Erythrocytes Induce Vascular Dysfunction in COVID-19.

Current knowledge regarding mechanisms underlying cardiovascular complications in patients with COVID-19 is limited and urgently needed. We shed light on a previously unrecognized mechanism and unravel a key role of red blood cells, driving vascular dysfunction in patients with COVID-19 infection. We establish the presence of profound and persistent endothelial dysfunction in vivo in patients with COVID-19. Mechanistically, we show that targeting reactive oxygen species or arginase 1 improves vascular dysfunction mediated by red blood cells. These translational observations hold promise that restoring the redox balance in red blood cells might alleviate the clinical complications of COVID-19-associated vascular dysfunction.

Implant Attributes or Patient Characteristics? Factors Affecting Outcome after Breast Augmentation in Transgender Women.

Implant-based breast augmentation is a valuable tool for treatment of gender dysphoria in transgender women. The aim was to assess whether implant attributes, plane selection, and patient characteristics had an impact on the surgical outcome, and to compare these parameters between transgender and cisgender breast augmentations. Methods: A cohort of transgender women who underwent breast augmentation at our department during 2009-2018 were retrospectively studied. The cohort was also compared with a cohort of 12,884 mainly cisgender women registered in the Swedish breast implant registry (BRIMP) during 2014-2019. Results: A total of 143 transgender individuals were included, with a median follow-up of 5.7 years. Complications occurred in 20 patients (14.0%), four patients (2.8%) underwent acute reoperation, and 20 patients (14.0%) had secondary corrections. No differences were seen in complication rates when comparing prepectoral with subpectoral placement (15.1% versus 12.9%; P = 0.81); size, less than 400 mL versus greater than or equal to 400 mL (14.7% versus 13.3%; P = 0.81), or the shape of the implants, round versus anatomic (10.7% versus 22.2%; P = 0.10). In comparison with the cohort from BRIMP, the transgender cohort had more round implants (72.0% versus 60.7%; P < 0.01), larger implants (44.1% had volumes of 400-599 mL, compared with 25.4%; P < 0.0001), and more prepectoral placement (51.0% versus 7.3%; P < 0.0001). The risk of reoperation less than 30 days was 1.2% in BRIMP and 2.8% in the transgender cohort (P = 0.08). Conclusions: In transgender women, implants are often larger, round, and placed prepectoral' compared with cisgender women. Despite these differences, complication rates were equivalent. Implant attributes, surgical techniques, and patient characteristics were not independently associated with the rate of complications.

Improved Surgical Outcome with Double Incision and Free Nipple Graft in Gender Confirmation Mastectomy.

BACKGROUND: Mastectomy and chest-wall contouring is the most common gender confirmation surgery. With increasing prevalence of transgender individuals, there is a demand for better surgical outcomes and aesthetic results. Our aim was to evaluate surgical techniques used and assess modifications in gender confirmation mastectomies at Karolinska University hospital in Stockholm, Sweden. METHODS: A retrospective cohort study was performed on 464 patients undergoing gender confirmation mastectomies in our department between 2009 and 2018. Patient demographics, psychiatric comorbidity, surgical method, and outcome were analyzed. Follow-up was at least one year. RESULTS: The most frequently used surgical technique for gender confirmation mastectomies was double incision with free nipple graft (243 patients, 52.4%), followed by periareolar incision (113 patients, 24.4%) and semicircular incision (67 patients, 14.4%). The double incision technique and periareolar technique were associated with 18.9% and 28.3% complications, 3.3% and 12.4% acute reoperations, 28.4% and 65.5% secondary revisions, respectively. The double incision technique increased from being used in 17.8% of all mastectomies during 2009-2013 to 62.9% during 2014-2018, while periareolar incision decreased from 43.0% to 18.5%. CONCLUSIONS: The current study describes a successful transition of surgical technique from periareolar incision to double incision with free nipple graft in gender confirmation mastectomy, leading to significant improvements in the overall outcome with fewer complications, less acute reoperations and less secondary corrections. Hence, we consider the double incision with free nipple graft technique to be the favored technique in the vast majority of cases in female-to-male chest wall contouring.

Management of the Midface in the Transgender Patient.

Management of the midface has a central role to achieve harmony in the transgender patient requesting facial feminization surgery. The relative projection of separate areas of the craniofacial skeleton largely determines the appearance of the facial framework. In this article the authors describe the management of the midface; bony remodeling and soft tissue aspects, in the transgender patient.

Quality of life improves early after gender reassignment surgery in transgender women.

BACKGROUND: Few studies have examined the long-term quality of life (QoL) of individuals with gender dysphoria, or how it is affected by treatment. Our aim was to examine the QoL of transgender women undergoing gender reassignment surgery (GRS). METHODS: We performed a prospective cohort study on 190 patients undergoing male-to-female GRS at Karolinska University Hospital between 2003 and 2015. We used the Swedish version of the Short Form-36 Health Survey (SF-36), which measures QoL across eight domains. The questionnaire was distributed to patients pre-operatively, as well as 1, 3, and 5 years post-operatively. The results were compared between the different measure points, as well as between the study group and the general population. RESULTS: On most dimensions of the SF-36 questionnaire, transgender women reported a lower QoL than the general population. The scores of SF-36 showed a non-significant trend to be lower 5 years post-GRS compared to pre-operatively, a decline consistent with that of the general population. Self-perceived health compared to 1 year previously rose in the first post-operative year, after which it declined. CONCLUSIONS: To our knowledge, this is the largest prospective study to follow a group of transgender patients with regards to QoL over continuous temporal measure points. Our results show that transgender women generally have a lower QoL compared to the general population. GRS leads to an improvement in general well-being as a trend but over the long-term, QoL decreases slightly in line with that of the comparison group. Level of evidence: Level III, therapeutic study.

Midface Osteotomies for Feminization of the Facial Skeleton.

Facial feminization surgery is a term to describe the surgical alteration of a masculine facial appearance to a more feminine appearance, which is most commonly performed for male-to-female transsexual individuals. To alter the midfacial relations, segmentalized osteotomies were performed in selected patients expanding on the established techniques for facial feminization surgery. All patients underwent a preoperative 3D computerized tomography scan and 3D photography before and after the surgery. The inclusion of the midface in surgery was determined based on the relative projection and angle of the zygomatic body compared with the supraorbital region (the supraorbital region was reduced in all patients). Patients were prospectively followed up by 3D surface photography and 3D computerized tomography scans. Rotation and advancement of the zygomatic region was found to be an effective way to further feminize the midfacial appearance in selected male-to-female transsexual patients. No major surgical complications occurred. Although somewhat technically challenging, we suggest that midface surgery should be considered for feminizing purposes in order for the patient to achieve a long-term favorable result compared with other alternative methods.

Long-Term Sensitivity and Patient-Reported Functionality of the Neoclitoris After Gender Reassignment Surgery.

INTRODUCTION: A cornerstone of treating gender dysphoria for transgender women is gender reassignment surgery (GRS) encompassing vaginoplasty and clitoroplasty. The neoclitoris is harvested as a flap with a neurovascular pedicle from the proximal dorsal part of the glans penis. Few long-term follow-ups exist on postoperative sensation and patient-reported sexual functionality of the neoclitoris. AIM: To examine the sensitivity of the neoclitoris and its relation to orgasm and sexual function at least 1 year after GRS. METHODS: Twenty-two patients were included, with a mean follow-up of 37 months (range = 12-63) after initial surgery. Tactile and vibratory sensitivities were measured with Semmes-Weinstein monofilaments and the Bio-Thesiometer vibratory measurement device, respectively. A questionnaire was provided to the patients, as were interview questions about body image, orgasm, pain, and general satisfaction with the surgery. MAIN OUTCOME MEASURES: Tactile and vibratory sensitivities of the neoclitoris and questionnaire on satisfaction with orgasm, sexual function, and general satisfaction. RESULTS: The average tactile threshold for the clitoris was 12.5 g/mm2 and the average vibratory threshold was 0.3 µm. Most participants (86%) experienced orgasm after surgery, had no or little pain, and were satisfied with the surgery. No statistical correlation was found between better or worse objective pressure and vibratory thresholds and patient answers to questions about the clitoris in the Body Image Scale for Transsexuals questionnaire. CONCLUSION: The neoclitoris derived from the glans penis in GRS provides long-term clitoral sensation that is erogenous. Overall, the vast majority of patients who undergo male-to female GRS experience orgasm and are satisfied with the surgery.

Lower Eyelid Complications in Facial Fracture Surgery.

BACKGROUND: Facial fractures may lead to sequelae due to the trauma but also as a result of surgery. Complications to lower eyelid incisions include ectropion, scleral show, entropion, canthal malposition, and lid edema. The aim of this study was to compare the occurrence of such complications depending on whether a subciliary or transconjunctival incision was used for surgical access. METHODS: All consecutive patients surgically treated for a facial fracture between June 2005 and December 2012 with a lower eyelid incision and a minimal follow-up of 6 months were included in this retrospective study. Patients were grouped according to type of lower eyelid incision (transconjunctival vs subciliary). RESULTS: Out of 128 patients, 37 (29%) had a subciliary and 91 (71%) had a transconjunctival incision. In the subciliary incision group, 3 patients (8.1%) had ectropion and 4 patients (11%) had scleral show whereas 2 patients (2.2%) had ectropion, 4 patients (4.4%) had scleral show, and 2 patients (2.2%) displayed canthal malposition in the transconjunctival incision group. The differences between the groups were not statistically significant. No patient had an entropion. CONCLUSIONS: Subciliary incisions had a higher incidence of ectropion and scleral show compared with transconjunctival incisions. Transconjunctival incisions did show a low risk of canthal malposition needing surgical correction; however, the actual numbers were low. Based on this and earlier studies, the authors routinely perform transconjunctival incisions, without a lateral canthotomy if possible, for surgery of facial fractures.

Long-term sensory disturbances after orbitozygomatic fractures.

BACKGROUND: Orbitozygomatic fractures often lead to infraorbital nerve (ION) injury, and affected sensibility is a common long-term complaint within this patient group. We present a long-term follow-up study where the validated von Frey filament system was used for testing ION sensibility. Furthermore, we examined the incidence of persistent nerve injury and whether more complex fractures led to more pronounced ION sensibility disturbances. METHODS: Patients treated for facial fractures involving the orbitozygomatic complex were included and the follow-up time was 3 years or more. Depending on the location and severity of the fractures, the patients were divided into 4 groups. The patients answered a questionnaire before ION sensibility testing with von Frey filaments. RESULTS: Eighty-one patients were examined: 65 males (80%) and 16 females (20%). Examinations were conducted between 3.0 and 7.6 years (mean 4.9 years) after injury. Sixteen patients (20%) had affected and 6 patients (7.4%) had severely affected ION sensibility according to von Frey testing. No statistically significant differences were found in terms of questionnaire score between the groups. There was also no statistically significant correlation between questionnaire results and log von Frey values. Although the effect of groups could not be statistically verified using the log von Frey values, a larger proportion of patients with complex fractures had higher log von Frey values than the other groups. CONCLUSIONS: Patients with complex fractures report more permanent sensory disturbance of the ION after surgery than those with isolated orbitozygomatic fractures, although this could not be verified statistically with von Frey filament testing at several locations. Hence, a validated method for testing facial sensibility such as von Frey filaments, although sensitive, is inadequate to determine all aspects of sensory malfunction after orbitozygomatic fractures. This suggests that the patient's experience of long-term sensation after trauma may not be correlated with objective measures.

Solely Penile Skin for Neovaginal Construction in Sex Reassignment Surgery.

BACKGROUND: Gender reassignment surgery due to transsexualism (International Classification of Diseases, Tenth Revision: F64.0) is a procedure becoming increasingly common worldwide as a result of a significant increase in diagnostic incidence. Several methods have been described for this complex surgery, but no internationally agreed upon gold standard exists, in particular with regard to which methods allow for creating a sufficient neovaginal depth. METHODS: We use a 2-stage technique using solely penile skin for creating a neovaginal cavity and present the long-term outcome in terms of measured neovaginal depth. Eighty patients were included. Patients' neovaginal depth was measured in a standardized fashion 6 months or more after initial surgery. Results were compared with published data on female anatomy. RESULTS: The average neovaginal depth achieved was 10.2 cm. Having had a postoperative complication and noncompliance to neovaginal dilatation were both negatively correlated with neovaginal depth, whereas higher body mass index was not. Most patients received a neovaginal depth sufficient for penetrative intercourse and within the range for biological women. CONCLUSIONS: Using solely penile skin for the vaginal lining is a satisfactory surgical method to achieve adequate vaginal depth, provided that the postoperative dilatation regimen is followed. This holds true regardless of age or body mass index.

Persistent diplopia after fractures involving the orbit related to nerve injury.

BACKGROUND: Fractures in the facial skeleton are common and may lead to orbital sequelae caused by the injury and/or the surgery. In this long-term follow-up, we examined the nature of sequelae after facial fractures involving the orbit and whether a higher complexity of the fractures produced more sequelae compared to simpler fracture patterns, and if so, to what extent. METHODS: Patients surgically treated for facial fractures involving the orbit at the Karolinska University Hospital with a follow-up duration of ≥3 years were included in this retrospective study and were examined by a neuro-ophthalmologist. Based on the location and severity of the fractures, the patients were divided into four groups according to fracture complexity: 1) isolated zygomatic fracture, 2) isolated orbital floor blowout fracture, 3) zygomatic fracture combined with blowout fracture and 4) bilateral or multiple fracture patterns. RESULTS: Out of 154 patients, 81 patients (53%) attended follow-up examinations, 65 male (80%) and 16 female (20%). The duration of follow-up was 3.0-7.6 years (mean of 4.9 years). The incidence of diplopia was 3.7%, visual loss 2.5%, dystopia 4.9% and visible enophthalmos (>2 mm) 8.6%. Severe diplopia (2.5%) was due to nerve injuries. Visual loss was encountered only in group 4 with complex fractures. Fracture complexity had an effect on the presence of any sequelae, with group 4 presenting a higher percentage of patients with sequelae than the other three groups. However, no statistically significant effect of group could be found on the individual, quantitative output values of dystopia and enophthalmos. CONCLUSIONS: In this study, severe persistent diplopia in patients was due to nerve injuries, which emphasizes the need for preoperative ophthalmologic examinations, in all patients with fractures involving the orbit. A higher fracture complexity was found to lead to a higher percentage of patients presenting sequelae.

Hypoxia-induced arterial differentiation requires adrenomedullin and notch signaling.

Hypoxia (low oxygen) and Notch signaling are 2 important regulators of vascular development, but how they interact in controlling the choice between arterial and venous fates for endothelial cells during vasculogenesis is less well understood. In this report, we show that hypoxia and Notch signaling intersect in promotion of arterial differentiation. Hypoxia upregulated expression of the Notch ligand Dll4 and increased Notch signaling in a process requiring the vasoactive hormone adrenomedullin. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, hypoxia-mediated upregulation of the arterial marker genes Depp, connexin40 (Gja5), Cxcr4, and Hey1 required Notch signaling. In conclusion, the data reveal an intricate interaction between hypoxia and Notch signaling in the control of endothelial cell differentiation, including a hypoxia/adrenomedullin/Dll4 axis that initiates Notch signaling and a requirement for Notch signaling to effectuate hypoxia-mediated induction of the arterial differentiation program.

Protective immunization against Staphylococcus aureus infection in a novel experimental wound model in mice.

A novel murine experimental wound infection model was used to assess the efficacy of multi-component immunization against Staphylococcus aureus infection. Necrotic lesions were induced in mice with venom from Bothrops asper and infected with a low inoculum, 1 × 10(2) CFU. The wound infection model therefore more resembles a clinical case of S. aureus infection compared with conventional infection models where far more bacteria are required. Before infection, mice were immunized with four recombinant S.aureus proteins expressed from Escherichia coli: (i) domains 1-3 of Extracellular adherence protein (Eap), (ii) Efb - D (fusion protein combining Extracellular fibrinogen binding protein (Efb) and a fibronectin binding domain (D) of the fibronectin binding protein (FnBP) and (iii) clumping factor A (ClfA). In the immunized group, lower bacterial colonization, undisturbed crust formation and significantly faster wound healing were found compared with the unimmunized control group. Efb and Eap have previously been found to impair wound healing and neutralization of these proteins by antibodies restores a more natural wound healing process. This effect is further also enhanced by the proposed opsonic activity of antibodies against ClfA and FnBP.

Control of Notch-ligand endocytosis by ligand-receptor interaction.

In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand-receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1(WT)) in the absence of active Notch signaling. Both Jagged1(WT) and Jagged1(Ndr) interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1(WT) showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1(WT), but not Jagged1(Ndr), trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1(WT) in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1(Ndr) did not exert a dominant-negative effect over Jagged1(WT) in terms of receptor activation. Finally, in Jag1(Ndr/Ndr) mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1(Ndr) ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands.

Sustained inflammation due to nuclear factor-kappa B activation in irradiated human arteries.

OBJECTIVES: The aim of this study was to investigate gene expression networks related to cardiovascular disease in radiated human arteries. BACKGROUND: Recent epidemiological studies have shown that radiotherapy is associated with cardiovascular disease years after treatment. However, the molecular mechanisms underlying late effects of radiation are poorly described. METHODS: Arterial biopsies from radiated and nonradiated human conduit arteries, from the same patient, were simultaneously harvested during microvascular free tissue transfer for cancer-reconstruction in 13 patients, 4 to 500 weeks from radiation treatment. Radiated and nonradiated arteries were compared, with Affymetrix (Santa Clara, California) microarrays on a subset of the material to generate candidate genes. A Taqman (Applied Biosystems, Foster City, California) low-density array of 45 selected genes was designed for analysis of the whole material. RESULTS: Thirteen genes were synchronously expressed in all patients (p = 0.0015), including CCL8, CCL3, CXCL2, DUSP5, FGFR2, HMOX1, HOXA9, IL-6, MMP-1, PTX3, RDH10, SOD2, and TNFAIP3. A majority of differentially regulated genes related to the nuclear factor-kappa B (NF-kappaB) signaling pathway and were dysregulated even years after radiation. The NF-kappaB activation was confirmed by immunohistochemistry and immunofluorescence. CONCLUSIONS: In the present study, we found sustained inflammation due to NF-kappaB activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-kappaB. We also suggest that HOXA9 might be involved in the regulation of NF-kappaB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation.

Endothelial activation with prothrombotic response in irradiated microvascular recipient veins.

BACKGROUND: Surgical wounds within previously irradiated tissues are common in reconstructive surgery and subject to an increased incidence of postoperative complications due to vascular dysfunction, including thrombosis in both microvascular anastomosis and the microcirculatory bed. However, there is no study that has described gene expression patterns in radiated human blood vessels. This study aims to determine if radiation can induce changes in gene expression that can promote thrombus formation in human microvascular recipient veins. METHODS: Paired biopsies from radiated recipient veins and non-radiated flap veins were simultaneously harvested from 15 patients during free-flap reconstruction, 4-215 weeks from termination of radiation. Radiated and non-radiated veins were compared using a custom-made Taqman(®) low-density array (TLDA) to analyse differential gene expression in a large number of genes involved in inflammation and coagulation. Results were confirmed by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Results from TLDA indicate an acute increase of cytokines and leucocyte adhesion molecules related to activation of transcription factor nuclear factor kappa-B (NF-kB), confined to the first 3 months after radiotherapy treatment. Results were confirmed by RT-PCR and activity localised to the endothelium by immunohistochemistry. RT-PCR analyses of genes associated with coagulation showed sustained expression of plasminogen activator inhibitor-1 (PAI-1) in radiated veins. CONCLUSION: We found an acute inflammatory response with endothelial activation, followed by a sustained PAI-1 gene expression in irradiated microvascular recipient veins that can explain adverse effects years after radiation, such as microvascular occlusion and poor surgical wound healing. We believe that the results contribute to the search for therapeutic adjuncts to cope with the adverse effects of radiation therapy and strongly advocate postoperative, rather than preoperative, radiotherapy whenever possible.