Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway.

Most tumor cells undergo apoptosis in circulation and at the metastatic organ sites due to host immune surveillance and a hostile microenvironment. It remains to be elucidated whether dying tumor cells have a direct effect on live tumor cells during the metastatic process and what the underlying mechanisms are. Here we report that apoptotic cancer cells enhance the metastatic outgrowth of surviving cells through Padi4-mediated nuclear expulsion. Tumor cell nuclear expulsion results in an extracellular DNA-protein complex that is enriched with receptor for advanced glycation endproducts (RAGE) ligands. The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation. In addition, we identified nuclear expulsion products in human patients with breast, bladder and lung cancer and a nuclear expulsion signature correlated with poor prognosis. Collectively, our study demonstrates how apoptotic cell death can enhance the metastatic outgrowth of neighboring live tumor cells.

A fast, fully validated GC-MS method using a simplified pretreatment for the quantification of short and branched chain fatty acids in human stool.

The study of short (SCFAs) and branched chain fatty acids (BCFAs) in human stool related to gastrointestinal diseases, gut microbiota, metabolism, and diet has dramatically increased. As a result, a fast, reliable method with minimal pretreatment is needed for quantification of these metabolites (acetic, propionic, isobutyric, butyric, isovaleric, valeric, and caproic acid) in stool. Therefore, a GC-MS method meeting this criterion was developed. A bias sampling study showed no statistical difference (p > 0.05) in analyte means when comparing 100 mg subsamples of homogenized to non-homogenized samples (n = 6, p values 0.153-0.910). Stool samples were homogenized, diluted with 80:20 water:methanol (v/v), and adjusted to a pH of 1.5-2.5. Samples were vortexed, centrifuged, and directly injected into the GC-MS using pulsed splitless injection offering twofold-to-threefold signal enhancement over a 10:1 split injection. DB-FATWAX Ultra Inert Polyethylene Glycol (PEG) Column showed no peak tailing, reduced responses, or retention time shifts after 1,476 stool injections, while other columns failed before 361 injections. Intra- and inter-day accuracy for stool supernatant samples ranged from -10.21% to 8.88% and -13.25% to 9.91%, while intra- and inter-day precision ranged from 0.21% to 1.21% and 0.89% to 2.84% coefficient of variation (CV), respectively. This method demonstrates excellent linearity (0.9999-1.0000) and low limits of quantification (1.50-8.01 µM). Stool samples proved stable stored at -20°C up to 28 days, and recoveries ranged from 85.04% to 106.59%. Matrix effects in stool are non-significant determined by comparing standard and stool supernatant calibration curve slopes (p > 0.05).

Outcomes following robot-assisted versus laparoscopic sleeve gastrectomy: the New York State experience.

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) represents more than half of all bariatric procedures in the USA, and robot-assisted sleeve gastrectomy (RSG) is becoming increasingly common. There is a paucity of evidence regarding postoperative surgical outcomes (> 30 days) in RSG patients, especially as these patients move between multiple hospital systems. METHODS: Using 2012-2018 New York State's inpatient and ambulatory data from the Statewide Planning and Research Cooperative System, bivariate and multivariate analyses were employed to examine patient long-term outcomes, postoperative complications, and charges following RSG versus LSG in unmatched and propensity score-matched (PSM) samples. RESULTS: Among the 72,157 minimally invasive sleeve gastrectomies identified, 2365 (2.6%) were RSGs. In the PSM sample (2365 RSG matched to 23,650 LSG), RSG cases were more likely to be converted to an open procedure (2.3% vs 0.2% LSG patients, p < 0.01) and had a longer mean length of stay (LOS; 2.1 vs. 1.8 days LSG, p < 0.01). Postoperative complications were not different between RSG and LSG patients, but the proportion of emergency room visits resulting in inpatient readmissions was higher among RSG patients (5.5% vs. 4.2% in LSG patients, p < .01). Among the super obese (body mass index ≥ 50) patients, conversions to open procedure and LOS were also significantly higher for RSG versus LSG cases. Average hospital charges for the index admission ($47,623 RSG vs $35,934 LSG) and cumulative changes for 1 year from the date of surgery ($57,484 RSG vs $43,769 LSG) were > 30% higher for RSG patients. CONCLUSIONS: RSG patients were more likely to have conversions to open procedures, longer postoperative stay, readmissions, and higher charges for both the index admission and beyond, compared to LSG patients. No clear advantages emerged for the utilization of the robotic platform for either average risk or extremely obese patients.

Two Fifth-Generation Fighter Pilots Discovered with Latent Autoimmune Diabetes.

BACKGROUND: Fighter pilots undergo extensive medical screening but may still miss rare diseases like latent autoimmune diabetes in adults (LADA). LADA patients have circulating autoantibodies directed against pancreatic beta cell antigens and present with frank diabetes late in life which may elude conventional military flight screening.CASE REPORT: Two fifth-generation fighter pilots, a 38-yr-old man (patient 1) and a 27-yr-old man (patient 2), with no significant past medical histories developed symptoms of fatigue, weight loss, episodic polyuria, and arthralgia. Patient 1's symptoms were initially thought to have been caused by COVID-19, but he subsequently tested negative for viral infection. Lab work instead showed elevated TSH, HgbA1C 11.4%, positive GAD-65, anti-TPO, and anti-islet cell antibodies. Patient 2 developed symptoms following a military deployment and a 72-h diarrheal illness. Due to flight status, patient 2 did not seek expert medical attention for several months, but lab work found HgbA1C of 10.4%, positive GAD-66, and ZnT8 antibodies. Both patients were started on insulin therapy. Patient 1 was also started on levothyroxine for hypothyroidism and retired from flying duties. Patient 2 eventually transitioned to metformin without insulin and returned to flying duties with an aeromedical waiver.DISCUSSION: Our patients maintained peak physical fitness throughout their selection and aviation careers, which likely delayed their clinical presentation. Current USAF flight rules prohibit insulin use with flying fighter aircraft. Early antibody screening during pilot selection may be a cost-effective means of diagnosis as traditional screening techniques are unlikely to detect LADA.Zhang JX, Berry J, Kim NM, Gray JJ, Fotheringham S, Sauerwein TJ. Two fifth-generation fighter pilots discovered with latent autoimmune diabetes. Aerosp Med Hum Perform. 2022; 93(2):106-110.

Is New York State good at managing hollow viscus injury?

BACKGROUND: There are an estimated 100,000 cases of abdominal injury (ABI) in the USA, annually resulting in over $12 billion in direct medical cost and $18 billion in lost productivity. This study assesses the timeliness, safety, and efficacy of the surgical management of abdominal injuries (ABIs), hollow viscus injuries (HVIs), and colonic injuries (CIs) for patients residing in New York State (NYS). METHODS: Using data from NYS's Statewide Planning and Research Cooperative System (SPARCS), we identified all trauma patients with ABI admitted between 2006 and 2015. We subdivided ABI into HVI and CI using diagnosis and procedure codes and examined processes of care and outcomes adjusting for patient characteristics, injury severity score, structural, and process indicators. RESULTS: We identified 31,043 hospitalized patients with ABI, 71% were incurred from blunt forces. Most patients with ABI (72%) were treated at a Level I/II trauma center (TC) and 7% patients were transferred to Level I/II TC. Failure to be treated at Level I/II TC was associated with 16% increased hazard of death. HVI was diagnosed in 23% of ABI patients (n = 7294); 18% experienced delayed hollow viscus repair (dHVR); dHVR was associated with a 76% increased hazard of death. CI was diagnosed in 9% of ABI patients (n = 2921) and 18% experienced dHVR. Seventy-five percent of CI were repaired primarily (n = 1354). Less than 37% of stomas were reversed by 4 years of index trauma. CONCLUSION: Most abdominal trauma in NYS was caused by motor vehicle accidents, falls, and assault. dHVR and not being treated at Level I/II TC were associated with worse outcomes. More research is needed to reduce under-triage and delays in the operative treatment of blunt abdominal trauma.

Monolithic Approach for Next-Generation Aircraft Design Considering Airline Operations and Economics.

Traditional approaches to design and optimization of a new system often use a system-centric objective that does not consider how the operator will use this new system alongside other existing systems. When the new system design is incorporated into the broader group of systems, the performance of the operator-level objective can be sub-optimal due to the unmodeled interaction between the new system and the other systems. Among the few available references that describe attempts to address this disconnect, most follow an MDO-motivated sequential decomposition approach of first designing an optimal system and then providing this system to the operator who decides the best way to use this new system along with the existing systems. This paper addresses this issue by including aircraft design, airline operations, and revenue management "subspaces"; and presents an approach that could simultaneously solve these subspaces posed as a monolithic optimization problem. The monolithic approach makes the problem an expensive MINLP problem and is extremely difficult to solve. We use a recently developed optimization framework that simultaneously solves the subspaces to capture the "synergy" in the problem. The results demonstrate that simultaneously optimizing the subspaces leads to significant improvement in the fleet-level objective of the airline when compared to the previously developed sequential subspace decomposition approach. The results also showcase that maximizing revenue and minimizing operating cost independently need not lead to a maximized profit solution for the airline.

Evaluation of the Pig-Tailed Macaque (Macaca nemestrina) as a Model of Human Staphylococcus aureus Nasal Carriage.

Staphylococcus aureus nasal carriage is a common condition affecting both healthy and immunocompromised populations and provides a reservoir for dissemination of potentially infectious strains by casual contact. The factors regulating the onset and duration of nasal S. aureus colonization are mostly unknown, and a human-relevant animal model is needed. Here, we screened 17 pig-tailed macaques (Macaca nemestrina) for S. aureus carriage, and 14 of 17 animals tested positive in the nose at one or both screening sessions (8 weeks apart), while the other 3 animals were negative in the nose but positive in the pharynx at least once. As in humans, S. aureus colonization was densest in the nose, and treatment of the nostrils with mupirocin ointment effectively cleared the nostrils and 6 extranasal body sites. Experimental nasal S. aureus colonization was established with 104 CFU/nostril, and both autologous and nonautologous strains survived over 40 days without any apparent adverse effects. A human nasal S. aureus isolate (strain D579, sequence type 398) was carried in 4 of 6 animals for over 3 weeks. Nostrils that did eradicate experimentally applied S. aureus exhibited neutrophilic innate immunity marked by elevated nasal interleukin-1ß (IL-1ß), IL-8, and monocyte chemotactic protein 1 levels and a 10-fold decreased IL-1 receptor antagonist/IL-1ß ratio within 7 days postinoculation, analogous to the human condition. Taken together, pig-tailed macaques represent a physiological model of human S. aureus nasal carriage that may be utilized for testing natural colonization and decolonization mechanisms as well as novel classes of anti-S. aureus therapeutics.

Electronic Brief Intervention and Text Messaging for Marijuana Use During Pregnancy: Initial Acceptability of Patients and Providers.

BACKGROUND: Marijuana is the most widely used illicit substance during pregnancy. Technology-delivered brief interventions and text messaging have shown promise in general and pregnant samples but have not yet been applied to marijuana use in pregnancy. OBJECTIVE: The objective of the study was to evaluate, among pregnant women and prenatal care providers, the acceptability of an electronic brief intervention and text messaging plan for marijuana use in pregnancy. METHODS: Participants included patients (n=10) and medical staff (n=12) from an urban prenatal clinic. Patient-participants were recruited directly during a prenatal care visit. Those who were eligible reviewed the interventions individually and provided quantitative and qualitative feedback regarding software acceptability and helpfulness during a one-on-one interview with research staff. Provider-participants took part in focus groups in which the intervention materials were reviewed and discussed. Qualitative and focus group feedback was transcribed, coded manually, and classified by category and theme. RESULTS: Patient-participants provided high ratings for satisfaction, with mean ratings for respectfulness, interest, ease of use, and helpfulness ranging between 4.4 and 4.7 on a 5-point Likert scale. Of the 10 participants, 5 reported that they preferred working with the program versus their doctor, and 9 of 10 said the intervention made them more likely to reduce their marijuana use. Provider-participants received the program favorably, stating the information presented was both relevant and important for their patient population. CONCLUSIONS: The findings support the acceptability of electronic brief intervention and text messaging for marijuana use during pregnancy. This, combined with their ease of use and low barrier to initiation, suggests that further evaluation in a randomized trial is appropriate.