Hand Therapy Regimen for Functional Recovery Following Combined Face and Bilateral Hand Transplantation.

Intensive postoperative rehabilitation therapy is associated with positive functional recovery in hand transplants (HTs). Our goal is to share the hand therapy protocol developed for our patient who underwent a combined face and bilateral HT. The patient is a 23-year-old right-hand-dominant male with a history of third-degree burns to 80% of his body following a motor vehicle accident. A multidisciplinary evaluation established his candidacy for a combined face and bilateral HT, and surgery took place in August 2020. Our individualized hand therapy protocol consisted of 4 phases. The pre-surgery phase focused on planning the orthotics and patient/caregivers' education on the rehabilitation process. The intensive care unit (ICU)/acute care phase involved hand allograft protection and positioning via orthotic fabrication, safe limb handling, and edema/wound management. The inpatient rehabilitation phase aimed to prepare the patient for independent living via neuromuscular and sensory re-education, improvement of upper extremities strength/flexibility, training basic activities of daily living, and providing a home exercise program (HEP). Finally, the outpatient phase aimed to maximize our patient's range of motion and independency in performing his routine activities and HEP. The patient's post-transplant functional outcomes showed a significant improvement compared to the pre-operative baseline. We hope this report sheds light on a comprehensive hand therapy program in HT.

Scheduling practices for pregnant emergency medicine residents.

Background: Night shift work is associated with adverse pathophysiologic effects on maternal and fetal well-being. Although emergency medicine (EM) residents work frequent night shifts, there is no existing guidance for residency program directors (PDs) regarding scheduling pregnant residents. Our study assessed scheduling practices for pregnant EM residents, differences based on program and PD characteristics, barriers and attitudes toward implementing a formal scheduling policy, and PDs' awareness of literature describing adverse effects of night shifts on maternal-fetal outcomes. Methods: We conducted an anonymous, web-based survey of U.S. EM residencies (N = 276). Quantitative data were summarized; chi-square analysis and logistic regression were used to assess relationships between program and PD characteristics and schedule accommodations. Qualitative description was used to analyze an open-ended question, organizing findings into major and minor themes. Results: Of the 167 completed surveys (response rate 61%), 67% of programs reported no formal policy for scheduling pregnant residents but made adjustments on an individual basis including block changes (85%), decreased (46%) or no night shifts (34%), and working shifts earlier in pregnancy to cover later shifts (20%). Barriers to adjustments included staffing constraints (60%), equity concerns (45%), or impact on wellness (41%) among all residents and privacy (28%). PDs endorsed scheduling adjustments as important (mean 8.1, 0-10 scale) and reported guidance from graduate medical education governance would be useful (60%). Larger program size, but not PD gender or proportion of female residents, was associated with an increased likelihood of scheduling modifications. Twenty-five percent of PDs reported little knowledge of literature regarding night shift work and pregnancy. Qualitative themes supported quantitative findings. Conclusions: Most EM residency programs do not have formal scheduling policies for pregnant residents, but most PDs support making adjustments and do so informally. More education and guidance for PDs are needed to promote the development of formal policies.

Generational 'othering': The myth of the Millennial learner.

CONTEXT: The health professions education (HPE) literature is replete with recommendations for how educators should adapt practices to the needs of generations of learners using generation theory to bridge perceived differences between learners and educators. Yet the evidence supporting the application of generation theory in HPE has not been critically examined. If unsubstantiated, these applications may perpetuate biases towards learners they are intended to support. METHODS: This paper critically reviews generation theory in the HPE literature, with particular focus on recent recommendations regarding "Millennial" learners. We used Google Scholar, MEDLINE, EBSCO, JSTOR and PsycINFO to search for articles pertaining to the origins and uses of generation theory within and outside HPE. This synthesis is presented as a preliminary understanding of how ideas of generation theory arose and permeated the HPE literature, and explores the effects of generation theory on education practices. RESULTS: In the HPE literature, the translation of generation theory into practice recommendations generally follows a pattern consistent with translations advanced in other literatures: broad generalisations drawn from limited data are used as evidence to support instructional approaches specifically designed for generational cohorts. Outside HPE, this application of generation theory has been criticised as a form of stereotyping that ignores the internal differences and diversity inherent in any large group of people. Accordingly, problematising the needs of generations such as "Millennial" learners in the HPE literature may perpetuate narrow or privileged assumptions by educators. CONCLUSIONS: Generational archetypes such as that of the "Millennial learner" are myths that perpetuate unfounded generalisations about cohorts, reinforce power differentials between age groups, and minimise the unique needs of individuals. To individualise and strengthen teaching practices in HPE, we recommend adopting "generational humility" as a means to more purposefully address the dynamic social, cultural and historical influences that shape individuals within each generation of learners.

Development and Empirical Testing of a Novel Team Leadership Assessment Measure: A Pilot Study Using Simulated and Live Patient Encounters.

BACKGROUND: Team leadership is critical to health care resuscitation team performance. There has been increased focus on competency in team leadership behaviors; however, there is still variability in how team leadership is assessed within emergency medicine. The objective of this study was to develop and pilot a novel team leadership assessment measure for emergency medicine resuscitation teams. METHODS: Team leadership dimensions and associated behaviors were identified through a systematic literature review and expert consensus. Included behaviors were used to create behaviorally anchored rating scales, which were then revised based on subject matter expert ratings. Four raters from three different academic institutions observed 30 video-recorded resuscitations (20 simulated and 10 actual patient care resuscitations). Mean leadership scores were calculated. Intraclass coefficients (ICCs) were calculated for each item and for overall leadership scores. Leader scores for the simulation-based scenarios were compared to external variables including level of training, team process, clinical performance, and team situational awareness. The study was conducted from July 2017 through June 2018. RESULTS: Leadership scores ranged from 2.23 to 4.30 (mean [±SD] = 3.18 [±0.50]). The ICC for the overall score was 0.79 for all observations, 0.87 for simulation-based observations, and 0.24 for the patient care observations. Team leadership scores on simulation-based observations did not correlate with available external variables. CONCLUSIONS: We developed a novel team leadership assessment measure for emergency medicine resuscitation teams with supporting validity evidence, including content validity and response process. The measure demonstrated acceptable inter-rater reliability when applied to simulation-based medical resuscitations; however, this did not translate to trauma resuscitations in the actual patient care setting.

Detecting rare asymmetrically methylated cytosines and decoding methylation patterns in the honeybee genome.

Context-dependent gene expression in eukaryotes is controlled by several mechanisms including cytosine methylation that primarily occurs in the CG dinucleotides (CpGs). However, less frequent non-CpG asymmetric methylation has been found in various cell types, such as mammalian neurons, and recent results suggest that these sites can repress transcription independently of CpG contexts. In addition, an emerging view is that CpG hemimethylation may arise not only from deregulation of cellular processes but also be a standard feature of the methylome. Here, we have applied a novel approach to examine whether asymmetric CpG methylation is present in a sparsely methylated genome of the honeybee, a social insect with a high level of epigenetically driven phenotypic plasticity. By combining strand-specific ultra-deep amplicon sequencing of illustrator genes with whole-genome methylomics and bioinformatics, we show that rare asymmetrically methylated CpGs can be unambiguously detected in the honeybee genome. Additionally, we confirm differential methylation between two phenotypically and reproductively distinct castes, queens and workers, and offer new insight into the heterogeneity of brain methylation patterns. In particular, we challenge the assumption that symmetrical methylation levels reflect symmetry in the underlying methylation patterns and conclude that hemimethylation may occur more frequently than indicated by methylation levels. Finally, we question the validity of a prior study in which most of cytosine methylation in this species was reported to be asymmetric.

Proprioception retraining for a patient with chronic wrist pain secondary to ligament injury with no structural instability.

STUDY DESIGN: Case report. INTRODUCTION: Previously published studies demonstrate the importance of the sensory innervation of the carpal ligaments and the implication for the sensorimotor control of the wrist. In addition, this case considers key rehabilitation concepts to include the dart-throwing motion and the stabilizing effect of the forearm muscles. PURPOSE OF THE STUDY: To describe the rehabilitation program for a patient with chronic wrist pain, diagnosed with a partial tear of the dorsal intercarpal ligament and a sprain of the scapholunate ligament of the right wrist. METHODS: The patient participated in a staged treatment plan over a 3-month period (20 sessions), which began with a focus on proprioceptive awareness and joint position sense retraining. The treatment progressed to strengthening of specific muscles to enhance stability of the wrist joint. The patient completed the Quick Disabilities of the Arm, Shoulder and Hand and the patient-rated wrist evaluation on initial evaluation, re-evaluation at ninth session, and discharge at 20th session. RESULTS: Raw scores in the Quick Disabilities of the Arm, Shoulder and Hand and the patient-rated wrist evaluation improved from 33 and 61.5 on initial evaluation to 18 and 17.5 on discharge, respectively. CONCLUSIONS: Sensorimotor techniques including proprioceptive retraining may improve pain, neuromuscular control, and functional outcomes in patients with chronic wrist pain due to ligament injury. The effectiveness of proprioceptive retraining needs to be evaluated in a well-designed randomized controlled trial recruiting this patient population. LEVEL OF EVIDENCE: 5.

Differential expression of melanopsin isoforms Opn4L and Opn4S during postnatal development of the mouse retina.

Photosensitive retinal ganglion cells (pRGCs) respond to light from birth and represent the earliest known light detection system to develop in the mouse retina. A number of morphologically and functionally distinct subtypes of pRGCs have been described in the adult retina, and have been linked to different physiological roles. We have previously identified two distinct isoforms of mouse melanopsin, Opn4L and Opn4S, which are generated by alternate splicing of the Opn4 locus. These isoforms are differentially expressed in pRGC subtypes of the adult mouse retina, with both Opn4L and Opn4S detected in M1 type pRGCs, and only Opn4L detected in M2 type pRGCs. Here we investigate the developmental expression of Opn4L and Opn4S and show a differential profile of expression during postnatal development. Opn4S mRNA is detected at relatively constant levels throughout postnatal development, with levels of Opn4S protein showing a marked increase between P0 and P3, and then increasing progressively over time until adult levels are reached by P10. By contrast, levels of Opn4L mRNA and protein are low at birth and show a marked increase at P14 and P30 compared to earlier time points. We suggest that these differing profiles of expression are associated with the functional maturation of M1 and M2 subtypes of pRGCs. Based upon our data, Opn4S expressing M1 type pRGCs mature first and are the dominant pRGC subtype in the neonate retina, whereas increased expression of Opn4L and the maturation of M2 type pRGCs occurs later, between P10 and P14, at a similar time to the maturation of rod and cone photoreceptors. We suggest that the distinct functions associated with these cell types will develop at different times during postnatal development.

Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo.

Protein-tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin and leptin sensitivity. PTP1B overexpression in adipose tissue and skeletal muscle of humans and rodents may contribute to insulin resistance and obesity. The mechanisms mediating PTP1B overexpression in obese and diabetic states have been unclear. We find that adipose tissue inflammation and the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) regulate PTP1B expression in vivo. High fat feeding of mice increased PTP1B expression 1.5- to 7-fold in adipose tissue, liver, skeletal muscle, and arcuate nucleus of hypothalamus. PTP1B overexpression in high fat-fed mice coincided with increased adipose tissue expression of the macrophage marker CD68 and TNFalpha, which is implicated in causing obesity-induced insulin resistance. TNFalpha increased PTP1B mRNA and protein levels by 2- to 5-fold in a dose- and time-dependent manner in adipocyte and hepatocyte cell lines. TNFalpha administration in mice increased PTP1B mRNA 1.4- to 4-fold in adipose tissue, liver, skeletal muscle, and hypothalamic arcuate nucleus and PTP1B protein 2-fold in liver. Actinomycin D treatment blocked, and high dose salicylate treatment inhibited by 80%, TNFalpha-induced PTP1B expression in adipocyte cell lines, suggesting TNFalpha may induce PTP1B transcription via nuclear factor kappaB (NFkappaB) activation. Chromatin immunoprecipitation from adipocyte cell lines and liver of mice demonstrated TNFalpha-induced recruitment of NFkappaB subunit p65 to the PTP1B promoter in vitro and in vivo. In mice with diet-induced obesity, TNFalpha deficiency also partly blocked PTP1B overexpression in adipose tissue. Our data suggest that PTP1B overexpression in multiple tissues in obesity is regulated by inflammation and that PTP1B may be a target of anti-inflammatory therapies.

Macrophage migration inhibitory factor governs endothelial cell sensitivity to LPS-induced apoptosis.

Human endothelial cells (EC) are typically resistant to the apoptotic effects of stimuli associated with lung disease. The determinants of this resistance remain incompletely understood. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by human pulmonary artery EC (HPAEC). Its expression increases in response to various death-inducing stimuli, including lipopolysaccharide (LPS). We show here that silencing MIF expression by RNA interference (MIF siRNA) dramatically reduces MIF mRNA expression and the LPS-induced increase in MIF protein levels, thereby sensitizing HPAECs to LPS-induced cell death. Addition of recombinant human MIF (rhMIF) protein prevents the death-sensitizing effect of MIF siRNA. A common mediator of apoptosis resistance in ECs is the death effector domain (DED)-containing protein, FLIP (FLICE-like inhibitory protein). We show that LPS induces a transcription-independent increase in the short isoform of FLIP (FLIP(s)). This increase is blocked by MIF siRNA but restored with the addition of recombinant MIF protein (rHMIF). While FLIP(s) siRNA also sensitizes HPAECs to LPS-induced death, the addition of rhMIF does not affect this sensitization, placing MIF upstream of FLIP(s) in preventing HPAEC death. These studies demonstrate that MIF is an endogenous pro-survival factor in HPAECs and identify a novel mechanism for its role in apoptosis resistance through the regulation of FLIP(s). These results show that MIF can protect vascular endothelial cells from inflammation-associated cell damage.

Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury.

Cardiopulmonary bypass (CPB) causes acute lung injury. Reactive oxygen species (ROS) from NADPH oxidase may contribute to this injury. To determine the role of NADPH oxidase, we pretreated pigs with structurally dissimilar NADPH oxidase inhibitors. Low-dose apocynin (4-hydroxy-3-methoxy-acetophenone; 200 mg/kg, n = 6), high-dose apocynin (400 mg/kg, n = 6), or diphenyleneiodonium (DPI; 8 mg/kg) was compared with diluent (n = 8). An additional group was treated with indomethacin (10 mg/kg, n = 3). CPB was performed for 2 h with deflated lungs, complete pulmonary artery occlusion, and bronchial artery ligation to maximize lung injury. Parameters of pulmonary function were evaluated for 25 min following CPB. Blood chemiluminescence indicated neutrophil ROS production. Electron paramagnetic resonance determined the effect of apocynin and DPI on in vitro pulmonary endothelial ROS production following hypoxia-reoxygenation. Both apocynin and DPI attenuated blood chemiluminescence and post-CPB hypoxemia. At 25 min post-CPB with Fi(O(2)) = 1, arterial Po(2) (Pa(o(2))) averaged 52 +/- 5, 162 +/- 54, 335 +/- 88, and 329 +/- 119 mmHg in control, low-dose apocynin, high-dose apocynin, and DPI-treated groups, respectively (P < 0.01). Indomethacin had no effect. Pa(O(2)) correlated with blood chemiluminescence measured after drug administration before CPB (R = -0.60, P < 0.005). Neither apocynin nor DPI prevented the increased tracheal pressure, plasma cytokine concentrations (tumor necrosis factor-alpha and IL-6), extravascular lung water, and pulmonary vascular protein permeability observed in control pigs. NADPH oxidase inhibition, but not xanthine oxidase inhibition, significantly blocked endothelial ROS generation following hypoxia-reoxygenation (P < 0.05). NADPH oxidase-derived ROS contribute to the severe hypoxemia but not to the increased cytokine generation and pulmonary vascular protein permeability, which occur following CPB.

Effect of bronchial artery blood flow on cardiopulmonary bypass-induced lung injury.

Cardiovascular surgery requiring cardiopulmonary bypass (CPB) is frequently complicated by postoperative lung injury. Bronchial artery (BA) blood flow has been hypothesized to attenuate this injury. The purpose of the present study was to determine the effect of BA blood flow on CPB-induced lung injury in anesthetized pigs. In eight pigs (BA ligated) the BA was ligated, whereas in six pigs (BA patent) the BA was identified but left intact. Warm (37 degrees C) CPB was then performed in all pigs with complete occlusion of the pulmonary artery and deflated lungs to maximize lung injury. BA ligation significantly exacerbated nearly all aspects of pulmonary function beginning at 5 min post-CPB. At 25 min, BA-ligated pigs had a lower arterial Po(2) at a fraction of inspired oxygen of 1.0 (52 +/- 5 vs. 312 +/- 58 mmHg) and greater peak tracheal pressure (39 +/- 6 vs. 15 +/- 4 mmHg), pulmonary vascular resistance (11 +/- 1 vs. 6 +/- 1 mmHg x l(-1) x min), plasma TNF-alpha (1.2 +/- 0.60 vs. 0.59 +/- 0.092 ng/ml), extravascular lung water (11.7 +/- 1.2 vs. 7.7 +/- 0.5 ml/g blood-free dry weight), and pulmonary vascular protein permeability, as assessed by a decreased reflection coefficient for albumin (sigma(alb); 0.53 +/- 0.1 vs. 0.82 +/- 0.05). There was a negative correlation (R = 0.95, P < 0.001) between sigma(alb) and the 25-min plasma TNF-alpha concentration. These results suggest that a severe decrease in BA blood flow during and after warm CPB causes increased pulmonary vascular permeability, edema formation, cytokine production, and severe arterial hypoxemia secondary to intrapulmonary shunt.

Effect of cGMP on lung microvascular endothelial barrier dysfunction following hydrogen peroxide.

The authors determined the effect of cyclic guanosine 3',5'-monophosphate (cGMP) on hydrogen peroxide (H(2)O(2))-induced barrier dysfunction in bovine lung microvascular endothelial cell (BLMVEC) monolayers and compared the results to bovine pulmonary artery endothelial cells (BPAECs). In BLMVECs, H(2)O(2) (250 microM) caused a 31.9% +/- 4.8% decrease in transendothelial electrical resistance (TER) associated with increased actin stress fiber formation, intercellular gaps, and intracellular calcium concentration ([Ca(2+)](i)). The cGMP analogue 8-(p-chlorophenylthio)-cGMP (8p-CPT-cGMP; 30 or 50 microM) prevented the H(2)O(2)-induced decrease in TER (p <.001) as well as the cytoskeletal rearrangement and intercellular gap formation. 8-pCPT-cGMP (50 microM) attenuated the peak (418.8 +/- 42.1 versus 665.2 +/- 38.0 nmol/L; p <.001) and eliminated the sustained increase in [Ca(2+)](i) (193.5 +/- 21.3 versus 418.8 +/- 42.1 nmol/L; p <.001) caused by H(2)O(2). 8-pCPT-cGMP also increased TER (14.2% +/- 2.2%; p <.05) and decreased [Ca(2+)](i) (201.2 +/- 12.5 vs. 214.4 +/- 12.1 nmol/L; p <.03) before H(2)O(2). In BPAECs, 8p-CPT-cGMP significantly attenuated H(2)O(2)-induced increases in permeability and [Ca(2+)](i) but less effectively than in BLMVECs. These results suggest that in BLMVECs, cGMP countered the adverse effects of H(2)O(2) on barrier function by preventing actin cytoskeletal rearrangement and attenuating the increase in [Ca(2+)](i).

Inhibition of inwardly rectifying K(+) channels by cGMP in pulmonary vascular endothelial cells.

Endothelial barrier dysfunction is typically triggered by increased intracellular Ca(2+) concentration. Membrane-permeable analogs of guanosine 3',5'-cyclic monophosphate (cGMP) prevent disruption of endothelial cell integrity. Because membrane potential (E(m)), which influences the electrochemical gradient for Ca(2+) influx, is regulated by K(+) channels, we investigated the effect of 8-bromo-cGMP on E(m) and inwardly rectifying K(+) (K(IR)) currents in bovine pulmonary artery and microvascular endothelial cells (BPAEC and BMVEC), using whole cell patch-clamp techniques. Both cell types exhibited inward currents at potentials negative to -50 mV that were abolished by application of 10 microM Ba(2+), consistent with K(IR) current. Ba(2+) also depolarized both cell types. 8-Bromo-cGMP (10(-3) M) depolarized BPAEC and BMVEC and inhibited K(IR) current. Pretreatment with Rp-8-cPCT-cGMPS or KT-5823, protein kinase G (PKG) antagonists, did not prevent current inhibition by 8-bromo-cGMP. These data suggest that 8-bromo-cGMP induces depolarization in BPAEC and BMVEC due, in part, to PKG-independent inhibition of K(IR) current. The depolarization could be a protective mechanism that prevents endothelial cell barrier dysfunction by reducing the driving force for Ca(2+) entry.