ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease.

Patients with corticosteroid-refractory acute graft-versus-host disease (aGVHD) have a low one-year survival rate. Identification and validation of novel targetable kinases in patients who experience corticosteroid-refractory-aGVHD may help improve outcomes. Kinase-specific proteomics of leukocytes from patients with corticosteroid-refractory-GVHD identified rho kinase type 1 (ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histological GVHD severity in mice and was synergistic with JAK1/2 inhibition, without compromising graft-versus-leukemia-effects. ROCK1/2-inhibition in macrophages or dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with CD80, CD86, MHC-II expression and IL-6, IL-1ß, iNOS and TNF production in myeloid cells. This was accompanied by impaired T cell activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and DC migration. NF-κB signaling was reduced in myeloid cells following ROCK1/2 inhibition. In conclusion, ROCK1/2 inhibition interferes with immune activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings.

Increased rate of enteric bacteria as cause of periprosthetic joint infections in patients with liver cirrhosis.

INTRODUCTION: Periprosthetic joint infections (PJI) are a major complication in joint-arthroplasty. Rifampicin is often used as an additional agent to treat PJI, because it penetrates bacterial biofilms. However, rifaximin, belonging to the same antibiotic class as rifampicin, is frequently used to prevent episodes of hepatic encephalopathy in patients with cirrhosis and may induce resistance to rifampicin. The aim of this study was to examine the microbial pattern of periprosthetic joint infections in cirrhotic patients and to test the hypothesis that intake of rifaximin increases the rate of resistance to rifampicin in periprosthetic joint infections. METHODS: A cohort of cirrhotic patients and PJI (n = 25) was analysed on the characteristics of bacterial isolates from sonication and tissue analysis. In a second step a subgroup analysis on the development of rifampicin resistant bacterial specimens, depending on the intake of rifaximin (8 rifaximin intake patients vs. 13 non rifaximin intake patients) was performed. RESULTS: Intestinal bacteria were found in 50% of the specimens, which was significantly more frequent than in a control cohort. By comparison of the single bacterial isolates, rifampicin resistance was detected in 69.2% (9/13) of the rifaximin-intake samples. In contrast, the non-rifaximin-intake isolates only were resistant to rifampicin in 22.2% (4/18) of the cases (p = 0.01). The odds ratio for developing a rifampicin-resistance through rifaximin intake was calculated as OR = 13.5. CONCLUSION: Periprosthetic joint infections have a high incidence of being caused by enteric bacteria in cirrhotic patients. Due to this change in microbial pattern and the innate resistance to rifampicin of most of gram-negative bacteria, the therapy with rifampicin should be carefully considered. The association between the use of rifaximin and developed resistance to rifampicin has a major impact on the treatment of PJI.

Superior Ophthalmic Vein Thrombosis Induced by Orbital Cellulitis: An Ophthalmic Emergency.

Superior ophthalmic vein thrombosis (SOVT) is a rare ophthalmologic emergency. The most common etiologies include infection, trauma, inflammation, and malignancy, as well as thyroid-related orbitopathy. Early identification and timely intervention can lead to a significant decrease in complications that include cavernous sinus thrombosis (CST), vision loss, and death. This rare disease entity almost always makes its initial presentation to internal medicine or emergency medicine (EM) physicians. In this report, we present a case of SOVT that presented overnight to the emergency department for worsening right facial swelling and orbital pain. We discuss our experience with the evaluation and management of SOVT and provide a review of the currently available literature to emphasize the importance of obtaining a full history and physical examination, seeking early imaging studies, and ophthalmology consultation for patients with suspected SOVT.

The Abnormal Sinus Rhythm: Myxedema Coma Complicated by Subacute Cardiac Tamponade.

Subacute cardiac tamponade (SCT) is a potentially life-threatening condition that requires immediate medical attention. Combining careful history taking, focused physical exam, and the use of point of care ultrasound (POCUS) for early diagnosis with aggressive management can minimize potential complications. In patients with severe hypothyroidism and myxedema coma, clinical signs of cardiac tamponade may be masked and lead to delayed diagnosis. We present a case of a 67-year-old female with SCT secondary to myxedema coma, necessitating emergent pericardiocentesis following the identification of a large pericardial effusion with tamponade physiology. This case highlights the importance of thorough history taking with focused diagnostic workup, including POCUS in patients with an insidious presentation of SCT.

For Residents, by Residents: Developing a Physician Handoff Tool at a University Affiliated Community Hospital.

The 80-hour per week work limit resulted in an increased number of patient handoffs. A satisfactory handoff system should optimize the exchange of vital patient information while concisely minimizing error. This project describes our experience and lessons learned in successfully developing and implementing an Electronic Health Record (EHR)-integrated handoff system based on the I-PASS model. The handoff system, termed Physician Handoff, was refined through end-user feedback. End-users were evaluated on the quality of handoff in the following categories: Illness Severity, Patient Summary, Action List, and Situational Awareness. Resulting survey showed high adoption and satisfaction rate with Physician Handoff. Success can be attributed to interdepartmental collaboration, credentialing the users, and recognizing the importance of end-user feedback.

Suppression of CMV Infection with Letermovir in a Kidney Transplant Patient.

Infection with cytomegalovirus (CMV) with resistance to ganciclovir (GCV) is a therapeutic challenge in kidney transplant patients, because standard treatment options are nephrotoxic. We report the case of a kidney transplant recipient with GCV-resistant CMV disease, in whom letermovir, a novel inhibitor of CMV packaging, was administered off-label and prevented a relapse of disease once the CMV load was decreased by cidofovir. Furthermore, we observed significant drug interactions between letermovir and tacrolimus. LEARNING POINTS: Cytomegalovirus (CMV) disease with resistance to ganciclovir (GCV) is difficult to manage in transplant patients.Letermovir may become a new option for treatment and prophylaxis of GCV-resistant CMV infection, but assessment of treatment response is difficult.Letermovir may lead to drug interactions via CYP3A4.

Novel Coronavirus-Induced Right Ventricular Failure and Point of Care Echocardiography: A Case Report.

Various cardiovascular complications have been reported in patients with coronavirus disease 2019. Common complications include acute myocardial injury, myocarditis, arrhythmia, pericarditis, heart failure, and shock. We present a case of cor pulmonale diagnosed with serial point of care ultrasound. Given the current shortage of personal protective equipment (PPE) and high infectivity of this virus, we acknowledge the utility of this tool in obtaining important clinical information while minimizing exposure and PPE consumption.

Retention of a standard operating procedure under the influence of social stress and refresher training in a simulated process control task.

In a simulated process control task, we investigated the effects of refresher training and acute social stress on performing a standard operating procedure (SOP) containing a production and monitoring task and knowledge recall after a retention interval of two weeks. In a 2 × 2 between-group design (Factor 1: induced social stress, Factor 2: refresher training), 76 engineering students performed an SOP at t1 in week 1 and at t2 in week 3. A MANOVA in week three (t2) indicated a main effect of the refresher training for the SOP execution containing a production and a monitoring task and an impairing effect of stress on the monitoring task. That means that after a retention interval, stress mainly affects the SOP's monitoring task. An additional correlational analysis showed that knowledge test performance is negatively associated with cortisol level and that retentivity is a strong predictor for knowledge test performance and production task performance, too. Practitioner Summary: We investigated effects of social stress and refresher training on performing a standard operating procedure (SOP) after a retention interval of two weeks. The impact of social stress reduced the monitoring task performance as part of the SOP, but not the production outcome. Without refresher training, performance is significantly worse. Abbreviation: SOP: Standard Operating Procedure; MANOVA: Multivariate Analysis of Variance; CSB: Chemical Safety and Hazard Investigation Board; TSST: Trierer Social Stress Test; P-TSST: Placebo Trierer Social Stress Test; WaTrSim: Water Treatment Simulation; HPA axis: hypothalamic pituitary adrenal axis; WIT-2: Wilde Intelligenztest - 2; SPSS: Statistical Package for the Social Sciences; ANOVA: Analysis of Variance.

Pre-encoding stress induced changes in perceived stress, blood pressure and cortisol are differentially associated with recollection and familiarity.

Stress before encoding is often linked to impaired memory. Further influences of stress on memory are arousal of the to be learned material and memory retrieval type (free recall vs. recognition). In the current study we tested the influence of stress on memory encoding for neutral and negative arousing pictures in healthy young adults. A total of 80 participants (40 men) were subjected either to the socially evaluated cold pressure test or a control condition before encoding of arousing and neutral pictures. One day later participants underwent a recognition test. Results show different relationships between the obtained stress markers and recognition memory. Higher perceived stress ratings predicted poorer overall accuracy for arousing material. Lower perceived stress ratings and larger blood pressure increase predicted higher recollection values for arousing material. In contrast, a larger cortisol increase predicted lower familiarity values for arousing material. Concluding, activity of the sympathetic nervous system (SNS) and a lower feeling of perceived stress predict better recollection. HPA axis activity predicts lower familiarity. Pre-encoding induced changes in the perceived feeling of stress, activity of the SNS, and activity of the HPA axis show specific and distinct relationships to recognition memory.

Public speaking in front of an unreceptive audience increases implicit power motivation and its endocrine arousal signature.

The present study explored the motivational characteristics of the Trier Social Stress Test (TSST; Kirschbaum, Pirke, & Hellhammer, 1993). Seventy-two participants either completed the public-speaking component of the TSST or, as a control condition, the friendly TSST (Wiemers, Schoofs, & Wolf, 2013) and wrote picture stories both before and after treatment. Stories were coded for motivational imagery related to power, achievement, and affiliation as well as for activity inhibition, a marker of functional brain lateralization during stress. The TSST had a specific arousing effect on power motivation, but not on other motivational needs, on activity inhibition, or on story length. TSST-elicited increases in power imagery, but not in achievement or affiliation imagery, were associated with a relatively greater salivary alpha-amylase response and with a relatively lesser salivary cortisol response. These findings suggest that the TSST specifically induces power-related stress.

Cortisol broadens memory of a non-stressful social interaction.

RATIONALE: Stress and its associated hormonal cascade are known to enhance long-term memory consolidation. Recently we have shown that central details of a stressful situation (Trier Social Stress Test; TSST) are remembered better than central details of a similar but non-stressful control condition (friendly Trier Social Stress Test; fTSST). We reasoned that since cortisol concentrations increase during stress (TSST) but remain low during the control condition (fTSST), a pharmacological increase in cortisol during the fTSST might be able to mimic the stress effects observed previously. OBJECTIVE: The objective of the study was to assess the impact of a pharmacologically induced cortisol increase during the non-stressful friendly TSST on long-term memory for details presented during this event. METHODS: In a double-blind between-group design, participants (final sample: 20 men and 13 women) either received hydrocortisone (20 mg) or a placebo and were then exposed to a non-stressful social interaction (fTSST). Affect, salivary cortisol, and salivary alpha-amylase (sAA) were assessed before and after the fTSST. Recognition memory for objects presented during this situation was assessed 1 day later. RESULTS: Positive affect and sAA increased in response to the friendly TSST in both groups. Hydrocortisone enhanced memory for peripheral objects of the situation in men but not in women. Memory for central objects was not affected by the hormone. CONCLUSIONS: The results suggest that in a non-stressful positive social environment, cortisol induces a broadening rather than a narrowing of memory. In addition, the findings provide preliminary evidence that this effect might be more prominent in men.

Odors as effective retrieval cues for stressful episodes.

Olfactory information seems to play a special role in memory due to the fast and direct processing of olfactory information in limbic areas like the amygdala and the hippocampus. This has led to the assumption that odors can serve as effective retrieval cues for autobiographic memories, especially emotional memories. The current study sought to investigate whether an olfactory cue can serve as an effective retrieval cue for memories of a stressful episode. A total of 95 participants were exposed to a psychosocial stressor or a well matching but not stressful control condition. During both conditions were visual objects present, either bound to the situation (central objects) or not (peripheral objects). Additionally, an ambient odor was present during both conditions. The next day, participants engaged in an unexpected object recognition task either under the influence of the same odor as was present during encoding (congruent odor) or another odor (non-congruent odor). Results show that stressed participants show a better memory for all objects and especially for central visual objects if recognition took place under influence of the congruent odor. An olfactory cue thus indeed seems to be an effective retrieval cue for stressful memories.

Implicit need for achievement predicts attenuated cortisol responses to difficult tasks.

The present research tested the hypothesis that the implicit need for achievement (n Achievement) predicts attenuated cortisol (C) responses to difficult tasks, because it represents a propensity to view difficulty as a cue to mastery reward. In two studies, n Achievement was assessed through content-coding of imaginative stories and salivary C was assessed both at baseline and post-task. In Study 1 (N = 108 US students), n Achievement predicted an attenuated C response to a one-on-one competition in the laboratory, regardless of whether participants won or lost. In Study 2 (N = 62 German students), n Achievement predicted an attenuated C response to the Trier Social Stress Test (Kirschbaum, Pirke, & Hellhammer, 1993), but not to a non-stressful control task. In Study 2 only, the attenuating effect of n Achievement was moderated by gender, with only men showing the effect. Across both studies, the average effect size of the association between n Achievement and C responses to difficult tasks was r = -.28. These findings point to a role of n Achievement in emotion regulation.

What we remember from a stressful episode.

A stressful episode is thought to be consolidated better because of a stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis. However, human experimental studies addressing this hypothesis directly are lacking. Thus, we investigated memories of the stressful episode itself. Furthermore, we aimed to determine the influence of stress on recollection and familiarity processes. Participants (n=63) were subjected to a psychosocial stressor (Trier Social Stress Test, TSST) or a newly developed non-stressful control condition (friendly-TSST). During both conditions, they were exposed to a committee and visual stimuli, either bound to the situation (central) or not (peripheral). The next day, participants engaged in unexpected recognition tasks. Negative affect and salivary cortisol concentration increased in stressed but not in control participants. The following day, stressed participants recognized central objects and the committees' faces better than control participants. Furthermore, recollection contributed significantly more to memory performance in stressed than in control participants. Our findings are congruent with the idea of enhanced memory binding under stress combined with enhanced memory consolidation of information acquired during stress. What we remember from a stressful episode appears to be determined by the strength of the association between the stressor and the material to be remembered.

A friendly version of the trier social stress test does not activate the HPA axis in healthy men and women.

The trier social stress test (TSST) is a well-established laboratory stressor leading to a robust activation of the hypothalamus-pituitary-adrenal (HPA) axis. Existing control conditions are often not adequate to investigate participants' behavior during the situation as participants are often left alone in the room. This present study aimed to evaluate a friendly version of the TSST as control condition, the friendly-TSST (f-TSST). We expected that the f-TSST would not activate the HPA axis or increase the negative affect (NA). Forty-eight healthy male and female students (24 males) aged between 18 and 30 years were randomly exposed to either the TSST or the f-TSST. The latter features a similar structure and similar cognitive demands as in the TSST, and a social interaction with a committee. The main difference lies in the friendly and warm behavior of the committee opposed to the neutral and reserved behavior in the TSST, typically inducing social-evaluative threat. Salivary cortisol, salivary α-amylase (sAA), and affect were measured to evaluate the stress response to the respective procedure. As expected, the f-TSST neither activated the HPA axis nor increased the NA. The TSST by contrast led to an increase in both measures. A comparable and significant increase in the sAA-concentrations occurred in both conditions. The f-TSST could be useful as a standardized control condition for future stress studies. On a conceptual level our data indicate that mere social performance in the absence of social-evaluative threat and performance pressure does not activate the HPA axis.

Hamatometacarpal fracture-dislocation: distinctive three dimensional computed tomographic appearance.

We report here two fully documented cases of hamatometacarpal fracture-dislocation following trauma and treated in our hospital. In our cases, the patients suffered hamate fracture in association with metacarpal dislocation. In the first case, a dorsal oblique fracture of the hamate was associated with a dorsal dislocation of the base of the fourth metacarpal. In the second case, a dorsal oblique fracture of the hamate was not associated with a dorsal dislocation of the base of the fifth metacarpal. This diagnosis should be suspected on initial review of plain radiographs, which must include an oblique view because of diagnostic difficulty for this injury. We recommend three dimensional computed tomography (3D-CT) in any patient presenting with pain after blunt trauma to the hand to prevent in diagnosis. Open reduction and internal fixation of the fracture is indicated and relevant for displaced fracture.

Lunatomalacia in association with congenital synostosis between the capitate and the hamate.

This report describes a case of lunatomalacia associated with congenital synostosis between the capitate and the hamate, an association not previously reported. The case was examined in detail, and compared to the findings in the literature including observation regarding prognosis of lunatomalacia.

The initial fixation of the press-fit acetabular shell--clinical observation and experimental study.

The initial solid fixation of an uncemented acetabular component affects the amount of bone ingrowth. We had several problems with broken screws in cases of acetabular revision. In recent years, the development of uncemented components without screws has attempted to improve these problems. We started to use "press-fit"-type acetabular shells in November 1996. Our thirty cases undergoing 2 mm under-reaming show good initial stability. The aim of our biomechanical study was to assess the most suitable degree of under-reaming of the bony acetabulum for the implantation of an uncemented hemispherical porous coated component.

The relationship between postoperative results and bone dynamics in RA patients who underwent cementless Ortholoc II TKA: histomorphometric study.

Abstract We previously reported a histomorphometric study of iliac bone obtained at the time of cementless total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA). In this paper, we further extended our analysis to investigate the postoperative results and radiographs after TKA in association with bone metabolism. All the patients were female, ranging in age from 38 to 68 years (mean, 56.8 years). Histomorphometric results demonstrated that bone volume and trabecular thickness were decreased, whereas bone absorption and bone formation rate (BFR) were increased. The bone in patients with mutilating disease (MUD) showed remarkably increased bone turnover and osteoporosis compared with those of the more erosive subset (MES) patients. Sixteen out of the 20 patients were alive at the time of follow-up (follow-up period between 5 years 10 months and 8 years 11 months). Among them, 10 patients could be further examined. Radiolucent lines (RLL) were assessed by the modified Knee Society evaluation (scoring) system. The number of RLL (N-RLL) were correlated with BFR in morphometric examination. In addition, the weight-bearing zones in the N-RLL were more significantly correlated with BFR. The Japanese Orthopedic Association (JOA) score and pain score negatively correlated with eroded bone surface. The present study indicated that bone dynamics, rather than the bone volume at the time of TKA, were involved in the presence of RLL and in pain after surgery for TKA.