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Competing Interests: The authors report no conflicts of interest.

Background and Objectives: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD., Methods: The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated., Results: Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated., Discussion: Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD., Classification of Evidence: This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD., Trial Registration Information: The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: This study examined the association between PM2.5 levels and emergency department (ED) visits for selected health outcomes in Albuquerque, New Mexico, during the Wallow fire of 2011., Design: Measurements of 24-hour average concentrations of PM2.5 obtained from the City of Albuquerque were used to calculate wildfire smoke exposure in Albuquerque. Daily ED visits were collected by the New Mexico Department of Health from individual nonfederal licensed facilities in the Albuquerque area. Poisson regression was used to assess the relationship between ED visits for selected respiratory and cardiovascular conditions and varying levels of PM2.5 exposure., Setting: Albuquerque, New Mexico., Participants: Patients visiting an ED for select conditions before, during, and after the wildfire., Main Outcome Measure: Relative increase in ED visits for selected conditions during the wildfire period., Results: Analysis of PM2.5 exposure data and ED visits in Albuquerque before and during the Wallow fire indicated that compared with the period prior to the fire, there was an increased risk of ED visits for some respiratory and cardiovascular conditions during heavy smoke conditions, and risk varied by age and sex. The population of 65+ years was especially at risk for increased ED visits. There was a significantly increased risk of ED visits among the 65+ population for asthma (RR [relative rate] = 1.73, 95% confidence interval [CI] = 1.03-2.93) and for diseases of the veins, lymphatic and circulatory system (RR = 1.56, 95% CI = 1.00-2.43). For the age group of 20 to 64 years, there was a statistically significant increase in ED visits for diseases of pulmonary circulation (RR = 2.64, 95% CI = 1.42-4.9) and for cerebrovascular disease (RR = 1.69, 95% CI = 1.03-2.77)., Conclusions: High levels of PM2.5 exposure due to the Wallow fire were associated with increased ED visits for respiratory and cardiovascular conditions in Albuquerque. More effective and targeted preventive measures are necessary to reduce morbidity rates associated with wildfire smoke exposure among vulnerable populations.

Background: Fractional flow reserve (FFR) measurement of intermediate coronary stenoses is recommended by guidelines when demonstration of ischemia by noninvasive testing is unavailable. The study aims to evaluate the penetration of this recommendation into current thinking about revascularization strategies for stable coronary artery disease., Methods and Results: International Survey on Interventional Strategy was conducted via a web-based platform. First, participants' experiences in interventional cardiology were queried. Second, 5 complete angiograms were provided, presenting only focal intermediate stenoses. FFR and quantitative coronary angiography values were known; however, remained undisclosed. Determination of stenosis significance was asked for each lesion. In cases of uncertainty, the most appropriate adjunctive invasive diagnostic method among quantitative coronary angiography, intravascular ultrasound, optical coherence tomography, or FFR needed to be selected. International Survey on Interventional Strategy was taken by 495 participants who provided 4421 lesion evaluations. In 3158 (71%) decisions, participants relied solely on angiographic appearance that was discordant in 47% with the known FFR, using 0.80 as cutoff value. The use of FFR and imaging modalities was requested in 21% and 8%, respectively. Comparing 4 groups of participants according to the experience in FFR, angiogram-based decisions were less frequent with increasing experience (77% versus 72% versus 69% versus 67%, respectively; P<0.001). As a result, requests for FFR were more frequent (14% versus 19% versus 24% versus 28%, respectively; P<0.001) and rates of discordant decisions decreased (51% versus 49% versus 47% versus 43%, respectively; P<0.022)., Conclusions: The findings confirm that, even when all potential external constraints are virtually eliminated, visual estimation continues to dominate the treatment decisions for intermediate stenoses, indicative of a worrisome disconnect between recommendations and current practice., (© 2014 American Heart Association, Inc.)

Background: The differentiation between acute graft-versus-host disease (aGvHD) and infection is still a clinical challenge in patients after allogeneic hematopoietic stem-cell transplantation (HSCT). Definitive diagnosis is based on histologic findings, but a simple blood test for differentiation is missing., Methods: In a prospective study, we measured the plasma levels of erythrocyte-derived microparticles (EryMP) in 19 recipients during HSCT. Microparticles were isolated by differential centrifugation, double stained for glycophorin A (CD235) and annexin V, and analyzed by flow cytometry., Results: Eight patients developed aGvHD (42%), 15 patients developed infectious complications (79%), and two patients developed microangiopathic hemolytic anemia (11%). The levels of EryMP, as measured before conditioning therapy (535 × 10(6)/L in median), were not affected by total body irradiation, high-dose chemotherapy, or in vivo T-cell depletion. EryMP levels were unaffected in uncomplicated patients during aplasia (522 × 10(6)/L in median; P=0.394) or after engraftment (480 × 10(6)/L in median; P = 0.594) and in patients with infectious complications or sepsis (586 × 10(6)/L in median; P = 0.606). In contrast, in patients who developed aGvHD after HSCT, a 1.7-fold increase in the plasma levels of EryMP was observed (880 ×1 0(6)/L in median; P<0.001 compared with the time before therapy and P = 0.015 compared with patients with infections or sepsis)., Conclusion: Increased plasma levels of EryMP are present in patients who develop aGvHD but not in patients who develop infection or sepsis after HSCT. Therefore, EryMP are a potential, novel, blood marker that may be helpful in the diagnosis of this common complication after HSCT.

Local immunosuppressive mechanisms shape the tumor microenvironment and contribute to carcinogenesis. In ovarian cancer such mechanisms have been shown to influence survival. Dendritic cells (DCs) are central immunity regulators and induce potent cytotoxic T-cell responses as well as peripheral tolerance depending on modulatory stimuli. Here, we show that ovarian cancer-derived glycodelin (Gd), a glycoprotein that physiologically modulates local immunity in early pregnancy, induces a tolerogenic DC phenotype. Gd was isolated with high performance liquid chromatography from the malignant ascites of ovarian cancer patients. DCs were generated from monocytes of healthy donors and exposed to Gd with or without an inflammatory stimulus (tumor necrosis factor-alpha and interleukin 1-beta). We investigated the effect of Gd on DC surface marker expression, endopinocytotic activity, cytokine profile, and lymphoproliferative activity. DCs that were exposed to Gd altered their phenotype as seen by a differential expression of costimulatory molecules, whereas expression of DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, a marker of an immature phenotype, was increased. Functional data provided further evidence for the immature/tolerogenic properties of Gd-pretreated DCs. Antigen uptake was retained, production of interleukin-10 was increased, and lymphoproliferative activity was reduced. This effect was reversible by adding Gd-blocking antibodies. Gd, which is found in the malignant ascites of ovarian cancer patients, induces a tolerogenic phenotype in DC, thereby shaping an immunodeficient tumor micromilieu.

Background: Alterations of microparticles derived from different cell types are described in a number of diseases associated with inflammation and hemostatic disorders., Methods: In this prospective study, we firstly analyzed endothelial cell derived microparticles (EMP) in 19 hematopoietic stem cell recipients. Cultured human umbilical vein endothelial cells (HUVEC) stimulated with tumor necrosis factor-alpha (TNF-alpha) served as positive controls. EMP were analyzed by fluorescent activated cell sorting (FACS), detecting the particels via expression of CD62 (E-selectin) and anionic phospholipids binding to annexin V., Results: EMP were not significantly influenced by conditioning regimens with non-myeloablative chemotherapy and 4 Gy total body irradiation (TBI) or by myeloablative regimens containing 12 Gy TBI. During acute graft versus host disease (aGVHD), significantly higher levels of EMP were detected than in patients without aGVHD (18.5/microl s=10.1 vs. 14.6/microl SD = 11.5; P = 0.004) while infectious complications did not alter EMP levels significantly. Immunosuppressive therapy with corticosteroids tendentially elevated EMP levels. HUVEC treated with TNF-alpha 1 ng/ml, 10 ng/ml and 100 ng/ml released significantly more EMP than unstimulated cultures (30.0/microl ss = 13.6 vs. 126.8/microl SD = 66.9, P = 0.032 / vs. 683.3/microl SD = 349.9; P = 0.03 / vs. 489.3 s = 184.4; P = 0.013)., Conclusions: Elevation of EMP during aGVHD might express severe endothelial cell injury within this complication after hematopoietic stem cell transplantation and might serve as a diagnostic test for early differentiation of aGVHD from other transplanted related complications.

Gender differences in immune and organ functions have been described in different rodent models of trauma- and pressure-controlled hemorrhagic shock. We hypothesized that gender influences the regulation of plasma and tissue fluids in rats under such conditions. To study this we used male and weight matched proestrus female Sprague-Dawley rats, which were assigned to three groups (n = 7/group): sham, maximal bleedout (trauma and 45 min of blood pressure at 35 mmHg without resuscitation), or 5 h after completion of trauma-hemorrhage and resuscitation. Trauma-hemorrhage involved midline laparotomy and approx. 90 min of hemorrhagic shock (35 mmHg), followed by fluid resuscitation (4x the shed blood volume with Ringers lactate). (51)Cr-EDTA, (125)I-albumin distribution, and wet weight/dry weight were used to calculate plasma volume and extracellular fluid volume and cellular water content. Proestrus female rats showed significantly higher plasma volumes compared with weight-matched males. The volume of blood withdrawn in the first 15 min of hemorrhagic shock was significantly less in proestrus females compared with males; however, there was no significant difference in the total shed blood volume. Moreover, proestrus females showed less interstitial edema formation compared with male rats at 5 h after resuscitation. We conclude that differences in the regulation of plasma and tissue volumes exist between males and proestrus females during and after trauma-hemorrhage. The increased circulating blood volume could contribute the improved immune and organ functions in proestrus females under those conditions.

The final appearance of the reconstructed breast is greatly dependent on the relative amounts of skin and breast tissue excised at the time of the mastectomy and on the exact location of the skin incision. A complete mastectomy may be performed using modified skin incisions to avoid the sacrifice of unnecessary breast skin. The type of skin-sparing incision used varies based on the exact location of the tumor and the size of the breast, but it always includes the nipple-areola complex and the biopsy site. The presence of local recurrence, distant disease, or death was determined in 50 consecutive patients who had skin-sparing mastectomies and immediate breast reconstruction between 1985 and 1991 to ascertain the safety of the procedure. The period of follow-up ranged from 23 to 121 months, with a mean of 57 months and a median of 51.5 months. There was no local recurrence, active distant disease was present in five patients, two patients died of distant disease, and there were two unrelated deaths.

Fourteen patients underwent Le Fort III midface advancement using distraction techniques. Six have cephalometric documentation extending beyond 1 year postoperatively, and the positions of cephalometric points A and orbitale over time are reported here. Excellent stability of advancement at the occlusal level and some relapse at the level of orbitale are documented. Elimination or diminution of obstructive sleep apnea occurred in all patients so affected, and one of two patients with tracheostomy has been decannulated. Speech effects have been mild or transient. No untoward effects on extraocular muscle function have occurred.

The purpose of this study was to demonstrate the potential advantages of applying distraction osteogenesis techniques to the correction of orbital and midfacial hypoplasia in craniosynostosis syndromes. Fifteen children with various craniosynostosis syndromes underwent Le Fort III advancement assisted by gradual distraction utilizing a pair of internal distraction devices custom-fabricated for each child. The surgical procedure consisted of a Le Fort III osteotomy, implantation of internal devices with initiation of distraction intraoperatively, and an accelerated rate of midfacial advancement over the next 3 to 5 days. Activation of the distraction hardware was accomplished by a percutaneous pin, which was removed at the end of the distraction protocol, allowing the internal devices to fixate the fragment for a minimum of 6 months during the period of consolidation. With follow-up ranging between 3 to 38 months, the average orbital and midfacial advancement was 19.7 mm (range, 12.0-30.0 mm). Proptosis was lessened and facial proportions significantly improved in all patients. Serious complications were not encountered. The modified distraction protocol utilized in this group of patients was aimed at addressing the unique requirements of pediatric craniofacial surgery, and resulted in almost twice the amount of correction previously reported for traditional rigid fixation techniques.

The purpose of this report is to demonstrate a practical clinical method for advancement of the midface using a combination of Le Fort III osteotomy and gradual distraction. Use of internal, submergible distraction devices and modification of the Ilizarov distraction protocol are presented. Case reports show the effect of departing from the Ilizarov protocol by eliminating the latency period, initiating distraction intraoperatively, and rapidly distracting the segments postoperatively. A method of controlling fragment distraction rate by regulating pressures within the osteotomy site is described. The design and surgical application of internal distraction devices are shown. Nine patients with midface hypoplasia related to craniofacial anomalies underwent Le Fort III osteotomies assisted by gradual distraction. Ages ranged from 4 to 13 years. Custom internal distraction devices were employed to meet the unique requirements of each patient. Activation of the distraction device was accomplished by a percutaneous pin that remained in place for 3 to 5 days. The rate of transport was determined by regulating the forces within the distraction site. The internal devices remained in place for 6 months for fixation of the transported fragment. Midface advancement, measured as the anterior displacement of the infraorbital rim, ranged from 16 to 30 mm, with a mean of 20 mm. The typical force required to produce incremental movement of the Le Fort III osteotomy was found to be between 7 and 9 kg as transport exceeded 10 mm. Four patients with obstructive sleep apnea prior to surgery had resolution of the disorder. All the midface advancements remained clinically stable. Establishment of osseous continuity was verified by surgical examination in the four patients in whom the distraction devices have been removed. Combining intraoperative advancement of the Le Fort III osteotomy with gradual distraction consistently resulted in larger movements than could be achieved with conventional osteotomies and rigid fixation alone. The pediatric craniofacial skeleton responds differently to distraction than does the orthopedic skeleton. Eliminating the latency period, establishing a substantial bone gap intraoperatively, and rapidly distracting the fragment postoperatively did not adversely affect the osseous union in these patients. The internal, submergible feature of the device design offers advantages in patient acceptance, fixation stability, and wound management. This method of Le Fort III midface advancement has been shown to be clinically practical and effective.

The temporoparietal fascial flap is a recognized technique for the transfer of vascularized tissue in the craniofacial region. The flap has a predictable axial vessel, provides thin vascularized tissue, and can be harvested with minimal donor-site morbidity. The temporoparietal fascial flap is well suited for orbital or eyelid reconstruction because of its proximity to the orbit. The flap is useful for reconstruction of anatomic barriers between the orbit, intracranial cavity, and paranasal sinus spaces. We present four patients in whom the temporoparietal fascial flap was used for orbital reconstruction following extirpative surgery for orbital neoplasm and two patients in whom the flap was used for lower eyelid and malar reconstruction.

Skin-sparing mastectomy by definition describes the procedure of mastectomy, either simple or modified radical, with a minimum amount of skin excision. The surgical skin excision must: (1) include the nipple-areola complex, (2) include the biopsy site, and (3) allow for access to the axilla for possible dissection. In 27 mastectomies, the senior author has had direct input in the preoperative skin planning. All patients underwent immediate breast reconstruction. In large-breasted women, the mastectomy was performed to a Wise-type pattern. In small-breasted women, the mastectomy involved minimal skin excision followed by reconstruction. Non-continuous incisions were frequently used in small-breasted women, thereby minimizing breast scarring. When appropriately applied, skin-sparing mastectomy can greatly improve the final aesthetic result of the breast.

Tissue expansion can be a valuable tool in the reconstruction of soft-tissue defects in craniofacial clefts. To our knowledge, there have been no reports in the literature of the use of tissue expanders to help solve this problem. We report the case of a child with an atypical Tessier no. 3 craniofacial cleft who had a forehead tissue expander placed, inflated, and thus used to provide sufficient local facial skin for repair of the soft-tissue defect.

In selected patients with lower quadrant breast masses, large breasts, and sufficient abdominal tissue, standard techniques for breast reconstruction can be modified to improve overall results. The transverse abdominal island flap can be deepithelialized and mobilized to reconstruct unilateral or bilateral defects. Furthermore, skin markings prior to mastectomy that conform to a modified Wise pattern will allow for more aesthetic positioning of eventual scars. We present a case report of a patient who underwent immediate breast reconstruction with bilateral deepithelialized lower rectus abdominis myodermal flaps.

Three-dimensional imaging is an adjunct to preoperative evaluation and surgical management in some patients with complex anatomic defects of various etiologies. Deformities defined by conventional computerized tomography can be viewed as accurate three-dimensional images calculated from the original scan. The images are viewed on a high-resolution video monitor and can be photographed for a permanent record. A computer-controlled milling device can use these data to fabricate prostheses. The prostheses aid reconstructive surgery through use as an alloplastic implant, as a template to fashion autogenous bone grafts, or as a model for tissue removal. We have utilized three-dimensional imaging in combination with computer-assisted prosthesis manufacture in six patients with complex orbitocranial deformities. Four patients have undergone reconstructive surgery with satisfactory results and no complications thus far. The use of computer-designed prostheses adds a new aspect to orbitocranial reconstructive surgery that facilitates increased accuracy in the correction of anatomic defects.

We have reviewed our experience with 22 microvascular free-tissue transfers in children. Ages range from 2 to 14 years; the success rate was 96 percent. Two patients underwent reexploration for postoperative hemorrhage, possibly due to treatment with low-molecular-weight dextran. No vessel spasm was observed, compared with a 28 percent incidence in our adult series of 154 patients. The vessels were in pristine condition. Operative time was shorter (6.1 hours) than in our adult series (9.7 hours). Average hospital stay was 10 days (compared to 23 days for adults). All children have resumed almost normal activity within 2 months (4 months for adults). Results of this study indicate that microvascular free-tissue transfer can be accomplished safely and expeditiously in children. Care should be taken in preoperative and postoperative planning, however, especially concerning immobilization.

After 15 years of experience and 50 cases, we think that the axial frontonasal flap is of great value for the repair of large skin defects of the nose. This flap mobilizes all the skin cover of the nose located above the defect and the adjacent frontal skin and rotates it on a vascular pedicle existing at the level of the inner canthi. The excess of skin of the glabella is then transferred to the nose, and this large flap allows coverage of the defect without tension or distortion. The long-term results are very good, with a hardly visible repair in 26 of 50 patients, the long scar being very well hidden at the periphery of the nose.

AMI remains a diagnostic and therapeutic challenge for the critical care nurse. As research and technology progress, a thorough understanding of the pathophysiology of AMI is necessary to appreciate and apply advances in the treatment of this condition. Likewise, if reductions in the morbidity and mortality of AMI are to be achieved, the nurse must be aware of potential complications, especially those related to ischemia, myocardial dysfunction, and dysrhythmia. Prompt diagnosis and treatment of the complications of AMI are the best approaches for minimizing fatalities, reducing hospital stays, and providing the best prognosis for patients with AMI.

The complete survival of a teres major--latissimus dorsi skin-muscle flap for chest reconstruction is reported in a patient in whom the primary neurovascular pedicle of the latissimus muscle had previously been sacrificed. At operation, collateral vessels of 1-mm proportions were noted to have developed between the innervated teres major and denervated latissimus dorsi muscle. In this case, the teres major muscle rotated with the latissimus muscle to affect reconstruction of a full-thickness anterior chest resection. This report suggests the possibility of a denervated, relatively devascularized muscle obtaining additional blood supply from adjacent innervated vascularized muscles and supports the concept of rotating the muscles as a unit to encourage viability of the denervated component.