Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema.

Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.

Intravenous gentamicin therapy induces functional type VII collagen in patients with recessive dystrophic epidermolysis bullosa: an open-label clinical trial.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable widespread blistering skin disorder caused by mutations in the gene encoding for type VII collagen (C7), the major component of anchoring fibrils. OBJECTIVES: To evaluate the efficacy and safety of intravenous (IV) gentamicin readthrough therapy in patients with RDEB harbouring nonsense mutations. The primary outcomes were increased expression of C7 in patients' skin and safety assessments (ototoxicity, nephrotoxicity, autoimmune response); secondary outcomes included measuring wound healing in target wounds and assessment by a validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) scoring system. METHODS: An open-label pilot trial to assess two different IV gentamicin regimens between August 2018 and March 2020 with follow-up through to 180 days post-treatment was carried out. Three patients with RDEB with confirmed nonsense mutations in COL7A1 in either one or two alleles and decreased baseline expression of C7 at the dermal-epidermal junction (DEJ) of their skin participated in the study. Three patients received gentamicin 7.5 mg kg-1 daily for 14 days and two of the three patients further received 7.5 mg kg-1 IV gentamicin twice weekly for 12 weeks. Patients who had pre-existing auditory or renal impairment, were currently using ototoxic or nephrotoxic medications, or had allergies to aminoglycosides or sulfate compounds were excluded. RESULTS: After gentamicin treatment, skin biopsies from all three patients (age range 18-28 years) exhibited increased C7 in their DEJ. With both regimens, the new C7 persisted for at least 6 months post-treatment. At 1 and 3 months post-treatment, 100% of the monitored wounds exhibited > 85% closure. Both IV gentamicin infusion regimens decreased EBDASI total activity scores. Of the patients assessed with the EBDASI, all exhibited decreased total activity scores 3 months post-treatment. All three patients completed the study; no adverse effects or anti-C7 antibodies were detected. CONCLUSIONS: IV gentamicin induced the readthrough of nonsense mutations in patients with RDEB and restored functional C7 in their skin, enhanced wound healing and improved clinical parameters. IV gentamicin may be a safe, efficacious, low-cost and readily available treatment for this population of patients with RDEB.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and life-threatening inherited skin disease that causes widespread skin blisters that heal with scarring. RDEB affects around 1 in every 100,000 individuals globally. The condition is caused by a mutation in the gene coding for type VII collagen (C7), resulting in a deficiency of C7. C7 is a vital component of the skin as it is responsible for holding the skin's upper two layers together. To date, there are no approved systemic treatments that can cure RDEB. This study, from the United States, aimed to evaluate the effectiveness and safety of intravenous (medicine delivered directly into a patient's vein) gentamicin (an antibiotic) for people with RDEB who have nonsense mutations in their genes (a type of mutation that prevents the production of complete proteins by introducing an inappropriate 'stop signal'). We gave gentamicin to three patients with RDEB every day for 14 days, and two of the three patients further received intravenous gentamicin twice a week for 12 weeks. After gentamicin treatment, all three patients showed increased expression of C7. With both regimens, the new C7 stayed for at least 6 months after the treatment. At 1 and 3 months after treatment, 100% of the wounds being monitored in the patients had closed by more than 85%. All three patients completed the study, and no side-effects were experienced. In conclusion, intravenous gentamicin increased the production of C7 and improved wound healing and quality of life in patients with RDEB carrying nonsense mutations. Intravenous gentamicin may offer a safe, effective, low-cost and readily available therapy in patients with RDEB.

Influence of Anatomic Locations of T1b Melanomas and Patient Age on Outcomes.

BACKGROUND: There are no guidelines on when to more strongly recommend sentinel lymph node biopsy (SLNB) for T1b melanomas. OBJECTIVE: To examine whether anatomic locations of T1b melanomas and patient age influence metastases. METHODS: We conducted a retrospective study using data from two hospitals in Los Angeles County from January 2010 through January 2020. RESULTS: Out of 620 patients with primary melanomas, 566 melanomas were staged based on the American Joint Committee on Cancer 8th edition melanoma staging. Forty-one were T1b, of which 13 were located on the face/ear/scalp and 28 were located elsewhere. T1b melanomas located on the face/ear/scalp had an increased risk of lymph node or distant metastasis compared with other anatomic sites (31% vs 3.6%, P=0.028). For all melanomas, the risk of lymph node or distant metastasis decreased with age of 64 years or greater (P<0.001 and P=0.034). For T1b melanomas, the risk of distant metastasis increased with increasing age (P=0.047). LIMITATIONS: Data were from a single county.  Conclusion: T1b melanomas of the face/ear/scalp demonstrated a higher risk of lymph node or distant metastasis and may help guide the recommendation of SLNB, imaging, and surveillance. Younger patients may be more strongly considered for SLNB and older patients with T1b melanomas may warrant imaging.  J Drugs Dermatol. 2024;23(5):306-310. doi:10.36849/JDD.7667.

A diffuse, pustular eruption in a neonate: Recognizing SAMD9L-associated autoinflammatory disease (SAAD).

A 3-week-old baby with hydrops fetalis, acute respiratory failure, and shock of unknown etiology developed a diffuse, pustular rash with worsening inflammatory markers and respiratory status despite antimicrobials. Whole exome sequencing revealed a de novo, frameshift mutation in the SAM9DL gene, leading to the diagnosis of SAMD9L-associated autoinflammatory disease.

The prognostic role of advanced hemodynamic variables in patients with left ventricular assist devices.

BACKGROUND: Invasive hemodynamic variables obtained from right heart catheterization have been used for risk-stratifying patients with advanced heart failure (HF). However, there is a paucity of data on the prognostic value of invasive hemodynamic variables in patients with left ventricular assist devices (LVAD). We hypothesized that cardiac power output (CPO), cardiac power efficiency (CPE), and left ventricular stroke work index (LVSWI) can serve as prognostic markers in patients with LVADs. METHODS: Baseline hemodynamic data from patients who had LVAD ramp studies at our institution from 4/2014 to 7/2018 were prospectively collected, from which advanced hemodynamic variables (CPO, CPE, and LVSWI) were retrospectively analyzed. Univariate and multivariable analyses were performed for hemocompatibility-related adverse events (HRAE), HF admissions, and mortality. RESULTS: Ninety-one participants (age 61 ± 11 years, 34% women, 40% Black or African American, and 38% ischemic cardiomyopathy) were analyzed. Low CPE was significantly associated with mortality (HR 2.42, 95% CI 1.02-5.74, p = 0.045) in univariate analysis and Kaplan-Meier analysis (p = 0.04). Low LVSWI was significantly associated with mortality (HR 2.13, 95% CI 1.09-4.17, p = 0.03) in univariate analysis and Kaplan-Meier analysis (p = 0.02). CPO was not associated with mortality. CPO, CPE, and LVSWI were not associated with HRAE or HF admissions. CONCLUSIONS: Advanced hemodynamic variables can serve as prognostic indicators for patients with LVADs. Low CPE and LVSWI are prognostic for higher mortality, but no variables were associated with HF admissions or HRAEs.

Comparison between the CASIA SS-1000 and Pentacam in measuring corneal curvatures and corneal thickness maps.

PURPOSE: To compare the intra-device repeatability and inter-device reproducibility between two anterior segment imaging instruments, the CASIA SS-1000 (Tomey Corp., Nagoya, Japan) and Pentacam (OCULUS, Arlington, WA) in measuring anterior segment parameters. METHODS: Single-center, prospective clinical trial. Participants ≥20 years of age were included. One eye was randomly selected, each imaged by three CASIA SS-1000 devices and three Pentacam devices by three different examiners. Each photographer operated a pair of devices, one CASIA SS-1000 and one Pentacam. The image order for each participant was determined by a random permutation table. Three images were taken from each device. A total of 18 images were taken for each eye. Ratios of the standard deviations, referenced as (CASIA/Pentacam), were calculated to compare the repeatability and reproducibility of the two imaging instruments. RESULTS: In all, 66 participants with a mean age of 46.4 years (±21.7) were enrolled in the study. All repeatability ratios and intra-device variability were less than 1 (anterior corneal curvature: flat = 0.86, steep = 0.85; posterior corneal curvature: flat = 0.43, steep = 0.61; and map: thinnest = 0.22; central = 0.24, 2 mm = 0.26, 4 mm = 0.27, and 6 mm = 0.30). All reproducibility ratios, which measure the inter-device variability, were less than 1 (anterior corneal curvature: flat = 0.58, steep = 0.73; posterior corneal curvature: flat = 0.25, steep = 0.31; and pachymetry map: thinnest = 0.20; central = 0.20; 2 mm = 0.20; 4 mm = 0.19; and 6 mm = 0.22). A ratio of less than 1 indicates that the CASIA SS-1000 has more consistent measurements. CONCLUSIONS: The CASIA SS-1000 was found to have better repeatability and reproducibility compared to the Pentacam for both corneal curvature and pachymetry maps. This greater consistency may require further study to determine whether the decreased variability can be translated into improved clinical results.

Simultaneous Heart-Liver Transplantation for Congenital Heart Disease in the United States: Rapidly Increasing With Acceptable Outcomes.

BACKGROUND AND AIMS: There are more adults than children living with congenital heart disease (CHD) in the United States, with a growing proportion requiring heart-liver transplantation (HLT). Our aim was to ascertain the frequency, outcomes, and prognostic factors in this patient population. APPROACH AND RESULTS: United Network for Organ Sharing data on adult patients who underwent heart transplantation (HT) from 2009 through March 2020 were analyzed. The primary study outcome was patient survival. Cox proportional-hazards modeling assessed for mortality associations. There were 1,084 HT recipients: 817 (75.4%) CHD HTs only, 74 (6.8%) CHD HLTs, 179 (16.5%) non-CHD HLTs, and 14 (1.3%) heart-liver-kidney transplants. The number of CHD HLTs increased from a prior rate of 4/year to 21/year in 2019. Among patients with CHD, the 5-year survival rates were 74.1% and 73.6% in HTs only and HLTs, respectively (P = 0.865). There was a higher rate of allograft failure attributable to rejection in CHD HTs only compared with CHD HLTs (3.2% versus 0.4%; P = 0.014). Only 25 out of 115 HT-performing hospitals undertook CHD HLTs. Higher-volume centers (averaging one CHD HLT per year) had a 5-year patient survival rate of 83.0% compared with 61.3% in lower-volume centers (P = 0.079). Among HLT recipients, total bilirubin (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.12) and diabetes (HR = 2.97, 95% CI = 1.21-7.31) were independently associated with increased mortality risk, whereas CHD and age were not. CONCLUSIONS: The rate of HLT for adult CHD in the United States is rising dramatically. The survival outcomes between CHD HT only and CHD HLT groups are comparable; however, the HLT group had lower rates of acute rejection. Among HLT recipients, diabetes and elevated bilirubin are associated with increased posttransplant mortality risk. An average of one CHD HLT per year could be considered a minimum quality metric at transplant centers.

Combined heart-liver-kidney transplant: The university of Chicago medicine experience.

BACKGROUND: Until recently, combined heart-liver-kidney transplantation was considered too complex or too high-risk an option for patients with end-stage heart failure who present with advanced liver and kidney failure as well. AIMS: The objective of this paper is to present our institution's best practices for successfully executing this highly challenging operation. At our institution, referral patterns are most often initiated through the cardiac team. RESULTS: Determinants of successful outcomes include diligent multidisciplinary patient selection, detailed perioperative planning, and choreographed care transition and coordination among all transplant teams. The surgery proceeds in three distinct phases with three different teams, linked seamlessly in planned handoffs. The selection and perioperative care are executed with determined collaboration of all of the invested care teams. CONCLUSIONS: Combined heart-liver-kidney transplantation can be successfully done by careful selection, coordination, and execution.

Clinical outcomes of grafted vs. percutaneous axillary intra-aortic balloon pump support as a bridge to transplantation: a propensity score-matched analysis.

OBJECTIVES: The purpose of this study is to investigate the early and late outcomes of axillary intra-aortic balloon pump (IABP) implantation as a bridge to heart transplantation, comparing the grafted technique with the percutaneous technique. METHODS: Between July 2009 and January 2020, 163 patients underwent an axillary IABP insertion as a bridge to heart transplantation. Among them, 97 patients underwent axillary IABP implantation through a graft sutured onto the axillary artery (Group A) and 66 patients underwent percutaneously (Group B). Propensity matching identified 53 matched pairs for analysis (C-statistics 0.741). The primary outcomes of interest included IABP-related complications, success rate of a bridge to transplantation, in-hospital mortality, and late survival. RESULTS: In the propensity-score matched cohort, there were no significant differences in the baseline characteristics between the two groups. The operation time was significantly longer in Group A than in Group B (141.5 ± 38.3 min vs 42.7 ± 19.3 min, p < 0.01). The complication rates including stroke, re-exploration for bleeding, and aortic event were not significantly different between Group A and B. However, Group A required more transfusion and re-exploration for bleeding. The success rate of a bridge to transplantation was similar between Group A (47/53, 88.7%) and Group B (47/53, 88.7%). There were no significant differences in in-hospital mortality and late survival between two groups. CONCLUSION: In the propensity score matching analysis, there were not any significant differences between the two groups in IABP-related complications, in-hospital mortality, and late survival. The percutaneous technique provided a shorter operation time and less requirement of transfusion and re-exploration for bleeding compared to the grafted technique. The percutaneous technique might be favorable when feasible.

Proximal ascending aorta size is associated with the incidence of de novo aortic insufficiency with left ventricular assist device.

We sought to assess the impact of the aortic root geometry on developing de novo aortic insufficiency (AI) in patients undergoing left ventricular assist device (LVAD). In total, 114 patients underwent LVAD implantation between February 2016 and January 2020 were included in this study (HeartMate3 N = 68, HeartWare N = 46). Significant aortic insufficiency was defined as mild-to-moderate or greater in echocardiography. The cohort was divided into two groups; those who developed significant AI (Group AI: n = 13) and did not (Group non-AI: n = 101). The primary outcomes of interest included late survival and predictors for significant AI. The patients in Group AI were older than Group non-AI (62.6 ± 11.9 vs 51.3 ± 14.0 years, p < 0.01). The diameter of proximal ascending aorta in Group AI was larger than Group non-AI (31.0 ± 5.0 vs 27.4 ± 4.3 mm, p < 0.01). Aortic valve remained closed in 53.8% in Group AI and 36.6% in Group non-AI (p = 0.24). The late survival was not significantly different between the groups (67.1% vs 76.0% at 3 years, log rank = 0.97). The Cox hazard model showed that larger proximal ascending aortic diameter/BSA (HR 1.55, CI 1.19-2.04, p < 0.01) and not-opening aortic valve (HR 4.73, CI 1.43-16.9, p = 0.01) were independent risk factors for significant AI. The cutoff value of proximal ascending aortic diameter/BSA was 15.5 (area under curve: 0.770, sensitivity: 0.69, specificity: 0.79). Dilated proximal ascending aorta at the time of LVAD surgery and not-opening aortic valve during follow-up were associated with the incidence of de novo significant AI.

Significant vascular complications in percutaneous axillary intra-aortic balloon pump.

OBJECTIVE: Axillary Intra-aortic balloon pump (IABP) has been increasingly utilized for hemodynamic support in heart failure patients. Vascular complications associated with axillary IABP such as dissection or rupture are relatively rare but not negligible that could negatively affect clinical outcomes. We summarized our experiences. METHODS: This is a retrospective study reviewing of all patients receiving an axillary IABP between June 2016 and November 2020. A total of 199 patients underwent percutaneous axillary IABP placement. 6 patients (6/199, 3.0%) were complicated with arterial/aortic dissection or rupture during the procedures or the course of treatment. We described their clinical presentations and outcomes. RESULTS: Vascular complications included acute type A aortic dissection in 2 patients, descending aortic rupture in 1 patient, abdominal aortic rupture along with type B aortic dissection in 1 patient, and the localized left subclavian artery dissection in 2 patient. 2 type A aortic dissection cases were surgically treated: 1 with emergent left ventricle assist device and ascending aorta replacement, the other with emergent left ventricle assist device. Emergent endovascular treatment was successfully performed in 2 aortic rupture cases. The left subclavian artery dissection cases were managed medically. The postoperative/treatment course was uneventful in all patients. CONCLUSION: Percutaneous axillary IABP therapy can cause significant vascular complications. Early diagnosis and prompt treatment would be the key to improve the clinical outcomesv.

Postoperative tolvaptan use in left ventricular assist device patients: The TOLVAD randomized pilot study.

PURPOSE: Tolvaptan, a selective vasopressin type-2 antagonist, has been shown to increase serum sodium (Na) and urine output in hyponatremic left ventricular assist device (LVAD) patients in retrospective studies. In this prospective randomized pilot study, we aimed to assess the efficacy of tolvaptan in this population. METHODS: We conducted a prospective, randomized, non-blinded pilot study of LVAD recipients with post-operative hyponatremia (Na < 135 mEq/L) (NCT05408104). Eligible participants were randomized to receive tolvaptan 15 mg daily in addition to usual care versus usual care alone. The primary outcome was a change in Na level and estimated glomerular filtration rate (eGFR), from the first post-operative day of hyponatremia (the day of randomization) to discharge. RESULTS: A total of 33 participants were enrolled, and 28 underwent randomization (median age 55 [IQR 50-62]), 21% women, 54% Black, 32% ischemic cardiomyopathy, median baseline Na 135 (IQR 134-138). Fifteen participants were randomized to tolvaptan (TLV) and 13 were randomized to usual care alone (No-TLV). Mean change in Na from randomization to discharge in the TLV group was 2.7 mEq/L (95%CI 0.7-4.7, p = 0.013) and 1.8 (95%CI 0.5-4.0, p = 0.11) in the No-TLV group, though baseline and final Na levels were similar between groups. The mean change in eGFR was 2.6 ml/min/1.73 m2 (95%CI 10.1-15.3, p = 0.59) in TLV versus 7.5 ml/min/1.73 m2 (95%CI 5.2-20.2, p = 0.15) in No-TLV. TLV participants had significantly more urine output than No-TLV patients during their first 24 h after randomization (3294 vs 2155 ml, p = 0.043). CONCLUSION: TLV significantly increases urine output, with nominal improvement in Na level, in hyponatremic post-operative LVAD patients without adversely impacting renal function.

Incidence of postoperative week 1 management changes after resident-performed phacoemulsification cataract surgery.

BACKGROUND: The goal of this study was to investigate the incidence of departures from routine care at the postoperative week 1 (POW1) visit following uneventful resident-performed cataract surgery in asymptomatic patients who had a normal postoperative day 1 (POD1) examination. METHODS: A retrospective chart review of phacoemulsification surgeries performed by the senior resident class at Montefiore Medical Center between June 20, 2018 and April 1, 2019 was performed. The most recent preoperative visit note, operative report, POD1 visit note, and POW1 visit note were evaluated and variables were recorded. Exclusion criteria consisted of any complications that would have necessitated close follow-up and a POW1 visit, whether discovered preoperatively, intraoperatively, at the POD1 visit, or leading up to the POW1 visit. The primary outcome measure was the incidence of unanticipated management changes at the POW1 visit following resident-performed cataract surgery. RESULTS: The charts of 292 surgical cases of 234 patients that underwent phacoemulsification with intraocular lens implantation were reviewed. 226 cases (77%) had an uncomplicated pseudophakic fellow-eye history, with a routine surgery, and POD1 examination. 19 of these patients had symptomatic presentations at the POW1 timepoint, and an additional 30 had no POW1 visit at all. In total, 177 cases were included in the study, and only 4 of these cases (2.3%) had an unexpected management change at the POW1 visit. CONCLUSIONS: Asymptomatic patients who underwent uncomplicated cataract surgeries performed by resident surgeons followed by a routine POD1 visit had a low incidence of unexpected management changes at the POW1 visit. These results suggest that regularly scheduled POW1 visits could potentially be omitted for patients deemed to be at low risk for complications, and instead performed on an as-needed basis.

Lucio phenomenon with concomitant necrotizing fasciitis and acute kidney injury.

Lucio phenomenon is a rare vasculopathy that can occur in patients with Hansen disease, particularly diffuse lepromatous leprosy. It is characterized by retiform purpura and necrotic ulcerations, most commonly affecting the extremities. Diagnosing Lucio phenomenon can be challenging, especially when secondary bacterial infections occur. We report a patient with Lucio phenomenon who presented with acute necrotizing fasciitis of his left upper extremity and a 10-year history of chronic ulcerations. Shortly following admission, he also developed acute kidney injury. The necrotizing fasciitis was treated with prompt surgical debridement and intravenous antibiotics. Biopsy and PCR of a right upper extremity ulcer confirmed the presence of Mycobacterium lepromatosis. Multidrug therapy and prednisone were used to treat the Lucio phenomenon. After initiating treatment, no new lesions developed, kidney function improved, and the patient underwent successful skin graft of his left upper extremity. Although corticosteroid use is controversial, our patient's marked response to multidrug therapy with prednisone highlights the importance of this regimen in severe presentations of Lucio phenomenon. To the best of our knowledge, only two other cases of Lucio phenomenon confirmed to be caused by M. lepromatosis have been reported in living patients (rather than retrospectively identified post-mortem), underscoring the importance of the presented clinical course and treatment regimen.

Aortic Pulsatility Index: A Novel Hemodynamic Variable for Evaluation of Decompensated Heart Failure.

BACKGROUND: Right heart catheterization for invasive hemodynamics has shown only modest correlation with clinical outcomes. We designed a novel hemodynamic variable that incorporates ventricular output and filling pressure. We anticipated that the aortic pulsatility index (API) would correlate with clinical outcomes in patients with heart failure. METHODS AND RESULTS: We retrospectively analyzed consecutive patients undergoing right heart catheterization with milrinone drug study at our institution (February 2013 to November 2019). The API was calculated as (systolic blood pressure - diastolic blood pressure)/pulmonary capillary wedge pressure. The primary outcome was freedom from advanced therapies, defined as the need for inotropes, temporary mechanical circulatory support, a left ventricular assist device, or orthotopic heart transplantation, or death at 30 days. A total of 224 patient encounters, age 57 years (48-66 years; 34% women; 31% ischemic cardiomyopathy) were included. In univariable analysis, lower baseline API was significantly associated with progression to advanced therapies or death at 30-days (odds ratio 0.43, 95% confidence interval 0.30-0.61; P < .001) compared with those on continued medical management. Receiver operator characteristic analysis specified an optimal cutpoint of 1.45 for API. A Kaplan-Meier analysis indicated an association of API with the primary outcome (79% for API ≥ 1.45 vs 48% for API < 1.45). In multivariable analysis, higher API was strongly associated with freedom from advanced therapies or death (odds ratio 0.38, 95% confidence interval 0.22-0.65, P ≤ .001), even when adjusted for baseline characteristics and routine right heart catheterization measurements. CONCLUSIONS: The API is a novel invasive hemodynamic measurement that is associated independently with freedom from advanced therapies or death at 30-day follow-up.

Donor-derived cell-free DNA is associated with cardiac allograft vasculopathy.

BACKGROUND: The role of donor-derived cell-free DNA (dd-cfDNA) in screening for cardiac allograft vasculopathy (CAV) is unknown. We hypothesized that dd-cfDNA correlates with CAV, markers of inflammation, and angiogenesis in stable heart transplant (HT) recipients. METHODS: Sixty-five HT recipients ≥2 years post-transplant, without recent rejection, were stratified by high (≥0.12%) versus low levels (<0.12%) of dd-cfDNA. A targeted amplification, next-generation sequencing assay (AlloSure® ; CareDx, Inc.) was used to detect dd-cfDNA. Peripheral blood inflammatory and angiogenesis markers were assessed using a multiplex immunoassay system (Bioplex® ). RESULTS: Of 65 patients, 58 patients had a known CAV status and were included. Thirty had high levels of dd-cfDNA (≥0.12%), and 28 had low levels (<0.12%). CAV was present in 63% of patients with high dd-cfDNA vs. 35% with low dd-cfDNA (p = .047). Donor-specific antibodies were present in 25% of patients with high dd-cfDNA vs. 3.8% in those with low dd-cfDNA (p = .03). There were no differences in rejection episodes, inflammatory, or angiogenesis markers. Importantly, dd-cfDNA levels were not different when stratified by time post-transplant. CONCLUSIONS: Higher dd-cfDNA levels were associated with CAV in stable chronic HT recipients. Further studies are warranted to investigate a possible association between dd-cfDNA levels and CAV severity and whether dd-cfDNA can predict CAV progression.

Discordance between immunofluorescence and immunohistochemistry C4d staining and outcomes following heart transplantation.

BACKGROUND: Capillary deposition of C4d is an important marker of antibody-mediated rejection (AMR) following heart transplantation (HT). There are two immunopathologic assay methods for detecting C4d: frozen-tissue immunofluorescence (IF) and paraffin immunohistochemistry (IHC). The clinical significance of discrepancy between the results of IF and IHC has not been understood. METHODS AND RESULTS: We reviewed 2187 biopsies from 142 HT recipients who had biopsies with assessment of both IF and IHC staining. Among them, 103 (73%) patients had negative IF and IHC C4d staining (Negative Group) and 32 (23%) patients had positive IF but negative IHC staining (Discordant Group). At the time of positive biopsy, 6 (19%) Discordant patients had graft dysfunction, compared to 5 (5%) Negative patients (p = .022). Cumulative incidence of cellular rejection at 1 year was comparable (31% vs. 29%, p = .46); however, cumulative incidence of AMR was significantly higher in the Discordant group (21% vs. 4%, p = .004). Overall 1-year survival was comparable (90% vs. 96%, p = .24); however, freedom from heart failure (HF) was significantly lower in the Discordant group (70% vs. 96%, p < .001). CONCLUSION: The Discordant group showed higher rates of graft dysfunction, AMR and HF admission than the Negative group.

Gentamicin Induces Laminin 332 and Improves Wound Healing in Junctional Epidermolysis Bullosa Patients with Nonsense Mutations.

Generalized severe junctional epidermolysis bullosa (GS-JEB) is an incurable and fatal autosomal recessively inherited blistering skin disease caused by mutations in the LAMA3, LAMB3, or LAMC2 genes. Most of these mutations are nonsense mutations that create premature termination codons that lead to impaired production of functional laminin 332, a protein needed for epidermal-dermal adherence. Gentamicin induces readthrough of nonsense mutations and restores the full-length protein in various genetic diseases. Using primary keratinocytes from three GS-JEB patients, we showed that gentamicin induced functional laminin 332 that reversed a JEB-associated, abnormal cell phenotype. In a subsequent open-label trial involving the same patients, we examined whether 0.5% gentamicin ointment applied topically to open skin wounds could promote nonsense mutation readthrough and create new laminin 332 in the patients' skin. Gentamicin-treated wounds exhibited increased expression of laminin 332 at the dermal-epidermal junction for at least 3 months and were associated with improved wound closure. There were no untoward side effects from topical gentamicin. The newly induced laminin 332 did not generate anti-laminin 332 autoantibodies in either the patients' blood or skin. Gentamicin readthrough therapy may be a treatment for GS-JEB patients with nonsense mutations.

Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma.

BACKGROUND: Glaucoma is one of the leading largely preventable causes of blindness in the world. It is usually  addressed first medically with topical intraocular pressure-lowering drops or by laser trabeculoplasty. In cases where such treatment fails, glaucoma-filtering surgery such as trabeculectomy, is commonly considered. Surgeons can differ in their technique when performing trabeculectomy, for example, the choice of the type of the conjunctival flap (fornix- or limbal-based). In a fornix-based flap, the surgical wound is performed at the corneal limbus; while in a limbal-based flap, the incision is further away. Many studies in the literature compare fornix- and limbal-based trabeculectomy with respect to outcomes and complications. OBJECTIVES: To assess the comparative effectiveness of fornix- versus limbal-based conjunctival flaps in trabeculectomy for adult glaucoma, with a specific focus on intraocular pressure (IOP) control and complication rates (adverse effects). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 3); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 23 March 2021. There were no restrictions to language or year of publication. SELECTION CRITERIA: We included RCTs comparing the benefits and complications of fornix- versus limbal-based trabeculectomy for glaucoma, irrespective of glaucoma type, publication status, and language. We excluded studies on children less than 18 years of age, since wound healing is different in this age group and the rate of bleb scarring postoperatively is high. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as per Cochrane criteria.  MAIN RESULTS: We did not identify any new eligible studies for this review update. As presented in the original review, we included six trials with a total of 361 participants. Two studies were conducted in the USA and one each in Germany, Greece, India, and Saudi Arabia. The participants of four trials had open-angle glaucoma; one study included participants with primary open-angle or primary closed-angle glaucoma, and one study did not specify the type of glaucoma. Three studies used a combined procedure (phacotrabeculectomy). Trabeculectomy with mitomycin C (MMC) was performed in four studies, and trabeculectomy with 5-fluorouracil (5-FU) was performed in only one study. None of the included trials reported trabeculectomy failure at 24 months. Only one trial reported the failure rate of trabeculectomy as a late complication. Failure was higher among participants randomised to the limbal-based surgery: 1/50 eyes failed trabeculectomy in the fornix group compared with 3/50 in the limbal group (Peto odds ratio  0.36, 95% confidence interval (CI) 0.05 to 2.61)); therefore we are very uncertain as to the relative effect of the two procedures on failure rate. Four studies including 252 participants provided measures of mean IOP at 12 months. In the fornix-based surgeries, mean IOP ranged from 12.5 to 15.5 mmHg and similar results were noted in limbal-based surgeries with mean IOP ranging from 11.7 to 15.1 mmHg without significant difference. Mean difference was 0.44 mmHg (95% CI -0.45 to 1.33; 247 eyes) and 0.86 mmHg, (95% CI -0.52 to 2.24; 139 eyes) at 12 and 24 months of follow-up, respectively. Neither of these pooled analyses showed a statistically significant difference in IOP between groups (moderate certainty evidence). One trial reported number of anti-glaucoma medications at 24 months of follow-up with no difference noted between surgical groups. However, three trials reported the mean number of anti-glaucoma medications at 12 months of follow-up without significant difference in the mean number of postoperative IOP-lowering medications between the two surgical techniques. Mean difference was 0.02, (95% CI -0.15 to 0.19) at 12 months of follow-up (high certainty evidence). Because of the small numbers of events and total participants, the risk of many reported adverse events was uncertain and those that were found to be statistically significant may have been due to chance. For risk of bias assessment: although all six trials were randomised selection bias was mostly unclear, with unclear random sequence generation in four of the six studies and unclear allocation concealment in five of the six studies. Attrition bias was encountered in only one trial which also suffered from reporting bias. All other trials had an unclear risk of reporting bias as there was no access to study protocols. All included trials were judged to have high risk of detection bias due to lack of masking of the outcomes. Trabeculectomy is quite a standard procedure and unlikely to induce bias due to surgeon 'performance', hence performance bias was not evaluated. AUTHORS' CONCLUSIONS: The main result of this review was that there was uncertainty as to the difference between fornix- and limbal-based trabeculectomy surgeries due to the small number of events and confidence intervals that cross the null. This also applied to postoperative complications, but without any impact on long-term failure rate between the two surgical techniques.

Impact of worsening of aortic insufficiency during HeartMate 3 LVAD support.

Aortic insufficiency remains a difficult to treat and highly morbid condition even in the era of HeartMate 3 left ventricular assist devices (LVADs). The prognostic nature of the longitudinal progression of aortic insufficiency, however, remains unknown. We prospectively collected data on patients who received HeartMate 3 LVAD implantation, who had assessments of aortic insufficiency using a novel Doppler echocardiography obtained at outflow graft at three (baseline) and 6 months postimplant. Patients with moderate or greater aortic insufficiency at baseline were excluded. The risk of aortic insufficiency progression on 1-year death and readmission for heart failure was investigated. In total, 41 patients (median 51 years old and 29 males) were included. All patients had less than moderate aortic insufficiency at baseline. Of them, 22 patients had worsening aortic insufficiency for 3 months following baseline assessments, which was associated with a significantly higher risk of 1-year death or heart failure readmission rate (41% vs. 11%, P = .023) with a hazard ratio of 3.24 (95% confidence interval 1.02-18.5, P = .038) adjusted for device speed at baseline and destination therapy indication. In patients with HeartMate 3 LVADs, progressive aortic insufficiency may be associated with a higher risk of 1-year death or readmission for heart failure. Close monitoring of patients with baseline aortic insufficiency should be considered as a measure to risk-stratify those for future adverse events.