomatic relief, and few wound complications despite chronic immunosuppression.

Endoscopy-guided transesophageal echocardiography for large esophageal varices: Use of the "Double Barrel" technique.

Rhythm control strategies in patients with esophageal varices and atrial arrhythmias pose a unique challenge. The left atrium should be imaged for a thrombus prior to attempting cardioversion or ablation, but the presence of varices is a relative contraindication for transesophageal echocardiography. We present a safe, novel technique of evaluating for left atrial thrombus with simultaneous transesophageal echocardiography and esophagogastroduodenoscopy using slim probes in a patient with large, high-risk esophageal varices, and symptomatic atrial flutter with rapid ventricular rates despite medical therapy.

Bayesian Stacked Parametric Survival with Frailty Components and Interval-Censored Failure Times: An Application to Food Allergy Risk.

To better understand the risk of exposure to food allergens, food challenge studies are designed to slowly increase the dose of an allergen delivered to allergic individuals until an objective reaction occurs. These dose-to-failure studies are used to determine acceptable intake levels and are analyzed using parametric failure time models. Though these models can provide estimates of the survival curve and risk, their parametric form may misrepresent the survival function for doses of interest. Different models that describe the data similarly may produce different dose-to-failure estimates. Motivated by predictive inference, we developed a Bayesian approach to combine survival estimates based on posterior predictive stacking, where the weights are formed to maximize posterior predictive accuracy. The approach defines a model space that is much larger than traditional parametric failure time modeling approaches. In our case, we use the approach to include random effects accounting for frailty components. The methodology is investigated in simulation, and is used to estimate allergic population eliciting doses for multiple food allergens.

FATAL FASCIOLOIDES MAGNA IN A LESSER SPOT-NOSED GUENON (CERCOPITHECUS PETAURISTA).

A 4-yr-old male intact lesser spot-nosed guenon (Cercopithecus petaurista), housed at a North American zoological facility, presented with acute lethargy, inappetence, and mild neurologic signs. Physical examination revealed hemorrhagic pleural effusion in the right hemithorax. This guenon's condition improved over several days but then deteriorated, and the guenon presented with lethargy and weakness. A hemorrhagic pleural effusion was identified within the left hemithorax. The guenon developed respiratory and cardiac arrest while anesthetized. Gross examination revealed tract formation in the liver, adhesions of the liver to the diaphragm, hemorrhagic thoracic and abdominal effusion, and a single trematode within the right hemithorax. Morphologic features and species identification by PCR confirmed that the parasite was Fascioloides magna. Histologic examination revealed tract formation in the liver associated with biliary hyperplasia, fibrosis and hepatic necrosis, severe bile peritonitis, and pleuritis. This is the first report of an infection by F. magna in a primate.

Renewable energy development threatens many globally important biodiversity areas.

Transitioning from fossil fuels to renewable energy is fundamental for halting anthropogenic climate change. However, renewable energy facilities can be land-use intensive and impact conservation areas, and little attention has been given to whether the aggregated effect of energy transitions poses a substantial threat to global biodiversity. Here, we assess the extent of current and likely future renewable energy infrastructure associated with onshore wind, hydropower and solar photovoltaic generation, within three important conservation areas: protected areas (PAs), Key Biodiversity Areas (KBAs) and Earth's remaining wilderness. We identified 2,206 fully operational renewable energy facilities within the boundaries of these conservation areas, with another 922 facilities under development. Combined, these facilities span and are degrading 886 PAs, 749 KBAs and 40 distinct wilderness areas. Two trends are particularly concerning. First, while the majority of historical overlap occurs in Western Europe, the renewable electricity facilities under development increasingly overlap with conservation areas in Southeast Asia, a globally important region for biodiversity. Second, this next wave of renewable energy infrastructure represents a ~30% increase in the number of PAs and KBAs impacted and could increase the number of compromised wilderness areas by ~60%. If the world continues to rapidly transition towards renewable energy these areas will face increasing pressure to allow infrastructure expansion. Coordinated planning of renewable energy expansion and biodiversity conservation is essential to avoid conflicts that compromise their respective objectives.

Dietary Tomato or Lycopene Do Not Reduce Castration-Resistant Prostate Cancer Progression in a Murine Model.

BACKGROUND: Dietary tomato products or lycopene protect against prostate carcinogenesis, but their impact on the emergence of castration-resistant prostate cancer (CRPC) is unknown. OBJECTIVE: We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. METHODS: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12-13 wk and the emergence of CRPC was monitored by ultrasound in each study. In Study 1, TRAMP mice (n = 80) were weaned onto an AIN-93G-based control diet (Con-L, n = 28), a 10% tomato powder diet (TP-L, 10% lyophilized w/w, n = 26), or a control diet followed by a tomato powder diet after castration (TP-Int1, n = 26). In Study 2, TRAMP mice (n = 85) were randomized onto a control diet with placebo beadlets (Con-Int, n = 29), a tomato diet with placebo beadlets (TP-Int2, n = 29), or a control diet with lycopene beadlets (Lyc-Int, n = 27) following castration (aged 12 wk). Tumor incidence and growth were monitored by ultrasound beginning at an age of 10 wk. Mice were euthanized 4 wk after tumor detection or aged 30 wk if no tumor was detected. Tissue weights were compared by ANOVA followed by Dunnett's test. Tumor volumes were compared using generalized linear mixed model regression. RESULTS: Ultrasound estimates for the in vivo tumor volume were strongly correlated with tumor weight at necropsy (R2 = 0.75 and 0.94, P <0.001 for both Studies 1 and 2, respectively). Dietary treatments after castration did not significantly impact cancer incidence, time to tumor detection, or final tumor weight. CONCLUSIONS: In contrast to studies of de novo carcinogenesis in multiple preclinical models, tomato components had no significant impact on the emergence of CRPC in the TRAMP model. It is possible that specific mutant subclones of prostate cancer may continue to show some antiproliferative response to tomato components, but further studies are needed to confirm this.

Paneled Saphenous Vein Grafts Compared to Internal Jugular Vein Grafts in Venous Reconstruction after Pancreaticoduodenectomy.

BACKGROUND: Venous resection during pancreaticoduodenectomy for the excision of pancreatic cancer allows for a more complete resection with negative margins, which increases survival. When the resected vein is greater than 3 cm, reconstruction with an interposition graft is recommended. However, consensus regarding the optimal venous conduit has not been reached. The objective of this study is to compare outcomes between the paneled saphenous vein graft (SVG) and internal jugular vein graft (IJVG) in portomesenteric venous reconstructions after pancreaticoduodenectomy. METHOD: A retrospective review was performed of patients undergoing pancreaticoduodenectomy requiring an interposition graft for venous reconstruction between 2011 and 2019. Patients were stratified based on the type of conduit used (paneled SVG or IJVG). Preoperative patient characteristics, reconstruction details, and postoperative outcomes including graft patency were recorded. RESULTS: During the study period, 18 patients met inclusion criteria (10 female, mean age: 63 years, age range: 41-82 years). Thirteen patients underwent reconstruction with paneled SVG and five with IJVG. Comparing SVG and IJVG groups, there were no significant differences in venous resection length, venous diameters at the resection margins, or splenic vein ligation rate. For the paneled SVG, the average length of harvested vein was 168 mm which rendered 3-paneled grafts with an average diameter of 12 mm. The time to complete the venous reconstructions did not differ between the two groups (SVG: 263+/-204 min, IJVG: 216+/-77 min, P = 0.63). There were five graft thrombosis, three in the SVG group (mean follow-up time of 17 months) and two in the IJVG group (mean follow-up time of 8 months). All but one of the graft thromboses occurred during the index hospitalization. There was one donor site seroma and wound dehiscence in the SVG group and none in the IJVG group. Hospital length of stay was longer for the IJVG group (IJVG: 15.2 days, SVG: 10.2 days, P = 0.03). However, in-hospital and late mortality did not differ between the groups. CONCLUSIONS: Paneled SVG and IJVG are both versatile and durable conduits for venous reconstruction after pancreaticoduodenectomy, able to accommodate a wide range of venous defects. In this small series, SVG has comparable outcomes to IJVG. Paneled SVG is a suitable alternative to IJVG for portomesenteric reconstruction.