Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

Multi-omics analysis reveals the potential pathogenesis and therapeutic targets of diabetic kidney disease.

Clinicians have long been interested in understanding the molecular basis of diabetic kidney disease (DKD)and its potential treatment targets. Its pathophysiology involves protein phosphorylation, one of the most recognizable post-transcriptional modifications, that can take part in many cellular functions and control different metabolic processes. In order to recognize the molecular and protein changes of DKD kidney, this study applied Tandem liquid chromatography-mass spectrometry (LC-MS/MS) and Next-Generation Sequencing, along with Tandem Mass Tags (TMT) labeling techniques to evaluate the mRNA, protein and modified phosphorylation sites between DKD mice and model ones. Based on Gene Ontology (GO) and KEGG pathway analyses of transcriptome and proteome, The molecular changes of DKD include accumulation of extracellular matrix, abnormally activated inflammatory microenvironment, oxidative stress and lipid metabolism disorders, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress has been emphasized as an important factor in DKD and progression to ESKD, which is directly related to podocyte injury, albuminuria and renal tubulointerstitial fibrosis. A histological study of phosphorylation further revealed that kinases were crucial. Three groups of studies have found that RAS signaling pathway, RAP1 signaling pathway, AMPK signaling pathway, PPAR signaling pathway and HIF-1 signaling pathway were crucial for the pathogenesis of DKD. Through this approach, it was discovered that targeting specific molecules, proteins, kinases and critical pathways could be a promising approach for treating DKD.

Association of Body Mass Index and Cardiometabolic Factors With Elderly Suicide: A Cohort Study of 101,518 Older Taiwanese.

BACKGROUND: Older people have the highest suicide rate across age groups in most countries. The prevalence of cardiometabolic risk factors also increases with age. We investigated the association between body mass index (BMI), cardiometabolic risk factors, and suicide in a large cohort of older people in Taiwan. METHODS: We conducted a cohort study using data from an elderly health examination program in Taipei City, Taiwan (2005-2010), linked to the national cause-of-death data files. We used competing risk Cox regression models to investigate the associations of BMI (kg/m2) and cardiometabolic factors with suicide after adjusting for sex, age, socioeconomic variables, chronic diseases, psychological distress, and cognitive function. RESULTS: Among 101,518 individuals aged ≥ 65 years, 92 died by suicide during an average follow-up of 3.9 years. Underweight (BMI<18.5) was associated with increased suicide risk (adjusted hazard ratio [aHR]=2.33, 95% confidence interval [CI] 1.20-4.52) (reference: normal weight). Low diastolic blood pressure was associated with increased suicide risk - aHR was 0.51 (95% CI 0.29-0.91) and 0.55 (95% CI 0.31-0.99) for the third and fourth quartiles of diastolic blood pressure (reference: the lowest quartile), respectively. Older people with a higher waist circumference (aHR per 1-standard-deviation increase=0.60 [95% CI 0.37-0.98]) and a higher number of metabolic syndrome criteria (aHR per 1-criterion increase=0.65 [95% 0.46-0.92]) had lower suicide risk. Systolic blood pressure, pulse rate, fasting blood glucose, and lipid profiles were not associated with suicide risk. CONCLUSIONS: Underweight, low diastolic blood pressure, and low waist circumference may be markers of increased suicide risk in older people.

Identification of PDK4 as Hub Gene for Diabetic Nephropathy Using Co-Expression Network Analysis.

INTRODUCTION: Diabetic nephropathy (DN) is related to type 1 and type 2 diabetes. They are the leading cause of end-stage renal disease, but the underling specific pathogenesis of DN is not yet clear. Our study was conducted to explore how DN changed the transcriptome profiles in the kidney. METHODS: The gene expression profile of microdissected glomeruli of 41 type 2 DN patients and 20 healthy controls were included. The sample dataset GSE96804 was obtained from the GEO database. Differentially expressed genes (DEGs) were analyzed in R with the limma package and the important modules were found by weighted gene co-expression network analysis (WGCNA) clustering. The modules were then analyzed based on Gene Ontology (GO) gene set enrichment analysis, and the hub genes were found out. We next validated the hub gene, PDK4, in a cell model of DN. We also constructed the PDK4-related PPI network to investigate the correlation between PDK4 expression and other genes. RESULTS: Heatmap and volcano map were drawn to illustrate the mRNA expression profile of 1,204 DEGs in both samples of DN patients and the control group. Using WGCNA, we selected the blue module in which genes showed the strongest correlation with the phenotype and the smallest p value. We also identified PDK4 as a hub gene. PDK4 expression was upregulated in human diabetic kidney tissue. Moreover, PDK4 was speculated to play a role in glomerular basement membrane development and kidney development according to the enrichment of functions and signaling pathways. Furthermore, PDK4 and two key genes GSTA2 and G6PC protein expression were verified highly expressed in the cell model of DN. CONCLUSION: During the pathogenesis of DN, many genes may change expression in a coordinated manner. The discovery of PDK4 as key gene using WGCNA is of great significance for the development of new treatment strategies to block the development of DN.

Mortality in anorexia nervosa and bulimia nervosa: A population-based cohort study in Taiwan, 2002-2017.

OBJECTIVE: To investigate natural- and unnatural-cause mortality at different follow-up time points in Taiwanese patients with anorexia nervosa (AN) and bulimia nervosa (BN). METHOD: In this longitudinal cohort study, 330,393 patients, including 2143 patients with AN, 13,590 with BN, and 20 times as many respective non-AN and non-BN patients, were followed up for 16 years. We performed conditional Cox regression survival analysis to examine the risk of mortality in the AN and BN groups relative to the comparison group. RESULTS: A total of 1242 patients died, including 101 and 343 patients with AN and BN, respectively. Mortality rates for AN and BN were 5.42 and 2.90 deaths per 1000 person-years, respectively. Compared with the non-AN group, the AN group had a significantly higher risk of both natural- and unnatural-cause mortality, and the BN group had a significantly higher risk of unnatural-cause mortality. Suicide was the most common cause of death, and suicide risk was significantly higher in both the AN and BN groups. All-cause mortality risk was the highest at the beginning of follow-up and markedly declined in the AN group. In the BN group, all-cause mortality risk was lower but stable at follow-up. The risk of unnatural-cause mortality remained high throughout the follow-up period for both the groups. CONCLUSIONS: Early detection and treatment for associated physical problems in patients with AN are crucial. Regular monitoring for unnatural-cause mortality events (mainly suicide) in AN and BN over time is also crucial. PUBLIC SIGNIFICANCE: AN had a significantly higher risk of both natural- and unnatural-cause mortality and BN had a significantly higher risk of death from unnatural causes. All-cause mortality risk was highest at the beginning of follow-up in AN, but unnatural-cause mortality risk remained high throughout the follow-up period for both groups. Our findings imply that early detection and treatment in AN and regular monitoring for unnatural-cause mortality events in AN and BN are crucial.

Risk of dialysis and renal diseases in patients with anorexia nervosa in Taiwan.

OBJECTIVE: To investigate the incidence and risk of renal-related complications in a nationwide cohort of Taiwanese patients with anorexia nervosa (AN). METHOD: This longitudinal cohort study analyzed the data of 43,951 individuals-comprising 2091 patients with AN and their controls matched (1:20) using propensity scores according to sex, age, degree of urbanization of residence, socioeconomic status, and year of diagnosis-from a population-based health insurance database; the study lasted 16 years. We used Kaplan-Meier curves to estimate the cumulative incidence of renal events. We also performed Cox proportional regression and constructed a risk model with death as a competing event (both adjusted for basic characteristics, renal diseases, and psychiatric comorbidities) to examine the risk of dialysis and renal outcomes in the AN group relative to the control group. RESULTS: In total, 204 and 10 patients with AN had renal-related outcomes and end-stage renal disease (ESRD), respectively. The cumulative incidence rates of all renal outcomes and ESRD in the AN group were 10.72% and .64%, respectively, at 10-year follow-up. Compared with the control group, the AN group had a significantly higher risk of acute dialysis (adjusted hazard ratio 2.10 [95% confidence interval 1.19-3.68]), hypokalemia, hypovolemia, nephritis, acute renal failure, and chronic renal failure. The AN group did not have a significantly higher risk of ESRD. DISCUSSION: The elevated risks of acute dialysis and some renal outcomes in AN highlight the importance of monitoring electrolyte imbalance and renal malfunctioning. PUBLIC SIGNIFICANCE: Malnutrition and purging behaviors may cause renal complications in patients with AN. In this longitudinal cohort study, we found that the 10-year cumulative incidence of all renal outcomes in AN was 10.72%, and that patients with AN had a two-fold higher risk of overall renal outcomes compared with those without AN. Our findings imply that weight restoration and ceasing purging behaviors are crucial for recovery from AN.

Endoscopic findings do not predict per-oral pyloromyotomy (POP) response.

INTRODUCTION: Gastroparesis is a life-altering diagnosis caused by the stomach's inability to function in the absence of a mechanical obstruction. The primary causes are idiopathic, diabetic, and postoperative. Our first-line treatment for medical refractory gastroparesis is the endoscopic per-oral pyloromyotomy (POP) procedure. Predicting clinical response cost effectively remains elusive. METHODS: All patients who underwent a POP procedure at our institution by a single surgical endoscopist from January 1, 2019 to June 30, 2020 were retrospectively reviewed. All endoscopic data were prospectively collected. The patients were followed by a survey including the Gastroparesis Cardinal Symptom Index (GCSI) and other relevant postoperative measures. The primary endpoint was clinical response defined as ≥ 1.0 decrease in the GCSI from preoperative to the time of survey. Secondary outcome was normalization of the gastric emptying study (GES). RESULTS: Our patient population is 85% female and has an average age of 44.8 years. The diagnosis of gastroparesis is 71% iatrogenic, 19% postoperative, and 10% diabetic. On endoscopy, 30% had bile in the stomach and 65% had any degree of pylorospasm. The primary outcome measure of clinical response was 39% at an average of 697 ± 151 days post-POP, but 66% of patients attested to an improvement in their symptoms. Of 68 postoperative gastric emptying studies 50% normalized at an average of 145 ± 98 days. Following univariate and multivariate analyses of preoperative data and endoscopic findings, there were no significant predictors of clinical response. A preoperative GCSI ≥ 2.6 trends toward significance (OR 6.87, p = 0.058). CONCLUSION: Endoscopic findings at the time of POP do not correlate with clinical response. The GCSI model currently used to measure clinical response may not accurately capture the full clinical picture. The long-term durability of endoscopic myotomy to treat medical refractory gastroparesis needs to be studied further to improve patient selection.

Physiologic tension of the abdominal wall.

BACKGROUND: Tension-free abdominal closure is a primary tenet of laparotomy. But this concept neglects the baseline tension of the abdominal wall. Ideally, abdominal closure should be tailored to restore native physiologic tension. We sought to quantify the tension needed to re-establish the linea alba in patients undergoing exploratory laparotomy. METHODS: Patients without ventral hernias undergoing laparotomy at a single institution were enrolled from December 2021 to September 2022. Patients who had undergone prior laparotomy were included. Exclusion criteria included prior incisional hernia repair, presence of an ostomy, large-volume ascites, and large intra-abdominal tumors. After laparotomy, a sterilizable tensiometer measured the quantitative tension needed to bring the fascial edge to the midline. Outcomes included the force needed to bring the fascial edge to the midline and the association of BMI, incision length, and prior lateral incisions on abdominal wall tension. RESULTS: This study included 86 patients, for a total of 172 measurements (right and left for each patient). Median patient BMI was 26.4 kg/m2 (IQR 22.9;31.5), and median incision length was 17.0 cm (IQR 14;20). Mean tension needed to bring the myofascial edge to the midline was 0.97 lbs. (SD 1.03). Mixed-effect multivariable regression modeling found that increasing BMI and greater incision length were associated with higher abdominal wall tension (coefficient 0.04, 95% CI [0.01,0.07]; p = 0.004, coefficient 0.04, 95% CI [0.01,0.07]; p = 0.006, respectively). CONCLUSION: In patients undergoing laparotomy, the tension needed to re-establish the linea alba is approximately 1.94 lbs. A quantitative understanding of baseline abdominal wall tension may help surgeons tailor abdominal closure in complex scenarios, including ventral hernia repairs and open or burst abdomens.

Laparoscopic versus robotic inguinal hernia repair: 1- and 2-year outcomes from the RIVAL trial.

INTRODUCTION: Robotic inguinal hernia repair is growing in popularity among general surgeons despite little high-quality evidence supporting short- or long-term advantages over traditional laparoscopic inguinal hernia repair. The original RIVAL trial showed increased operative time, cost, and surgeon frustration for the robotic approach without advantages over laparoscopy. Here we report the 1- and 2-year outcomes of the trial. METHODS: This is a multi-center, patient-blinded, randomized clinical study conducted at six sites from 2016 to 2019, comparing laparoscopic versus robotic transabdominal preperitoneal (TAPP) inguinal hernia repair with follow-up at 1 and 2 years. Outcomes include pain (visual analog scale), neuropathic pain (Leeds assessment of neuropathic symptoms and signs pain scale), wound morbidity, composite hernia recurrence (patient-reported and clinical exam), health-related quality of life (36-item short-form health survey), and physical activity (physical activity assessment tool). RESULTS: Early trial participation included 102 patients; 83 (81%) completed 1-year follow-up (45 laparoscopic vs. 38 robotic) and 77 (75%) completed 2-year follow-up (43 laparoscopic vs. 34 robotic). At 1 and 2 years, pain was similar for both groups. No patients in either treatment arm experienced neuropathic pain. Health-related quality of life and physical activity were similar for both groups at 1 and 2 years. No long-term wound morbidity was seen for either repair type. At 2 years, there was no difference in hernia recurrence (1 laparoscopic vs. 1 robotic; P = 1.0). CONCLUSIONS: Laparoscopic and robotic inguinal hernia repairs have similar long-term outcomes when performed by surgeons with experience in minimally invasive inguinal hernia repairs.

Robotic eTEP versus IPOM evaluation: the REVEAL multicenter randomized clinical trial.

BACKGROUND: For small to medium-sized ventral hernias, robotic intraperitoneal onlay mesh (rIPOM) and enhanced-view totally extraperitoneal (eTEP) repair have emerged as acceptable approaches that each takes advantage of robotic instrumentation. We hypothesized that avoiding mesh fixation in a robotic eTEP repair offers an advantage in early postoperative pain compared to rIPOM. METHODS: This is a multi-center, randomized clinical trial for patients with midline ventral hernias ≤ 7 cm, who were randomized to rIPOM or robotic eTEP. The primary outcome was pain (0-10) on the first postoperative day. Secondary outcomes included same-day discharge, length of stay, opioid consumption, quality of life, surgeon workload, and cost. RESULTS: Between November 2019 and November 2021, 100 patients were randomized (49 rIPOM, 51 eTEP) among 5 surgeons. Pain on the first postoperative day [median (IQR): 5 (4-6) vs. 5 (3.5-7), p = 0.66] was similar for rIPOM and eTEP, respectively, a difference maintained following adjustments for surgeon, operative time, baseline pain, and patient co-morbidities (difference 0.28, 95% CI - 0.63 to 1.19, p = 0.56). No differences in pain on the day of surgery, 7, and 30 days after surgery were identified. Same-day discharge, length of stay, opioid consumption, and 30-day quality of life were also comparable, though rIPOM required less surgeon workload (p < 0.001), shorter operative time [107 (86-139) vs. 165 (129-212) min, p < 0.001], and resulted in fewer surgical site occurrences (0 vs. 8, p = 0.004). The total direct costs for rIPOM and eTEP were comparable [$8282 (6979-11835) vs. $8680 (7550-10282), p = 0.52] as the cost savings for eTEP attributable to mesh use [$442 (434-485) vs. $69 (62-76), p = < 0.0001] were offset by increased expenses for operative time [$669 (579-861) vs. $1075 (787-1367), p < 0.0001] and use of more robotic equipment [$760 (615-933) vs. $946 (798-1203), p = 0.001]. CONCLUSION: The avoidance of fixation in a robotic eTEP repair did not reveal a benefit in postoperative pain to offset the shorter operative time and surgeon workload offered by rIPOM.

A highly stable human single-domain antibody-drug conjugate exhibits superior penetration and treatment of solid tumors.

The inefficient tumor penetration of therapeutic antibodies has hampered their effective use in treating solid tumors. Here, we report the identification of a fully human single-domain antibody (UdAb), designated as n501, targeting the oncofetal antigen 5T4. The high-resolution crystal structure indicates that n501 adopts a compact structure very similar to that of camelid nanobodies, and binds tightly to all eight leucine-rich repeats of 5T4. Furthermore, the UdAb n501 exhibits exceptionally high stability, with no apparent activity changes over 4 weeks of storage at various temperatures. Importantly, the UdAb-based antibody-drug conjugate (n501-SN38) showed much deeper tumor penetration, significantly higher tumor uptake, and faster accumulation at tumor sites than conventional IgG1-based antibody-drug conjugate (m603-SN38), resulting in improved tumor inhibition. These results highlight the potential of UdAb-based antibody-drug conjugates as a potential class of antitumor therapeutics with characteristics of high stability and strong tumor penetration for the effective treatment of solid tumors.

Evaluation of egg white hydrolysates on the hepatoprotective effect in vitro and in vivo.

The small molecule characteristics and nutritional value of egg white hydrolysates have been widely used. In the present study, in vitro and in vivo models were used to investigate the hepatoprotective effect of egg protein hydrolysate (EWH) by regulating the expression of antioxidant enzymes. The in vitro experiment results showed that 0.1, 0.5, and 1 mg/mL of EWH enhanced antioxidant activity in HepG2 cells by increased glutathione peroxidase (GPx) activity and reduced glutathione (GSH) levels. The in vivo experiment results showed that EWH (L) (38.5 mg/kg BW) and EWH (H) (385 mg/kg BW) alleviated carbon tetrachloride (CCl4)-induced hepatotoxicity in SD rats through reduced levels of serum aspartate aminotransferase (AST) alanine aminotransferase (ALT), and lipid peroxidation products malondialdehyde (MDA). In addition, EWH also ameliorates CCl4-induced hepatotoxicity in SD rats by increasing the antioxidant activity of GSH levels with a decrease in oxidized glutathione (GSSG) levels. Besides, EWH ameliorates liver tissue injuries by CCl4-induction. EWH has the highest glutamic acid in free amino acid composition, the second highest was aspartic acid, and the third was cystine, 204, 141, and 125 mg/100 g, respectively. These results suggest EWH has hepatoprotective potential through reduced lipid peroxidation products and enhanced antioxidant activity.

Investigation of the optimal production conditions for egg white hydrolysates and physicochemical characteristics.

This study aimed to investigate the potential of egg white protein hydrolysate (EWH) as a functional food by identifying the optimum production conditions for EWH with response surface methodology (the results of the sensory evaluation were considered as an essential quality indicator). At the same time, its physicochemical and biological activity was also evaluated. The optimal economic production conditions were selected: substrate concentration of 12.5%, enzyme content of 7.5%, and hydrolysis time at 100 min. The degree of hydrolysis (DH %) was 13.51%. In addition, to the better acceptance of the evaluation, it also helps to reduce the production cost of the protein hydrolysate, which is beneficial to future processing and applications. The antioxidant capacity experiments showed that EWH has good antioxidant activity, which presents a dose-dependent relationship. Hence, this study provides a theoretical basis for future research and application of EWH for processing applications, including dietary supplementation. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05708-0.

Bone marrow mesenchymal stem cell-derived exosomes shuttling miR-150-5p alleviates mechanical allodynia in rats by targeting NOTCH2 in microglia.

BACKGROUND: This study probes into the function and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes loaded with miR-150-5p in mechanical allodynia. METHODS: BMSCs were infected with miR-150-5p inhibition lentiviruses to obtain exosomes with low miR-150-5p expression. A L5 spinal nerve ligation (SNL) model was established in rats where exosomes, NOTCH2 overexpression/inhibition plasmids, or microglial cells were intrathecally administered. Hind paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of rats were measured. TUNEL staining was used to measure the apoptotic rate in rat spinal dorsal horn (SDH), ELISA to evaluate pro-inflammatory factor levels, and RT-qPCR, western blotting, and immunohistochemistry to detect miR-150-5p and NOTCH2 expression. Immunofluorescence was used for localizing exosomes and NOTCH2 and detecting the expression of OX42, a maker for microglia. Dual luciferase reporter and RNA pull down assays were performed to validate the putative binding between miR-150-5p and NOTCH2. RESULTS: NOTCH2 expressed at a high level and miR-150-5p was downregulated in SDH of SNL rats. Exosomes injected were localized in rat SDH. BMSC-exosomes or NOTCH2 downregulation increased PWT and PWL of SNL rats and reduced apoptosis and inflammation in SDH. In contrast, NOTCH2 overexpression aggravated mechanical allodynia and SDH injury. Moreover, inhibiting miR-150-5p in BMSC-exosomes offset the therapeutic effects of BMSC-exosomes. Microglia activation induced mechanical allodynia in wild rats, while intrathecal injection of microglial cells incubated with BMSC-exosomes showed alleviated mechanical allodynia in SNL rats. NOTCH2 was targeted by miR-150-5p. CONCLUSION: BMSC-derived exosomal miR-150-5p alleviates mechanical allodynia by targeting NOTCH2 in microglial cells.

The Efficacy of Liposomal Bupivacaine on Postoperative Pain Following Abdominal Wall Reconstruction: A Randomized, Double-blind, Placebo-controlled Trial.

OBJECTIVE: To study the efficacy of liposomal bupivacaine on postoperative opioid requirement and pain following abdominal wall reconstruction. SUMMARY BACKGROUND DATA: Despite the widespread use of liposomal bupivacaine in transversus abdominis plane block, there is inadequate evidence demonstrating its efficacy in open abdominal wall reconstruction. We hypothesized that liposomal bupivacaine plane block would result in decreased opioid requirements compared with placebo in the first 72 hours after surgery. METHODS: This was a single-center double-blind, placebo-controlled prospective study conducted between July 2018 and November 2019. Adult patients (at least 18 yrs of age) undergoing open, elective, ventral hernia repairs with mesh placed in the retromuscular position were enrolled. Patients were randomized to surgeon-performed transversus abdominis plane block with liposomal bupivacaine, simple bupivacaine, or normal saline (placebo). The main outcome was opioid requirements in the first 72 hours after surgery. Secondary outcomes included total inpatient opioid use, pain scores determined using a 100 mm visual analog scale, length of hospital stay, and patientreported quality of life. RESULTS: Of the 164 patients who were included in the analysis, 57 patients received liposomal bupivacaine, 55 patients received simple bupivacaine, and 52 received placebo. There were no differences in the total opioid used in the first 72 hours after surgery as measured by morphine milligram equivalents when liposomal bupivacaine was compared with simple bupivacaine and placebo (325 ± 225 vs 350 ± 284 vs 310 ± 272, respectively, P = 0.725). Similarly, there were no differences in total inpatient opioid use, pain scores, length of stay, and patient-reported quality of life. CONCLUSIONS: There are no apparent clinical benefits to using liposomal bupivacaine transversus abdominis plane block when compared with simple bupivacaine and placebo for open abdominal wall reconstruction.

Stage IV Non-breast Cancer Patients and Screening Mammography: It is Time to Stop.

BACKGROUND: Patients diagnosed with metastatic cancer have shortened life expectancy with questionable benefit of routine screening mammography (SM). The aim of this study was to evaluate the incidence and consequences of continued SM in the setting of reduced survival from stage IV non-breast cancer. METHODS: Women diagnosed with Stage IV non-breast cancer at a single institution from 2015 to 2019 were queried from the institutional tumor registry for demographics, stage IV cancer diagnosis, and survival. Incidence and timing of SM after stage IV diagnosis and further diagnostic workup were extracted from the medical record. RESULTS: 790 women with Stage IV non-breast cancer were identified, 109 (14%) had at least 1 SM, 23% required diagnostic mammography, 7% breast biopsy, and 1% breast surgery. No breast cancers were identified. SM was ordered most often in stage IV gynecological cancers (28%), with more common cancers still seeing a high percentage of patients screened (lung 10%, colorectal 15%). Study 3-year survival was 26% (95% confidence interval [CI] 23-30%), with 74% mortality during follow up and median time from Stage IV diagnosis to death of 1.2 years (CI 0.4-2.3 years). Of patients screened, 41/109 died within 2 years of undergoing SM. CONCLUSIONS: Despite low overall survival for patients diagnosed with metastatic non-breast cancer, 14% of women underwent SM which resulted in additional imaging, biopsies, and surgery with no new breast cancers identified. Continued SM in this population offers risk without benefit of reduced breast cancer mortality and should no longer continue in women with stage IV non-breast cancer.

Postoperative Respiratory Failure After Elective Abdominal Surgery: A Case-Control Study.

INTRODUCTION: Postoperative respiratory failure (PRF) contributes significantly to morbidity and mortality. We sought to identify patient characteristics and perioperative risk factors associated with PRF in patients undergoing elective abdominal surgery to improve patient outcomes. METHODS: We retrospectively reviewed patients undergoing elective abdominal surgery from 2011 to 2016 at our institution. An experimental group consisting of adult patients with the Patient Safety Indicator 11 diagnosis of PRF was compared with a time-matched control group. RESULTS: Each group consisted of 233 patients. Comorbidities associated with PRF included ascites, coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus type II, hypertension, and hypoalbuminemia (P < 0.05). American Society of Anesthesiologists score IV (20.2% versus 3.95%; P < 0.001), operative time (4.13 versus 2.55 h; P < 0.001), laparotomy with open operation (77.7% versus 45.5%; P < 0.001), and net intraoperative fluid balance (3635 versus 2410 mL; P < 0.001) were higher in patients with PRF. On multivariate analysis, age, American Society of Anesthesiologists score, chronic obstructive pulmonary disease, diabetes mellitus type II, laparotomy, and net intraoperative fluid balance maintained significance (P < 0.05). CONCLUSIONS: We identified contributing pre- and intra-operative risk factors for PRF undergoing elective abdominal surgery. These findings may help identify those at increased risk for respiratory failure and mitigate complications.

A novel and effective approach to generate germline-like monoclonal antibodies by integration of phage and mammalian cell display platforms.

Phage display technology allows for rapid selection of antibodies from the large repertoire of human antibody fragments displayed on phages. However, antibody fragments should be converted to IgG for biological characterizations and affinity of antibodies obtained from phage display library is frequently not sufficient for efficient use in clinical settings. Here, we describe a new approach that combines phage and mammalian cell display, enabling simultaneous affinity screening of full-length IgG antibodies. Using this strategy, we successfully obtained a novel germline-like anti-TIM-3 monoclonal antibody named m101, which was revealed to be a potent anti-TIM-3 therapeutic monoclonal antibody via in vitro and in vivo experiments, indicating its effectiveness and power. Thus, this platform can help develop new monoclonal antibody therapeutics with high affinity and low immunogenicity.

Gastroparesis with concomitant gastrointestinal dysmotility is not a contraindication for per-oral pyloromyotomy (POP).

INTRODUCTION: Per-oral pyloromyotomy (POP or G-POEM) provides significant short-term improvements in symptoms and objective emptying for patients with medically refractory gastroparesis, but it is unclear if patients with gastroparesis and co-existing dysmotility (small bowel or colonic delay) also benefit. In this study, we used wireless motility capsule (WMC) data to measure outcomes in patients with isolated gastroparesis (GP) and gastroparesis with co-existing dysmotility (GP + Dys) who underwent POP. METHODS: We retrospectively analyzed patients who had POP and completed WMC data during their evaluation of intestinal dysmotility. WMC data were reviewed to identify patients who demonstrated isolated GP or GP + Dys. Each patient's pre-op and post-op Gastroparesis Cardinal Symptom Index (GCSI) and 4-h solid-phase scintigraphy gastric emptying studies (GES) scores were compared to evaluate improvement. RESULTS: Of the entire cohort (n = 73), 89% were female with a mean age of 47.0 ± 15.0 years old. Gastroparesis etiologies were divided among idiopathic (54.8%), diabetic (26%), postsurgical (8.2%), autoimmune (5.5%), and multifactorial (5.5%). Forty-one patients (56%) had GP and 32 patients (44%) had GP + Dys. GCSI improved after POP whether the patient had isolated GP (- 12.31, p < 0.001) or GP + Dys (- 9.58, p < 0.001); however, there was no significant difference in total GCSI improvement between the two groups. A subset of patients had postoperative GES available (n = 47). In the isolated GP and GP + Dys cohorts, 15/28 (54%) and 12/19 (63%) patients had normal post-op 4-h GES, respectively, but no statistical difference between the two groups. CONCLUSION: Patients with medically refractory gastroparesis with and without concomitant gastrointestinal dysmotility show short-term subjective and objective improvement after POP. Concomitant small bowel or colonic dysmotility should not deter physicians from offering POP in carefully selected patients with gastroparesis.

The role of circular RNA in Diabetic Nephropathy.

Diabetic nephropathy (DKD) is the most common chronic microvascular complication of diabetes. About 20%-40% of diabetics develop DKD, which eventually leads to chronic kidney failure. Although progress has been made in diagnosis and treatment tools, diabetic nephropathy is still a major clinical problem. In recent years, circular RNA (CircRNA) has become a research hotspot. CircRNA is a non-coding RNA formed by covalently closing the 5 'and 3' ends of the precursor RNA. CircRNA has powerful biological functions. CircRNA can regulate the expression of target genes through competitive binding with microRNA, thus playing the biological role of endogenous RNA (CeRNA). Many studies have shown that circRNAs plays an important role in malignant tumors, autoimmune system diseases, coronary heart disease and other diseases. More and more studies have shown that it can also be used as a biomarker of diabetes and diabetic nephropathy. This review summarizes the origin, classification, biogenesis and regulatory mechanisms of circRNAs. In addition, the pathogenesis and clinical significance of circRNAs as competing endogenous RNAs involved in diabetic nephropathy were also introduced. This will help us fully understand the pathological mechanism of diabetic nephropathy and develop new therapeutic targets or treatment options to improve the prognosis of patients with diabetic nephropathy.