A comprehensive preanalytical protocol for fresh solid tumor biospecimens.

Nearly seventy percent of diagnostic lab test errors occur due to variability in preanalytical factors. These are the parameters involved with all aspects of tissue processing, starting from the time tissue is collected from the patient in the operating room, until it is received and tested in the laboratory. While there are several protocols for transporting fixed tissue, organs, and liquid biopsies, such protocols are lacking for transport and handling of live solid tumor tissue specimens. There is a critical need to establish preanalytical protocols to reduce variability in biospecimen integrity and improve diagnostics for personalized medicine. Here, we provide a comprehensive protocol for the standard collection, handling, packaging, cold-chain logistics, and receipt of solid tumor tissue biospecimens to preserve tissue viability.

Preanalytical protocol for fresh solid tumor biospecimens.

Nearly seventy percent of diagnostic lab test errors occur due to variability in preanalytical factors. 1-4 These are the parameters involved with all aspects of tissue processing, starting from the time tissue is collected from the patient in the operating room, until it is received and tested in the laboratory. While there are several protocols for transporting fixed tissue, organs, and liquid biopsies, such protocols are lacking for transport and handling of live solid tumor tissue specimens. There is a critical need to establish preanalytical protocols to reduce variability in biospecimen integrity and improve diagnostics for personalized medicine. 2,5 Here, we provide a comprehensive protocol for the standard collection, handling, packaging, cold-chain logistics, and receipt of solid tumor tissue biospecimens to preserve tissue viability.

Evaluation of Type 2 SLE symptoms in patients with a range of lupus nephritis activity.

BACKGROUND: Type 2 systemic lupus erythematosus (SLE) symptoms, including fatigue, fibromyalgia, and brain fog, contribute to poor health-related quality of life (HRQoL) in patients with lupus. To test the hypothesis that Type 1 (classical inflammatory lupus) activity is associated with Type 2 SLE activity, we characterized the features of Type 2 SLE in patients with a range of lupus nephritis (LN) activity. METHODS: This was a cross-sectional study of SLE patients [American College of Rheumatology (ACR) 1997 or Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria] from June 2018 to March 2020. Patients completed the Systemic Lupus Activity Questionnaire (SLAQ) and the Polysymptomatic Distress Scale. Patients were divided into groups based on their renal status. Active nephritis was defined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) lupus nephritis parameter. Differences across groups were analyzed by Fisher's exact test and ANOVA. RESULTS: In this cohort of 244 patients (93% female, mean age 43 years, 58% Black), 10% had active nephritis, 35% had historical nephritis, and 55% never had nephritis (non-nephritis). Active nephritis and non-nephritis patients had a similar burden of Type 2 SLE symptoms, despite a difference in Type 1 SLE activity. Patients with active nephritis had higher Type 2 PGA (Physician Global Assessment) scores and reported more Type 2 SLE symptoms than inactive nephritis patients. Patients with inactive nephritis had the lowest Type 2 SLE activity. CONCLUSIONS: While Type 2 SLE symptoms are common in SLE, our findings suggest that patients with active nephritis experience significant Type 2 SLE symptoms that may be ameliorated as nephritis improves. We also observed that non-nephritis patients had a similar burden of Type 2 SLE symptoms as patients with active nephritis, despite having on average lower Type 1 SLE activity. Therefore, the etiology of Type 2 SLE symptoms is likely multifactorial and may be driven by inflammatory and non-inflammatory biopsychosocial factors. Key Points • Patients with active nephritis experienced significant Type 2 symptoms that may be ameliorated as nephritis improves. • Non-nephritis patients had a similar burden of Type 2 SLE symptoms as patients with active nephritis, despite having on average lower Type 1 SLE activity. • Because etiology of Type 2 SLE symptoms is likely multifactorial and may be driven by inflammatory and non-inflammatory biopsychosocial factors.

Methodological approach for an integrated female-specific study of anxiety and smoking comorbidity.

Two primary ovarian hormones that fluctuate across the female menstrual cycle-estradiol and progesterone-have been independently linked in separate literatures to nicotine reinforcement and anxiety psychopathology. We identify existing methodological limitations in these literatures, describe an example protocol that was developed to address such limitations, highlight case examples, and offer insights on the resulting advantages and challenges. This protocol was an observational, prospective, within-subjects study of female cigarette smokers who were followed over the course of a complete menstrual cycle. Non-treatment seeking, female cigarette smokers (N = 50), between the ages of 18-40 who have a normal menstrual cycle (25-35 days in length) were recruited from the community. Females with anxiety or mood psychopathology represented 38.0% of the sample. Salivary progesterone and estradiol were assessed each morning via at-home saliva collection methods. Self-reported within-day momentary ratings of anxiety and nicotine reinforcement were collected using ecological momentary assessment (EMA) via a mobile app. Protocol compliance was >85%. Within- and between-subjects heterogeneity was observed in the progesterone and estradiol, anxiety, and nicotine craving measures, especially in the context of anxiety psychopathology. We aimed to integrate the anxiety and nicotine dependence literatures and advance the empirical study of the role of ovarian hormones. This protocol reflects an intensive, yet feasible approach to collecting daily-level naturalistic data related to estradiol, progesterone, anxiety, and nicotine reinforcement.

Conducting inclusive research in genetics for transgender, gender-diverse, and sex-diverse individuals: Case analyses and recommendations from a clinical genomics study.

A person's phenotypic sex (i.e., endogenous expression of primary, secondary, and endocrinological sex characteristics) can impact crucial aspects of genetic assessment and resulting clinical care recommendations. In studies with genetics components, it is critical to collect phenotypic sex, information about current organ/tissue inventory and hormonal milieu, and gender identity. If researchers do not carefully construct data models, transgender, gender diverse, and sex diverse (TGSD) individuals may be given inappropriate care recommendations and/or be subjected to misgendering, inflicting medical and psychosocial harms. The recognized need for an inclusive care experience should not be limited to clinical practice but should extend to the research setting, where researchers must build an inclusive experience for TGSD participants. Here, we review three TGSD participants in the Family History and Cancer Risk Study (FOREST) to critically evaluate sex- and gender-related survey measures and associated data models in a study seeking to identify patients at risk for hereditary cancer syndromes. Furthermore, we leverage these participants' responses to sex- and gender identity-related questions in FOREST to inform needed changes to the FOREST data model and to make recommendations for TGSD-inclusive genetics research design, data models, and processes.

Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

Nociception Control of Bilateral Single-Shot Erector Spinae Plane Block Compared to No Block in Open Heart Surgery-A Post Hoc Analysis of the NESP Randomized Controlled Clinical Trial.

Background and Objectives: The erector spinae plane block (ESPB) is an analgesic adjunct demonstrated to reduce intraoperative opioid consumption within a Nociception Level (NOL) index-directed anesthetic protocol. We aimed to examine the ESPB effect on the quality of intraoperative nociception control evaluated with the NOL index. Materials and Methods: This is a post hoc analysis of the NESP (Nociception Level Index-Directed Erector Spinae Plane Block in Open Heart Surgery) randomized controlled trial. Eighty-five adult patients undergoing on-pump cardiac surgery were allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 42). Both groups received general anesthesia. Preoperatively, group 2 received bilateral single-shot ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Until cardiopulmonary bypass (CPB) was initiated, fentanyl administration was individualized using the NOL index. The NOL index was compared at five time points: pre-incision (T1), post-incision (T2), pre-sternotomy (T3), post-sternotomy (T4), and pre-CPB (T5). On a scale from 0 (no nociception) to 100 (extreme nociception), a NOL index > 25 was considered an inadequate response to noxious stimuli. Results: The average NOL index across the five time points in group 2 to group 1 was 12.78 ± 0.8 vs. 24.18 ± 0.79 (p < 0.001). The NOL index was significantly lower in the ESPB-to-Control group at T2 (12.95 ± 1.49 vs. 35.97 ± 1.47), T3 (13.28 ± 1.49 vs. 24.44 ± 1.47), and T4 (15.52 ± 1.49 vs. 34.39 ± 1.47) (p < 0.001) but not at T1 and T5. Compared to controls, significantly fewer ESPB patients reached a NOL index > 25 at T2 (4.7% vs. 79%), T3 (0% vs. 37.2%), and T4 (7.1% vs. 79%) (p < 0.001). Conclusions: The addition of bilateral single-shot ESPB to general anesthesia during cardiac surgery improved the quality of intraoperative nociception control according to a NOL index-based evaluation.

Association between short interpregnancy interval and placenta accreta spectrum.

BACKGROUND: The incidence of placenta accreta spectrum is increasing in parallel with the growing number of cesarean deliveries performed. A shorter interpregnancy interval following cesarean delivery may prevent adequate scar healing, which could impact the risk of placenta accreta spectrum. OBJECTIVE: We aimed to investigate the association between short interpregnancy intervals and placenta accreta spectrum. STUDY DESIGN: We conducted a retrospective cohort study of patients at risk for placenta accreta spectrum at a tertiary academic center between 2002 and 2020. Our cohort was defined as pregnant individuals at risk for placenta accreta spectrum meeting the following criteria: placenta previa with previous cesarean delivery and/or uterine surgery, anterior low-lying placenta with previous cesarean delivery and/or uterine surgery, ≥3 previous cesarean deliveries, or any previous cesarean delivery with sonographic findings suspicious for placenta accreta spectrum. The primary outcome was surgically or histopathologically confirmed placenta accreta spectrum. Short interpregnancy interval was defined as <18 completed months from previous delivery and last menstrual period of the index pregnancy. Univariable analyses were performed with chi-square and Student's t-test, as appropriate, and Kruskal-Wallis for nonparametric variables. The unadjusted and adjusted odds ratios were calculated using multivariate logistic regression models. Covariates were selected if P<.2 in univariable analyses or defined a priori as clinically meaningful. The final models were derived using reverse stepwise selection of variables. We used Stata Statistical Software, version 15 (StataCorp, College Station, TX) to perform descriptive statistics. RESULTS: Of 262 patients at risk of placenta accreta spectrum with complete records, 112 (42.7%) had placenta accreta spectrum. Pregnant individuals with short interpregnancy intervals of <18 months were no more likely than those with optimal interpregnancy intervals to have previa (58% [46/80] vs 46% [84/182]; P=.09) or placenta accreta spectrum (49% [39/80] vs 40% [73/182]; P=.19). Short interpregnancy interval of <18 months was not associated with placenta accreta spectrum (unadjusted odds ratio, 1.06; 95% confidence interval, 0.62-1.80). This association did not change when adjusting for previa and number of previous cesarean deliveries (adjusted odds ratio, 1.04; 95% confidence interval, 0.51-2.15). In a secondary analysis, an interpregnancy interval of <12 months was also not associated with placenta accreta spectrum (unadjusted odds ratio, 0.79; 95% confidence interval, 0.04-1.56; adjusted odds ratio, 0.52; 95% confidence interval, 0.21-1.27). CONCLUSION: In patients at risk for placenta accreta spectrum, short interpregnancy intervals of <18 months or <12 months were not associated with placenta accreta spectrum, even when controlling for number of previous cesarean deliveries and previa. Short interpregnancy interval is not likely to be an important modifiable independent risk factor for placenta accreta spectrum.

Nociception Level Index-Directed Erector Spinae Plane Block in Open Heart Surgery: A Randomized Controlled Clinical Trial.

Background and Objectives: The erector spinae plane block (ESPB) is a multimodal opioid-sparing component, providing chest-wall analgesia of variable extent, duration, and intensity. The objective was to examine the ESPB effect on perioperative opioid usage and postoperative rehabilitation when used within a Nociception Level (NOL) index-directed anesthetic protocol. Materials and Methods: This prospective, randomized, controlled, open-label study was performed in adult patients undergoing on-pump cardiac surgery in a single tertiary hospital. Eighty-three adult patients who met eligibility criteria were randomly allocated to group 1 (Control, n = 43) and group 2 (ESPB, n = 40) and received general anesthesia with NOL index-directed fentanyl dosing. Preoperatively, group 2 also received bilateral single-shot ultrasound-guided ESPB (1.5 mg/kg/side 0.5% ropivacaine mixed with dexamethasone 8 mg/20 mL). Postoperatively, both groups received intravenous paracetamol (1 g every 6 h). Morphine (0.03 mg/kg) was administered for numeric rating scale (NRS) scores ≥4. Results: The median (IQR, 25th−75th percentiles) intraoperative fentanyl and 48 h morphine dose in group 2-to-group 1 were 1.2 (1.1−1.5) vs. 4.5 (3.8−5.5) µg·kg−1·h−1 (p < 0.001) and 22.1 (0−40.4) vs. 60.6 (40−95.7) µg/kg (p < 0.001). The median (IQR) time to extubation in group 2-to-group 1 was 90 (60−105) vs. 360 (285−510) min (p < 0.001). Two hours after ICU admission, 87.5% of ESPB patients were extubated compared to 0% of controls (p < 0.001), and 87.5% were weaned off norepinephrine compared to 46.5% of controls (p < 0.001). The median NRS scores at 0, 6, 12, 24, and 48 h after extubation were significantly decreased in group 2. There was no difference in opioid-related adverse events and length of stay. Conclusions: NOL index-directed ESPB reduced intraoperative fentanyl by 73.3% and 48 h morphine by 63.5%. It also hastened the extubation and liberation from vasopressor support and improved postoperative analgesia.

Thyroid Hormone Induces Oral Cancer Growth via the PD-L1-Dependent Signaling Pathway.

Oral cancer is a fatal disease, and its incidence in Taiwan is increasing. Thyroid hormone as L-thyroxine (T4) stimulates cancer cell proliferation via a receptor on integrin αvß3 of plasma membranes. It also induces the expression of programmed death-ligand 1 (PD-L1) and cell proliferation in cancer cells. Thyroid hormone also activates ß-catenin-dependent cell proliferation in cancer cells. However, the relationship between PD-L1 and cancer proliferation is not fully understood. In the current study, we investigated the role of inducible thyroid hormone-induced PD-L1-regulated gene expression and proliferation in oral cancer cells. Thyroxine bound to integrin αvß3 to induce PD-L1 expressions via activation of ERK1/2 and signal transducer and activator of transcription 3 (STAT3). Inactivated STAT3 inhibited PD-L1 expression and nuclear PD-L1 accumulation. Inhibition of PD-L1 expression reduced ß-catenin accumulation. Furthermore, nuclear PD-L1 formed a complex with nuclear proteins such as p300. Suppression PD-L1 expression by shRNA blocked not only expression of PD-L1 and ß-catenin but also signal transduction, proliferative gene expressions, and cancer cell growth. In summary, thyroxine via integrin αvß3 activated ERK1/2 and STAT3 to stimulate the PD-L1-dependent and ß-catenin-related growth in oral cancer cells.

Prophylactic Ureteral Stent Placement and Urinary Injury During Hysterectomy for Placenta Accreta Spectrum.

OBJECTIVE: To evaluate the association between prophylactic ureteral stent placement at the time of hysterectomy for placenta accreta spectrum and genitourinary injury. METHODS: We conducted a retrospective cohort study of patients with placenta accreta spectrum who underwent hysterectomy at two referral centers from 2001 to 2021. The exposure was prophylactic ureteral stent placement. The primary outcome, genitourinary injury, was a composite of bladder injury, ureteral injury, or vesicovaginal fistula. Secondary outcomes included components of the primary outcome. We evaluated differences between groups using χ 2 and t test. To evaluate differences in the primary outcome, we reported odds ratios (ORs) and adjusted odds ratios (aORs) using multivariable logistic regression analyses to control for potential confounding variables. We used a Cochran-Armitage χ 2 trend test to evaluate difference in stent use and injury over time. RESULTS: In total, 236 patients were included. Prophylactic ureteral stents were used in 156 surgeries (66%). Overall, genitourinary injury occurred less frequently in the stent group compared with the no stent group (28% vs 51%, OR 0.37, 95% CI 0.21-0.65). This association persisted after controlling for urgency of delivery, three or more prior cesarean deliveries, and whether a gynecologic oncologist was present (aOR 0.27, 95% CI 0.14-0.52). Unintentional bladder injury occurred less frequently in the stent group compared with the no stent group (13% vs 25%, P =.018), as did ureteral injury (2% vs 9%, P =.019). CONCLUSION: Prophylactic ureteral stent placement was associated with a decreased risk of genitourinary injury during hysterectomy for placenta accreta spectrum.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside improves female ovarian aging.

Reduced fertility associated with normal aging may reflect the over-maturity of oocytes. It is increasingly important to reduce aging-induced infertility since recent trends show people marrying at later ages. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, has been reported to have anti-inflammatory and anti-aging properties. To evaluate whether THSG can reduce aging-related ovarian damage in a female mouse model of aging, THSG was administered by gavage at a dose of 10 mg/kg twice weekly, starting at 4 weeks of age in a group of young mice. In addition, the effect of THSG in a group of aged mice was also studied in mice starting at 24 weeks of age. The number of oocytes in the THSG-fed group was higher than in the untreated control group. Although the percentage of secondary polar bodies (PB2) decreased during aging in the THSG-fed group, it decreased much more slowly than in the age-matched control group. THSG administration increased the quality of ovaries in young mice becoming aged. Western blotting analyses also indicated that CYP19, PR-B, and ER-ß expressions were significantly increased in 36-week-old mice. THSG also increased oocyte numbers in aged mice compared to mice without THSG fed. Studies of qPCR and immunohistochemistry (IHC) analyses of ovaries in the aged mice groups were conducted. THSG increased gene expression of anti-Müllerian hormone (AMH), a biomarker of oocyte number, and protein accumulation in 40-week-old mice. THSG increased the expression of pgc1α and atp6, mitochondrial biogenesis-related genes, and their protein expression. THSG also attenuated the fading rate of CYP11a and CYP19 associated with sex hormone synthesis. And THSG maintains a high level of ER-ß expression, thereby enhancing the sensitivity of estrogen. Our findings indicated that THSG increased or extended gene expression involved in ovarian maintenance and rejuvenation in young and aged mice. On the other hand, THSG treatments significantly maintained oocyte quantity and quality in both groups of young and aged mice compared to each age-matched control group. In conclusion, THSG can delay aging-related menopause, and the antioxidant properties of THSG may make it suitable for preventing aging-induced infertility.

Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells.

Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvß3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.

Longitudinal Education and Career Outcomes of a Cancer Research Training Program for Underrepresented Students: The Meharry-Vanderbilt-Tennessee State University Cancer Partnership.

This study examined longitudinal education and career outcomes of the Meharry-Vanderbilt-Tennessee State University Cancer Partnership, the longest-running National Cancer Institute (NCI) Comprehensive Partnerships in Advancing Cancer Health Equity (CPACHE) program site in the United States. Degree completion rates were calculated and progression along the entire postsecondary "pipeline" was quantified for 204 participants recruited between 2011 and 2020. For participants who had entered the workforce, career outcomes were also analyzed. Relative to comparison data, participants completed degrees and progressed through the higher education "pipeline" to earn advanced degrees at remarkably high rates; the majority entered careers in which they support or conduct cancer research. The latter is important, because most participants identify with demographic categories currently underrepresented in the cancer research workforce. This article makes two contributions to knowledge on research training programs for underrepresented students: 1) it quantifies participants' progression along the entire postsecondary education pipeline as well as into the workforce, and 2) it identifies points where participants are most prone to exit the pipeline rather than progress. We identify two types of exits-permanent and temporary-and offer empirically supported operational definitions for both. Evaluators may find the quantitative model and/or definitions useful for analyzing similar programs.

Managing Postoperative Nausea With an Application of Ice Pack to the Posterior Upper Neck.

PURPOSE: Measure effectiveness of a non-pharmacological approach to manage postoperative nausea (PON) by applying an ice pack to the posterior upper neck. DESIGN: This was an observational quality improvement project. The sample included adults 18 years old and older who received general anesthesia (inhalation and/or intravenous), recovering in Phase I or Phase II postoperative care unit (PACU) experiencing very mild to moderate nausea. Exclusion criteria were patients who experienced severe nausea or were actively vomiting; were admitted for head or neck plastic surgery; were hypothermic (< 36.0°C); patients who refused the ice pack, or the provider stated that placing an ice pack to the patient's posterior upper neck was contraindicated. METHODS: Patients who experienced mild to moderate PON had an ice pack applied to the posterior upper neck as first line management. If the patient's nausea continued to progress or did not improve within five minutes of ice pack application the patient was offered a different non-pharmacological approach or pharmacological approach to prevent vomiting as per standards of care. Demographics were collected and patient's level of nausea was documented at the time of ice pack application and after five minutes. FINDINGS: Of the 70 patients included in this study, 61% reported ice pack application as effective in mitigating their nausea, 14% were unsure, and 24% reported not effective. There was a significant decrease in nausea between baseline (2.3 ± 0.6; range 1-3) and five minutes post application (1.5 ± 1.1; range 0-4). The within subject baseline-post change (↓0.9 ± 1.1; P < .001) reflected a decrease in nausea. CONCLUSIONS: Application of an ice pack to the posterior upper neck, may effectively decrease very mild to moderate PON.

The Clinical Impact of Anti-HLA Donor Specific Antibody Detection Through First Year Screening on Stable Kidney Transplant Recipients.

Anti-HLA Donor Specific Antibody (DSA) detection post kidney transplant has been associated with adverse outcomes, though the impact of early DSA screening on stable patients remain unclear. We analyzed impact of DSA detection through screening in 1st year stable patients (n = 736) on subsequent estimated glomerular filtration rate (eGFR), death censored graft survival (DCGS), and graft failure (graft loss including return to dialysis or re-transplant, patient death, or eGFR < 20 ml/min at last follow up). Patients were grouped using 1st year screening into DSA+ (Class I, II; n = 131) or DSA- (n = 605). DSA+ group were more DR mismatched (p = 0.02), more sensitized (cPRA ≥90%, p = 0.002), less Caucasian (p = 0.04), and had less pre-emptive (p = 0.04) and more deceased donor transplants (p = 0.03). DSA+ patients had similar eGFR (54.8 vs. 53.8 ml/min/1.73 m2, p = 0.56), DCGS (91% vs. 94%, p = 0.30), and graft failure free survival (76% vs. 82%, p = 0.11). DSA timing and type did not impact survival. Among those with a protocol biopsy (n = 515), DSA detected on 1st year screening was a predictor for graft failure on multivariate analysis (1.91, 95% CI 1.03-3.55, p = 0.04). Overall, early DSA detection in stable patients was an independent risk factor for graft failure, though only among those who underwent a protocol biopsy.

When is transanal endoscopic surgery appropriate?

Rectal cancer is a complex medical diagnosis which requires critical decision-making on the part of physician and patient. Organ preservation with local excision for early stage rectal cancer, if done under the correct circumstances, allows for oncologically sound surgery with good patient outcomes. However, locally advanced disease as well as tumor location and size can change potential long-term outcomes. This article will investigate the technical and clinical aspects of transanal surgery and the decision-making algorithms for clinicians and patients.

Cirrhotic Cardiomyopathy-A Veiled Threat.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction in patients with liver cirrhosis without preexisting cardiac disease. According to the definition established by the World Congress of Gasteroenterology in 2005, the diagnosis of CCM includes criteria reflecting systolic dysfunction, impaired diastolic relaxation, and electrophysiological disturbances. Because of minimal or even absent clinical symptoms and echocardiographic signs at rest according to the 2005 criteria, CCM diagnosis is often missed or delayed in most clinically stable cirrhotic patients. However, cardiac dysfunction progresses in time and contributes to the pathogenesis of hepatorenal syndrome and increased morbidity and mortality after liver transplantation, surgery, or other invasive procedures in cirrhotic patients. Therefore, a comprehensive cardiovascular assessment using newer techniques for echocardiographic evaluation of systolic and diastolic function, allowing the diagnosis of CCM in the early stage of subclinical cardiovascular dysfunction, should be included in the screening process of liver transplant candidates and patients with cirrhosis in general. The present review aims to summarize the most important pathophysiological aspects of CCM, the usefulness of contemporary cardiovascular imaging techniques and parameters in the diagnosis of CCM, the current therapeutic options, and the importance of early diagnosis of cardiovascular impairment in cirrhotic patients.

Molecular mechanisms of sperm motility are conserved in an early-branching metazoan.

Efficient and targeted sperm motility is essential for animal reproductive success. Sperm from mammals and echinoderms utilize a highly conserved signaling mechanism in which sperm motility is stimulated by pH-dependent activation of the cAMP-producing enzyme soluble adenylyl cyclase (sAC). However, the presence of this pathway in early-branching metazoans has remained unexplored. Here, we found that elevating cytoplasmic pH induced a rapid burst of cAMP signaling and triggered the onset of motility in sperm from the reef-building coral Montipora capitata in a sAC-dependent manner. Expression of sAC in the mitochondrial-rich midpiece and flagellum of coral sperm support a dual role for this molecular pH sensor in regulating mitochondrial respiration and flagellar beating and thus motility. In addition, we found that additional members of the homologous signaling pathway described in echinoderms, both upstream and downstream of sAC, are expressed in coral sperm. These include the Na+/H+ exchanger SLC9C1, protein kinase A, and the CatSper Ca2+ channel conserved even in mammalian sperm. Indeed, the onset of motility corresponded with increased protein kinase A activity. Our discovery of this pathway in an early-branching metazoan species highlights the ancient origin of the pH-sAC-cAMP signaling node in sperm physiology and suggests that it may be present in many other marine invertebrate taxa for which sperm motility mechanisms remain unexplored. These results emphasize the need to better understand the role of pH-dependent signaling in the reproductive success of marine animals, particularly as climate change stressors continue to alter the physiology of corals and other marine invertebrates.