Multidisciplinary Management of Adult Patients with Chylothorax: A Consensus Statement.

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and 4 specialties (Pulmonary, Interventional Radiology, Thoracic Surgery & Nutrition) with experience and expertise in managing adult patients with chylothorax. We performed a literature and internet search for reports addressing 7 clinically relevant questions pertaining to the management of adult patients with chylothorax. This consensus statement, consisting of best practice statements based on expert consensus addressing these 7 PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience. Panel members participated in the development of the final best practice statements using the modified Delphi technique. Our consensus statement aims to offer guidance in clinical decision making when managing patients with chylothorax while also identifying gaps in knowledge and inform future research.

Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.

Bilateral Spontaneous Retrobulbar Hemorrhage due to Warfarin Misuse After Sinus Lavage.

While warfarin has historically played an important role in anticoagulation, direct oral anticoagulants have largely supplanted warfarin due to their improved safety profile and reduced need for monitoring. Herein, the authors report the case of a 64-year-old male who developed severe, bilateral retrobulbar hemorrhage following aggressive nasal lavage due to a supratherapeutic international normalized ratio from warfarin misuse. Visual acuity on arrival was hand-motion OD and no-light-perception OS. He underwent bilateral canthotomy with upper and lower lid cantholysis before transfer to a trauma center where his international normalized ratio was greater than 12. Reversal with vitamin K and prothrombin complex concentrate was initiated. Over the course of hospitalization, vision and swelling continued to improve and at 2-month follow-up his visual acuity was 20/20 OD and no-light-perception OS. This case outlines the risk of bleeding associated with warfarin misuse and advocates for the transition of patients to direct oral anticoagulants when possible.

From Patients to Providers: Assessing Impact of Normothermic Machine Perfusion on Liver Transplant Practices in the US.

BACKGROUND: Normothermic machine perfusion (NMP) of livers allows for the expansion of the donor pool and minimization of posttransplant complications. Results to date have focused on both donor and recipient outcomes, but there remains potential for NMP to also impact transplant providers. STUDY DESIGN: Using United Network for Organ Sharing Standard Transplant Analysis file data, adult deceased donors who underwent transplantation between January 1, 2016, and December 31, 2022, were identified. Transplanted livers were divided by preservation methods (static cold storage [SCS] and NMP) and case time (day-reperfusion 8 am to 6 pm ). Patient factors, transplant characteristics, and short-term outcomes were analyzed between Mahalanobis-metric-matched groups. RESULTS: NMP livers represented 742 (1.4%) of 52,132 transplants. NMP donors were more marginal with higher Donor Risk Index scores (1.78 ± 0.50 NMP vs 1.49 ± 0.38 SCS, p < 0.001) and donation after cardiac death frequency (36.9% vs 8.4%, p < 0.001). NMP recipients more often had model for end-stage liver disease (MELD) exception status (29.9% vs 23.4%, p < 0.001), lower laboratory MELD scores (20.7 ± 9.7 vs 24.3 ± 10.9, p < 0.001), and had been waitlisted longer (111.5 [21.0 to 307.0] vs 60.0 [9.0 to 245.0] days, p < 0.001). One-year graft survival (90.2% vs 91.6%, p = 0.505) was similar between groups, whereas length of stay was lower for NMP recipients (8.0 [6.0 to 14.0] vs 10.0 [6.0 to 16.0], p = 0.017) after adjusting for confounders. Notably, peak case volume occurred at 11 am with NMP livers (vs 9 pm with SCS). Overall, a higher proportion of transplants was performed during daytime hours with NMP (51.5% vs 43.0%, p < 0.001). CONCLUSIONS: NMP results in increased use of marginal allografts, which facilitated transplantation in lower laboratory MELD recipients who have been waitlisted longer and often have exception points. Importantly, NMP also appeared to shift peak caseloads from nighttime to daytime, which may have significant effects on the quality of life for the entire liver transplant team.

FGF5.

FGF5 functions as a negative regulator of the hair cycle in mammals. It is expressed in the outer root sheath of hair follicles during the late anagen phase of the hair cycle. It functions as a signaling molecule, mediating the transition of the anagen growth phase to catagen regression phase of the hair cycle. Spontaneous and engineered FGF5 mutations in mammalian animal models result in long hair phenotypes. In humans, inherited FGF5 mutations result in trichomegaly (long eyelashes). Knockdown of fgf5 in zebrafish embryos results in inner ear alterations. Alterations in FGF5 expression are also associated with various human pathologies.

Is it really a challenge to find positive attributes for international medical graduates predictive of success in family medicine residency?

In their paper "Challenges with international medical graduate selection: finding positive attributes predictive of success in family medicine residency," (BMC Prim Care 23(256):2-9, 2022) the authors report on their research into qualitative attributes that positively correspond to success in residency with the objective of assisting in the selection of International Medical Graduate (IMG) residents most likely to achieve success in family medicine residency. The authors found that positive predictors of IMG residents' success were: presence of a positive attitude, proficient communication skills, high level of clinical knowledge, and trainability. The authors conclude that selecting IMG residents who possess these attributes will result in residents developing increased aptitudes for patient care. A careful reading of the paper raises a number of concerns. MacFarlane (Can Med Educ J 12(4):132-40, 2021) points out that IMGs are already marginalized in the residency selection process. Our concern is that this paper may contribute to this marginalization through a tone of negativity or bias against IMGs and the use of biased language throughout the paper that tends to cast IMGs as being inferior and somehow less well prepared for residency than Canadian Medical Graduates (CMGs). We argue that the proposed predictors are generic and equally relevant to both CMGs and IMGs. In focusing on these predictors in IMGs specifically, the paper appears to imply, without evidence, that IMGs are inadequate in the identified areas. After reviewing the paper's references, the existing literature, and an analysis of language used, we conclude that IMGs are capable candidates for residency, and that the qualitative attributes outlined in the paper offer little utility for the selection of IMG residents relative to CMG residents.

One hundred cases of primary spontaneous pneumomediastinum: leukocytosis is common, pleural effusions and age over 40 are rare.

Background: Primary spontaneous pneumomediastinum (PSPM) is a benign condition, but it can be difficult to discriminate from Boerhaave syndrome. The diagnostic difficulty is attributable to a shared constellation of history, signs, and symptoms combined with a poor understanding of the basic vital signs, labs, and diagnostic findings characterizing PSPM. These challenges likely contribute to high resource utilization for diagnosis and management of a benign process. Methods: Patients aged 18 years or older with PSPM were identified from our radiology department's database. A retrospective chart review was performed. Results: Exactly 100 patients with PSPM were identified between March 2001 and November 2019. Demographics and histories correlated well with prior studies: mean age (25 years); male predominance (70%); association with cough (34%), asthma (27%), retching or emesis (24%), tobacco abuse (11%), and physical activity (11%); acute chest pain (75%), and dyspnea (57%) as the first and second most frequent symptoms and subcutaneous emphysema (33%) as the most common sign. We provide the first robust data on presenting vital signs and laboratory values of PSPM, showing that tachycardia (31%) and leukocytosis (30%) were common. No pleural effusion was found in the 66 patients who underwent computed tomography (CT) of the chest. We provide the first data on inter-hospital transfer rates (27%). 79% of transfers were due to concern for esophageal perforation. Most patients were admitted (57%), with an average length of stay (LOS) of 2.3 days, and 25% received antibiotics. Conclusions: PSPM patients frequently present in their twenties with chest pain, subcutaneous emphysema, tachycardia, and leukocytosis. Approximately 25% have a history of retching or emesis and it is this population that must be discriminated from those with Boerhaave syndrome. An esophagram is rarely indicated and observation alone is appropriate in patients under age 40 with a known precipitating event or risk factors for PSPM (e.g., asthma, smoking) if they have no history of retching or emesis. Fever, pleural effusion, and age over 40 are rare in PSPM and should raise concern for esophageal perforation in a patient with a history of retching, emesis, or both.

Expression of LIM domain-binding 3 (LDB3), a striated muscle Z-band alternatively spliced PDZ-motif protein in the nervous system.

LIM domain-binding 3 (LDB3) is a member of the Enigma family of PDZ-LIM proteins. LDB3 has been reported as a striated muscle-specific Z-band alternatively spliced protein that plays an important role in mechanosensory actin cytoskeleton remodeling. This study shows that LDB3 is broadly expressed in the central and peripheral nervous system of human and mouse. LDB3 is predominantly expressed in the adult stages compared to early development and at a significantly higher level in the spinal cord than in the brain. As in skeletal muscle and heart, LDB3 is extensively alternatively spliced in the neurons. Three novel splice isoforms were identified suggesting splicing-dependent regulation of LDB3 expression in the nervous system. Expression of LDB3 in the motor cortex, cerebellum, spinal motor neuron, peripheral nerve, and neuromuscular junction in addition to skeletal muscle indicates important roles for this PDZ-LIM family protein in motor planning and execution. Moreover, expression in the hippocampal neurons suggests roles for LDB3 in learning and memory. LDB3 interactors filamin C and myotilin are also expressed in the spinal motor neuron, nerve, and neuromuscular junction, thereby providing the basis for neurogenic manifestations in myopathies associated with mutations in these so-called muscle proteins.

Systems of Care Factors Should Be Considered in Regionalization of Congenital Cardiac Surgery.

BACKGROUND: Regionalization of care has been proposed to optimize outcomes in congenital cardiac surgery (CCS). We hypothesized that hospital infrastructure and systems of care factors could also be considered in regionalization efforts. METHODS: Observed-to-expected (O/E) mortality ratio and hospital volumes were obtained between 2015 and 2018 from public reporting data. Using a resource dependence framework, we examined factors obtained from American Hospital Association, Children's Hospital Association, and hospital websites. Linear regression models were estimated with volume only, then with hospital factors, stratified by procedural complexity. Robust regression models were reestimated to assess the impact of outliers. RESULTS: We found wide variation in the volume of congenital cardiac surgeries performed (89-3920) and in the surgical outcomes (O/E ratio range, 0.3-3.1). Six outlier hospitals performed few high-complexity cases with high mortality. Univariate analysis including all cases indicated that higher volume predicted lower O/E ratio (ß = -0.02; SE = 0.008; P = .011). However, this effect was driven by the most complex cases. Models stratified by The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category show that volume is a significant predictor only in category 5 cases (ß = -1.707; SE = 0.663; P = .012). Robust univariate regression accounting for outliers found no effect of volume on O/E ratio (ß = 0.005; SE = 0.002; P = .975). Elimination of outliers through robust multivariate regression decreased the volume-outcome relationship and found a modest relationship between health plan ownership and outcomes. CONCLUSIONS: Systems of care factors should be considered in addition to volume in designing regionalization in CCS. Patient-level data sets will better define these factors.

Body mass Index does not impact long-term survival of patients with idiopathic pulmonary fibrosis undergoing lung transplantation.

Objective: We investigated the impact of body mass index (BMI) on post-operative outcomes and survival of patients with interstitial pulmonary fibrosis (IPF) undergoing lung transplantation. Methods: We retrospectively reviewed 222 patients with IPF that underwent lung transplant (LT) at our institution from 2005 to 2019. Recipients were divided in 4 groups: group-1 consisted of underweight patients (BMI ≤18.5 kg/m2), group-2 of normal weight patients (BMI 18.5-25 kg/m2), group-3 of over-weight patients (BMI 25-29.9 kg/m2) and group-4 of obese patients (BMI ≥30 kg/m2). Results: Group-1 consisted of 13 (6%) patients, group-2 of 67 (30%) patients, group-3 of 79 (36%) patients, group-4 consisted of 63 (28%) patients. Median BMI for group-1 was 17 [interquartile range (IQR): 17, 18], for group-2 was 23 (22, 24), for group-3 was 29 (28, 29.5) and group-4 was 32 (31, 33). Patients in group-1 were significantly younger (p < 0.01). Single LT comprised the majority of operation type in group-2 to group-4 and it was significantly higher than group 1 (p < 0.01). Median follow-up time was 39 months (13-76). A total of 79 (35.5%) patients died by the end of study. Overall, five deaths occurred in group-1, 17 in group-2, 33 in group-3, and 24 in group-4. Kaplan-Meier analysis showed that mortality was not statistically significant between the groups (p = 0.24). Cox-regression analysis was used to assess other possible risk factors that could influence the effect of BMI on mortality, including transplant type (single, double), lung allocation score, and age, diabetes and creatinine levels at surgery. None of these factors were shown to affect patient mortality (p > 0.05). Overall reasons for death included graft failure (24%), infection (23%), respiratory failure (14%), and malignancy (13%). Conclusions: Body mass index does not impact long-term survival of patients with IPF undergoing lung transplantation.

Saccharin and aspartame excite rat retinal neurons.

Retinal sensitivity to a variety of artificial sweeteners was tested by monitoring changes in internal free calcium in isolated retinal neurons using Fluo3. Several ligands, including aspartame and saccharin elevated internal free calcium. The effects of these ligands were mediated by both ligand-gated membrane channels and G-protein coupled receptors. We explored the receptors responsible for this phenomenon. Surprisingly, mRNA for subunits of the sweet taste receptor dimer (T1R2 and T1R3) were found in retina. Interestingly, knockdown of T1R2 reduced the response to saccharin but not aspartame. But TRPV1 channel antagonists suppressed the responses to aspartame. The results indicate that artificial sweeteners can increase internal free calcium in the retinal neurons through multiple pathways. Furthermore, aspartame reduced the b-wave, but not the a-wave, of the electroretinogram, indicating disruption of communication between photoreceptors and second order neurons.

Distinct Uroplakin II Staining Pattern in Apocrine Breast Carcinoma.

Uroplakin II (UPII) has been shown as a highly specific marker of urothelial carcinoma; however, it can also stain subtypes of apocrine-differentiated breast carcinoma. Given that urothelium and breast epithelium share other common immunohistochemical markers, such as CK7 and GATA3, this can lead to a potential diagnostic pitfall. We stained a cohort of triple-negative breast cancer with UPII. Compared with the diffuse, cytoplasmic staining in urothelial carcinoma, UPII was positive in 38.9% of apocrine carcinoma (7/18) with a course, granular cytoplasmic staining pattern and negative in all nonapocrine triple-negative breast cancer cases. Furthermore, the same staining pattern was present in all apocrine metaplasia of the breast (4/4) and apocrine sweat glands in normal skin (6/6). This distinct subcellular localization of UPII staining in breast carcinoma can offer a potential solution to the above diagnostic pitfall.

A transgenic bacterial artificial chromosome approach to identify regulatory regions that direct Amhr2 and Osterix expression in Müllerian duct mesenchyme.

A transgenic mouse approach using bacterial artificial chromosomes (BAC) was used to identify regulatory regions that direct Müllerian duct expression for Amhr2 and Osterix (Osx, also known as Sp7). Amhr2 encodes the receptor that mediates anti-Müllerian hormone (AMH) signaling for Müllerian duct regression in male embryos. Amhr2 is expressed in the Müllerian duct mesenchyme of both male and female embryos. A ∼147-kb BAC clone containing the Amhr2 locus was used to generate transgenic mice. The transgene was able to rescue the block in Müllerian duct regression of Amhr2-null males, suggesting that the BAC clone contains regulatory sequences active in male embryos. Osx is expressed in the developing skeleton of male and female embryos but is also an AMH-induced gene that is expressed in the Müllerian duct mesenchyme exclusively in male embryos. Osx-Cre transgenic mice were previously generated using a ∼204-kb BAC clone. Crosses of Osx-Cre mice to Cre-dependent lacZ reporter mice resulted in reporter expression in the developing skeleton and in the Müllerian duct mesenchyme of male but not female embryos. Osx-Cherry transgenic mice were previously generated using a 39-kb genomic region surrounding the Osx locus. Osx-Cherry embryos expressed red fluorescence in the developing skeleton and Müllerian duct mesenchyme of male but not female embryos. In addition, female Osx-Cherry embryos ectopically expressing human AMH from an Mt1-AMH transgene activated red fluorescence in the Müllerian duct mesenchyme. These results suggest that the 39-kb region used to generate Osx-Cherry contains male-specific Müllerian duct mesenchyme regulatory sequences that are responsive to AMH signaling. These BAC transgenic mouse approaches identify two distinct regions that direct Müllerian duct mesenchyme expression and contribute fundamental knowledge to define a gene regulatory network for sex differentiation.