Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing.

A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.

Use of once-daily oral semaglutide and associated clinical outcomes among adults with type 2 diabetes in routine clinical practice in Canada: A multicentre, prospective real-world study (PIONEER REAL Canada).

AIM: PIONEER REAL Canada examined real-world clinical outcomes associated with the use of once-daily oral semaglutide in adults with type 2 diabetes. MATERIALS AND METHODS: This was a 34- to 44-week, multicentre, prospective, open-label, non-interventional study in adults who were treatment-naive to injectable glucose-lowering medication and initiated oral semaglutide in routine clinical practice. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to the end of the study (EoS). Secondary endpoints assessed at EoS were change from baseline in body weight (BW); the proportion of participants reaching HbA1c levels <7% and the composite endpoints, HbA1c reduction ≥1% point with BW reduction ≥3% and ≥5%; and treatment satisfaction measured using Diabetes Treatment Satisfaction Questionnaires (DTSQ) status and change. Primary analyses were based on the in-study observation period. RESULTS: In total, 182 participants initiated oral semaglutide (mean age, 58.6 years; HbA1c, 8.0%; BW, 93.7 kg). The estimated changes (95% confidence interval) from baseline to EoS in HbA1c and BW were -1.09% points (-1.24, -0.94; p < .0001) and -7.17% (-8.24, -6.11; p < .0001), respectively. At EoS, 53.7% of participants had HbA1c levels <7%; 39.3% and 31.6% reached HbA1c reduction ≥1% point plus BW reduction ≥3% and ≥5%, respectively. Treatment satisfaction significantly increased (DTSQ status, +4.47 points; DTSQ change, 11.83 points; both p < .0001). At EoS, 75.3% of participants remained on oral semaglutide (55.5% received oral semaglutide 14 mg). No new safety signals were identified for oral semaglutide. CONCLUSIONS: In PIONEER REAL Canada, participants treated with oral semaglutide in routine clinical practice experienced clinically relevant reductions in HbA1c and BW and increased treatment satisfaction.

Magnesium and Esophageal Pain After Peroral Endoscopic Myotomy of the Esophagus: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Postoperative esophageal pain occurs in 67% of patients after peroral endoscopic esophageal myotomy (POEM). Magnesium can act as a smooth muscle relaxant. This study investigated whether intraoperative magnesium can reduce postoperative esophageal pain in patients undergoing POEM. METHODS: In this double-blind, placebo-controlled trial, 92 patients were randomized to receive either magnesium sulfate as a 50 mg.kg-1 (total body weight) bolus followed by an infusion at 25 mg.kg-1.hr-1, or 0.9% saline. Intraoperative analgesia was standardized in all patients. The primary outcome was the score from a validated, modified Esophageal Symptoms Questionnaire (ESQ) in the postanesthesia care unit (PACU). Pain scores, opioid requirements, and questionnaire scores were collected through postoperative day 1. RESULTS: ESQ scores were significantly lower in the magnesium group in the PACU (median [25th-75th], 24 [18-31] vs 35 [28-42]; median difference [95% confidence interval, CI], 10 [6-13]; P < .0001) and on postoperative day 1 (16 [14-23] vs 30 [24-35]; P < .0001). Less opioids were needed in the magnesium group in the PACU (mean ± standard deviation [SD] [99% CI], 4.7 ± 10 [1-9] mg vs 29 ± 21 [21-37] mg; P < .0001) and on postoperative day 1 (1 ± 3.7 [0-2.5] mg vs 13 ± 23 [4-23] mg; P = .0009). Pain scores were lower in the magnesium group in the PACU (0 [0-3] vs 5 [5-7]; P < .0001) and on postoperative day 1 (0 [0-2] vs 4 [3-5]; P < .0001). CONCLUSIONS: Patients undergoing POEM randomized to receive intraoperative magnesium had sustained reductions in esophageal discomfort severity and opioid requirements 24 hours after surgery.

In symptomatic adults undergoing high-resolution manometry, long-term opioid use was linked to esophageal dysmotility.

SOURCE CITATION: Niu C, Zhang J, Bapaye J, et al. Systematic review with meta-analysis: chronic opioid use is associated with esophageal dysmotility in symptomatic patients. Am J Gastroenterol. 18 Aug 2023. [Epub ahead of print]. 37463432.

In patients with chronic neuropathic pain, cannabinoids improve sleep and reduce pain vs. placebo.

SOURCE CITATION: McParland AL, Bhatia A, Matelski J, et al. Evaluating the impact of cannabinoids on sleep health and pain in patients with chronic neuropathic pain: a systematic review and meta-analysis of randomized controlled trials. Reg Anesth Pain Med. 2022;48:180-190. 36598058.

Not Who You Are, But Who You Are With: Re-examining Women's Less Satisfying Sexual Debuts.

Gender differences in appraisals of first intercourse are among the largest in sexuality research, with women indicating less satisfying "sexual debuts" than men. Dispositional or "actor-level" explanations for this gender gap are pervasive, yet research has largely examined heterosexual debuts in which actor gender and partner gender are confounded. We assessed whether women's less satisfying sexual debuts are better explained by actor gender or partner gender, comparing experiences of women who debuted with men (WDM) with those of men and women who debuted with women (MDW, WDW). Retrospective accounts of sexual debut were collected from 3033 adults. At first intercourse, we found that WDW had equal physical and emotional satisfaction to MDW, and more satisfaction than WDM, suggesting satisfaction gaps owing to partner gender, not actor gender. This pattern did not extend to a comparison event (first masturbation), where WDW and WDM had similar satisfaction, but less satisfaction than MDW, suggesting an actor gender gap. To identify sources of satisfaction gaps, we probed for corresponding differences in the circumstances of sexual debut. Sexual circumstances were more strongly implicated than nonsexual ones, with relative deprivation of glans stimulation explaining relative dissatisfaction at first intercourse, but not first masturbation, and orgasm explaining it at both. Findings challenge the view that the satisfaction gap at first intercourse reflects an inherent difference between genders. Indeed, they demonstrate similarities when partner gender does not differ and suggest strategies for ensuring equal sexual satisfaction-and equal sexual rights realization-at (hetero) sexual debut.

Machine learning uncovers the most robust self-report predictors of relationship quality across 43 longitudinal couples studies.

Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner's ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person's own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships.

Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy.

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was the first immune checkpoint inhibitor approved by the FDA to treat metastatic melanoma patients. Multiple preclinical studies have proposed that Fc effector functions of anti-CTLA-4 therapy are required for anti-tumor efficacy, in part, through the depletion of intratumoral regulatory T cells (Tregs). However, the contribution of the Fc-independent functions of anti-CTLA-4 antibodies to the observed efficacy is not fully understood. H11, a non-Fc-containing single-domain antibody (VHH) against CTLA-4, has previously been demonstrated to block CTLA-4-ligand interaction. However, in vivo studies demonstrated lack of anti-tumor efficacy with H11 treatment. Here, we show that a half-life extended H11 (H11-HLE), despite the lack of Fc effector functions, induced potent anti-tumor efficacy in mouse syngeneic tumor models. In addition, a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. Thus, we demonstrate that Fc-independent functions of anti-CTLA-4 antibodies contributed to anti-tumor efficacy, which may indicate that non-Treg depleting activity of anti-CTLA-4 therapy could benefit cancer patients in the clinic.

Clinical and Radiologic Response of Central Giant Cell Granuloma to Denosumab: A 6-Year Prospective Observational Study.

Central giant cell granuloma (CGCG) is a rare lesion of the jaw occurring in young adults and adolescents. Surgery, the traditional mainstay of therapy, is associated with significant morbidity. Denosumab, a humanised monoclonal antibody to RANKL, is effective in a related entity, giant cell tumour of bone (GCTB), but experience in the more indolent CGCG is limited. This prospective observational study of all denosumab-treated CGCG at a tertiary referral centre (2015-2021) aimed to evaluate the safety, efficacy and recurrence risk using denosumab in CGCG at lower-frequency dosing than used for GCTB. All received standardised, time-limited courses of denosumab 120 mg with stepwise increase in dosing interval based on response. They were followed for up to 75 months using a radiation-minimising protocol: 3-monthly clinical, biochemical and radiological assessment (orthopantomograms, cone beam CT). Eight patients, median age 20.5 years [IQR 6], received 13 initial doses [IQR 10] of denosumab 120 mg. Radiologic response was seen after 5.5 doses [IQR 4.5]: ossification in all and size reduction in three. Recurrence occurred in four of seven completing therapy, observed 12 months post-cessation [IQR 6.5]. Larger baseline size, aggressive subtype and fewer than 12 initial doses were more common in the recurrence group. There was no osteonecrosis of the jaw. Hypocalcaemia occurred in one receiving modified dosing. This study represents the largest, most diverse cohort of denosumab-treated CGCG with the longest follow-up in literature. It demonstrates the efficacy of lower-frequency, time-restricted course of denosumab but highlights the risk of recurrence. Long-term follow-up is critical.

PEDF, a pleiotropic WTC-LI biomarker: Machine learning biomarker identification and validation.

Biomarkers predict World Trade Center-Lung Injury (WTC-LI); however, there remains unaddressed multicollinearity in our serum cytokines, chemokines, and high-throughput platform datasets used to phenotype WTC-disease. To address this concern, we used automated, machine-learning, high-dimensional data pruning, and validated identified biomarkers. The parent cohort consisted of male, never-smoking firefighters with WTC-LI (FEV1, %Pred< lower limit of normal (LLN); n = 100) and controls (n = 127) and had their biomarkers assessed. Cases and controls (n = 15/group) underwent untargeted metabolomics, then feature selection performed on metabolites, cytokines, chemokines, and clinical data. Cytokines, chemokines, and clinical biomarkers were validated in the non-overlapping parent-cohort via binary logistic regression with 5-fold cross validation. Random forests of metabolites (n = 580), clinical biomarkers (n = 5), and previously assayed cytokines, chemokines (n = 106) identified that the top 5% of biomarkers important to class separation included pigment epithelium-derived factor (PEDF), macrophage derived chemokine (MDC), systolic blood pressure, macrophage inflammatory protein-4 (MIP-4), growth-regulated oncogene protein (GRO), monocyte chemoattractant protein-1 (MCP-1), apolipoprotein-AII (Apo-AII), cell membrane metabolites (sphingolipids, phospholipids), and branched-chain amino acids. Validated models via confounder-adjusted (age on 9/11, BMI, exposure, and pre-9/11 FEV1, %Pred) binary logistic regression had AUCROC [0.90(0.84-0.96)]. Decreased PEDF and MIP-4, and increased Apo-AII were associated with increased odds of WTC-LI. Increased GRO, MCP-1, and simultaneously decreased MDC were associated with decreased odds of WTC-LI. In conclusion, automated data pruning identified novel WTC-LI biomarkers; performance was validated in an independent cohort. One biomarker-PEDF, an antiangiogenic agent-is a novel, predictive biomarker of particulate-matter-related lung disease. Other biomarkers-GRO, MCP-1, MDC, MIP-4-reveal immune cell involvement in WTC-LI pathogenesis. Findings of our automated biomarker identification warrant further investigation into these potential pharmacotherapy targets.

Perceptual Accuracy for Sexual Rejection in Romantic Relationships.

In the current research, we investigated perceptual accuracy in romantic partners' detection of sexual rejection. In two daily diary studies of predominantly cisgender heterosexual couples, we examined patterns of accuracy and bias concerning both the degree of sexual disinterest (Study 1; N = 98 couples) and occurrence of sexual rejection (Study 2; N = 115 couples), as well as how these perceptions were associated with satisfaction. Using a multi-method approach to capture both continuous and categorical operationalizations of sexual rejection (Study 1: truth and bias; Study 2: quasi-signal detection), we found that people were both accurate and biased in their perceptions of partner rejection. Across studies, results showed that people demonstrated general tracking accuracy in detecting a partner's sexual rejection, but they also overestimated the degree and occurrence of this rejection. Additionally, this overestimation bias was associated with lower daily relationship and sexual satisfaction. Overall, our findings highlight the importance of dyadic perceptions of sexual rejection in shaping daily relationship and sexual functioning.

A Longitudinal Investigation of Couples' Sexual Growth and Destiny Beliefs in the Transition to Parenthood.

Beliefs about sexuality tend to become more salient during sexual challenges and are associated with how individuals respond to these difficulties and, in turn, their sexual well-being. The transition to parenthood is marked by significant changes to couples' sexuality. As such, this period of vulnerability may be an important context in which these beliefs impact how couples manage sexual stressors and may have implications for their sexual well-being. In a longitudinal dyadic study, we examined whether couples' sexual growth beliefs (e.g., beliefs that sexual problems can be resolved through effort) and sexual destiny beliefs (e.g., beliefs that sexual problems reflect incompatibility with their partner) correspond with changes to various facets of couples' sexual well-being over time. First-time parent couples (N = 203) completed online surveys assessing these beliefs in pregnancy (32 weeks) and measures of sexual well-being (satisfaction, desire, and distress) in pregnancy (20 and 32 weeks) and across the postpartum period (3, 6, 9, 12 months). Dyadic latent growth curve models showed that expectant mothers who reported stronger sexual destiny beliefs in pregnancy reported higher sexual distress and lower sexual satisfaction at 3 months postpartum. When partners reported stronger sexual destiny beliefs in pregnancy, both they and new mothers reported greater sexual desire at 3 months postpartum. Unexpectedly, partners' higher sexual growth beliefs in pregnancy predicted mothers' lower sexual desire at 3 months postpartum. Sexual growth and destiny beliefs were not associated with change in couples' sexual well-being beyond 3 months postpartum. Findings shed light on the potential benefits and costs of sexual growth and destiny beliefs for couples' sexual well-being early in the postpartum period, but not over time.

Preoperative epidural steroid injections do not increase the risk of postoperative infection in patients undergoing lumbar decompression or fusion: a systematic review and meta-analysis.

PURPOSE: Epidural corticosteroid injections (ESI) are a mainstay of nonoperative treatment for patients with lumbar spine pathology. Recent literature evaluating infection risk following ESI after elective orthopedic surgery has produced conflicting evidence. Our primary objective was to review the literature and provide a larger meta-analysis analyzing the temporal effects of steroid injections on the risk of infection following lumbar spine surgery. METHODS: We conducted a query of the PubMed, Embase, and Scopus databases from inception until April 1, 2022 for studies evaluating the risk of infection in the setting of prior spinal steroid injections in patients undergoing lumbar spine decompression or fusion. Three meta-analyses were conducted, (1) comparing ESI within 30-days of surgery to control, (2) comparing ESI within 30-days to ESI between 1 and 3 months preoperatively, and (3) comparing any history of ESI prior to surgery to control. Tests of proportions were utilized for all comparisons between groups. Study heterogeneity was assessed via forest plots, and publication bias was assessed quantiatively via funnel plots and qualitatively with the Newcastle-Ottawa Scale. RESULTS: Nine total studies were included, five of which demonstrated an association between ESI and postoperative infection, while four found no association. Comparison of weighted means demonstrated no significant difference in infection rates between the 30-days ESI group and control group (2.67% vs. 1.69%, p = 0.144), 30-days ESI group and the > 30-days ESI group (2.34% vs. 1.66%, p = 0.1655), or total ESI group and the control group (1.99% vs. 1.70%, p = 0.544). Heterogeneity was low for all comparisons following sensitivity analyses. CONCLUSION: Current evidence does not implicate preoperative ESI in postoperative infection rates following lumbar fusion or decompression. Operative treatment should not be delayed due to preoperative steroid injections based on current evidence. There remains a paucity of high-quality data in the literature evaluating the impact of preoperative ESI on postoperative infection rates. LEVEL OF EVIDENCE: II.

Use of ICG Angiography in Head and Neck Reconstruction With the Supraclavicular Artery Island Flap.

PURPOSE: Adequate distal skin paddle perfusion is essential to preventing postoperative flap necrosis in head and neck reconstruction. To describe the use of indocyanine green angiography (ICGA), to assess skin paddle perfusion in the setting of head and neck reconstruction with the supraclavicular artery island flap at a single institution and assess the effect of ICGA use on the rate of postoperative skin paddle necrosis. METHODS: A retrospective cohort study consistently of patients who underwent head and neck reconstruction with a supraclavicular artery island flap for any indication at a tertiary medical center from 2010 to 2018. The predictor variable was ICGA use. The primary outcome was rate of skin paddle necrosis. Secondary outcomes included rates of post-operative overall complications, dehiscence, fistula, and reoperation. Covariates included demographic, operative, flap perfusion assessment, and postoperative variables. Retrospective assessment of distal flap perfusion was performed on available ICGA video recordings. Descriptive and bivariate statistics were computed. Statistical significance was set at P ≤ .05. RESULTS: A total of 104 patients were included and ICGA was used in 23 cases. In 10 of these cases, flap trimming was performed due to concern of flap hypoperfusion on ICGA. The median relative distal flap perfusion was 16.7 ± 2.6% in trimmed flaps, compared to 35 ± 13.2% in untrimmed flaps. ICGA use was not associated with rate of skin paddle necrosis (P = .76). CONCLUSIONS: ICGA is a viable method of assessing intraoperative supraclavicular artery island skin paddle perfusion and can help determine the need for distal flap trimming when tissue viability based on clinical findings alone is uncertain. ICGA use for skin paddles with uncertain perfusion on intraoperative clinical findings prevented a potential increase in postoperative necrosis compared to that of skin paddles with adequate perfusion on intraoperative clinical findings. Future studies are required to determine the minimum distal perfusion value that indicates hypoperfusion and the need for flap modification.

Physician satisfaction with telemedicine and in-person visits in otolaryngology.

OBJECTIVES: To investigate the differential factors associated with physician satisfaction between telemedicine and in-person visits in otolaryngology. METHODS: Study data included 646 telemedicine and 365 in-person encounters delivered from May-June 2020 at a tertiary center outpatient setting. Encounter-specific physician satisfaction was rated by 15 otolaryngologists using Provider Satisfaction Questionnaire (range 0-100) consisted of 5 items (patient needs addressed, patient involvement, adequacy of information given, quality of emotion support provided, and general interaction satisfaction). A multivariable linear mixed-effects model was used to explore patient demographic and clinical factors associated with physician satisfaction. RESULTS: Physician satisfaction scores for telemedicine and in-person visits were 83.0 [95 % CI: 77.0-88.9] and 88.1 [95 % CI: 82.5-93.6], respectively. Among telemedicine visits, physician satisfaction scores were significantly higher for follow-up (vs. new), videoconference (vs. telephone) encounters, and English-speaking patients in a multivariable model. New encounters had significantly lower satisfaction subdomain scores for adequacy of information given to the patient (ß = -4.7 [95 % CI: -7.3 to -2.0], p = 0.001) and addressing the needs of the patient among telemedicine visits (ß = -4.1, [95 % CI: -7.1 to -1.1], p = 0.007) while there were no differences in satisfaction scores between new vs follow-up visits among in-person visits. For non-English speaking patients, the physician satisfaction scores were significantly lower for subdomain scores assessing active patient participation (ß = -13.1, [95 % CI: -13.1 to -17.4], p < 0.001) and emotional support given to the patient (ß = -7.8, [95 % CI: -11.0 to -4.5], p < 0.001) for telemedicine visits. CONCLUSIONS: Telemedicine has been broadly adopted as an alternative option to deliver care in otolaryngology since COVID-19 pandemic. Appropriate triaging based on patient and encounter characteristics may enhance physician satisfaction and overall experiences with telemedicine. Further efforts are needed to provide adequate interpretation and videoconference services during telemedicine visits.

Stereoselective fatty acylation is essential for the release of lipidated WNT proteins from the acyltransferase Porcupine (PORCN).

The maintenance of adult animal tissues depends upon highly conserved intercellular signaling molecules that include the secreted WNT proteins. Although it is generally accepted that lipidation of WNTs by the acyltransferase Porcupine (PORCN) and their subsequent recognition by the Wntless (WLS) protein is essential for their cellular secretion, the molecular understanding of this process remains limited. Using structurally diverse fatty acyl donor analogs and mouse embryonic fibroblasts expressing PORCN protein from different metazoan phyla, we demonstrate here that PORCN active-site features, which are conserved across the animal kingdom, enforce cis-Δ9 fatty acylation of WNTs. Aberrant acylation of a WNT with an exogenously supplied trans-Δ9 fatty acid induced the accumulation of WNT-PORCN complexes, suggesting that the fatty acyl species is critical for the extrication of lipidated WNTs from PORCN. Our findings reveal a previously unrecognized fatty acyl-selective checkpoint in the manufacturing of a lipoprotein that forms a basis for WNT signaling sensitivity to trans fats and to PORCN inhibitors in clinical development.

Quantification of the Mean and Distribution of Hemoglobin Content in Normal Human Blood Using Cell Tracking Velocimetry.

The current clinical method for detecting anemia focuses on measuring the concentration of hemoglobin (Hb) in blood. However, recent developments in particle tracking algorithms and the understanding of the relationship between Hb and magnetism has enabled the quantitative measurement of the Hb content in a single red blood cell, RBC, based on magnetophoretic mobility. To further explore this relationship, 22 human blood samples obtained from 17 healthy volunteers were analyzed by the cell tracking velocimetry system, and the calculated Hb concentration from these measurements was compared to the values measured by UV-visible spectrophotometry, the standard method for measuring Hb in clinical laboratories. The results show close correlations between the mean of the spectrophotometric and magnetophoretic methods; however, single cell analysis with the magnetophoretic mobility method allows further elucidation of the distribution of Hb concentration within RBCs from a donor sample to be determined. Histograms of these magnetophoretic mobility distributions indicate that the fraction of RBCs that are below the bulk Hb concentration that defines anemia varies not only from donor to donor but also in the same donor over time. Consistent with a variable fraction below the anemic Hb concentration, the distribution around the mean has a large range. Previous studies have indicated that RBCs lose Hb during ex vivo storage; however, it is not known if this variability in the distribution of Hb content is a function of the age of the RBCs in a donor, suggesting a variable rate in RBC production between donors, or variability in available iron at the time of RBC formation. We suggest our cell tracking velocimetry system can reveal more information regarding this matter.

Gastric Dilatation Organoaxial Volvulus in a Dog.

A 9 yr old castrated male mixed-breed dog was presented for acute vomiting. Abdominal radiographs appeared to show a normal positioned stomach with marked gas dilation, which persisted despite frequent suctioning with a nasogastric tube. An abdominal ultrasound showed splenomegaly, malpositioning of the spleen, and the pyloroduodenal junction. A ventral midline celiotomy revealed an organoaxial gastric volvulus, rotating on the gastroesophageal, and pyloroduodenal junctions. The omentum was not overlying the stomach, typically seen in mesenteroaxial gastric volvulus. The body of the stomach was derotated with no evidence of gastric necrosis noted. The spleen was in the right cranial abdomen and returned to its normal anatomic position after derotation of the stomach. The patient recovered uneventfully and was discharged the next day. To the authors' knowledge, organoaxial gastric volvulus has not been reported in dogs. This is rare in humans but occurs most commonly in children <5 yr of age associated with hernias. The recommended treatment is surgical in majority of cases. As a result of the unusual orientation of the stomach, the diagnosis of gastric dilatation-volvulus was challenging. Organoaxial gastric volvulus demonstrates the need for further imaging and evaluation in cases of persistent gas dilation.

Acute Effects of Gastrocnemius/Soleus Self-Myofascial Release Versus Dynamic Stretching on Closed-Chain Dorsiflexion.

CONTEXT: Limited ankle dorsiflexion (DF) range of motion has been correlated with decreased flexibility of the gastrocnemius/soleus complex. Decreased ankle DF range of motion can lead to an increase in lower-extremity injuries, for example, acute ankle sprains, Achilles tendinopathy. OBJECTIVE: The purpose of this study was to determine whether a single application of the intervention to the gastrocnemius/soleus complex via multidirectional self-myofascial release using a foam roller, multiplanar dynamic stretch performed in downward dog, or a combination of both techniques acutely improved ankle DF. DESIGN: Subjects were assigned to groups via random card selection. Investigators provided verbal cues as needed to yield correct performance of interventions. Both interventions were performed twice for 1 minute using a dynamic walking rest of 30.48 m at a self-selected pace between interventions. Statistical analyses were completed using a 1-way analysis of variance, at α level ≤ .05. SETTING: A convenience sample study. PARTICIPANTS: A total of 42 asymptomatic physical therapy students (18 females and 24 males) with mean age of 26.12 (4.03) years volunteered to participate. INTERVENTIONS: Multidirectional self-myofascial release using a foam roller, multiplanar dynamic stretch performed in downward dog, or a combination of both techniques. MAIN OUTCOME MEASURES: Weight-bearing right ankle DF measurements were recorded in centimeters using a forward lunge technique (intraclass correlation coefficient = .98, .97, and .96). RESULTS: Data analysis revealed no significant difference between the 3 groups in all pre-post measurements (P = .82). Mean (SD) measurements from pretest to posttest for myofascial release, dynamic stretching, and combination interventions were 0.479 (0.7) cm, 0.700 (0.7) cm, and 0.907 (1.4) cm, respectively. CONCLUSION: Until further studies are conducted, the selection of technique to increase ankle DF range of motion should be based on each individual patient's ability, preference, and response to treatment.

Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving.

In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self-administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor-mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal.SIGNIFICANCE STATEMENT Here, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug-induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse.