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Background:Recent studies have shown that a majority of multiple myeloma (MM) patients (pts) in the United States (US) are triple-class exposed (TCE) after four lines of therapy (LOT), with poor prognosis for TCE patients. As treatment for MM evolves to include more advanced triplet and quadruplet regimens, a growing number of US pts are likely to reach TCE status in earlier lines of treatment. Therefore, we sought to evaluate the frequency of pts reaching TCE status after receiving two or more prior LOT (3L+) and their associated clinical outcomes.

Intracerebral hemorrhage and, more specifically, intraparenchymal hemorrhage, are devastating disease processes with poor clinical outcomes. Primary injury to the brain results from initial hematoma expansion while secondary hemorrhagic injury occurs from blood-derived products such as hemoglobin, heme, iron, and coagulation factors that overwhelm the brains natural defenses. Novel neuroprotective treatments have emerged that target primary and secondary mechanisms of injury. Nonetheless, translational application of neuroprotectants from preclinical to clinical studies has yet to show beneficial clinical outcomes. This review summarizes therapeutic agents and neuroprotectants in ongoing clinical trials aimed at targeting primary and secondary mechanisms of injury after intraparenchymal hemorrhage.

Female androgenetic alopecia or female-pattern hair loss (FPHL) is highly prevalent and has a great impact on the quality of life. The treatment is a routine challenge in dermatological practice, as many therapeutic options have a limited level of evidence and often do not meet patients expectations. Lack of knowledge of the pathogenesis of the hair miniaturization process and the factors that regulate follicular morphogenesis restricts the prospect of innovative therapies. There is also a lack of randomized, controlled studies with longitudinal follow-up, using objective outcomes and exploring the performance of the available treatments and their combinations. Topical minoxidil, which has been used to treat female pattern hair loss since the 1990s, is the only medication that has a high level of evidence and remains the first choice. However, about 40% of patients do not show improvement with this treatment. In this article, the authors critically discuss the main clinical and surgical therapeutic alternatives for FPHL, as well as present camouflage methods that can be used in more extensive or unresponsive cases.

•ECP-treated leukocytes cryopreserved at -80°C or -150°C for 3 months remain viable•These cells also retain apoptotic potential and therefore the ability to suppress GVHD•In vivoGVHD prevention studies are needed using cryopreserved ECP-treated leukocytes

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Cardiac manifestations are common in severe Coronavirus disease 2019 (COVID-19) with rates reported from 2% in non-ICU patients to 59% in non-survivors. Recent CDC data show that COVID-19 patients are at 1.7 higher risk of arrhythmia. AF, which is the most common arrhythmia, is a frequent complication of acute and long COVID-19. It has been reported that the SARS-CoV2 receptor, ACE2, is highly expressed in the heart, leading to the prevalent assumption that infectious virus likely underlies cardiac complications. However, the pathophysiology of cardiac disease in severe COVID-19 has yet to be clarified. We therefore compared the histologic and molecular findings in human cardiac tissue from fatal COVID-19 cases and age-matched controls. Hematoxylin and eosin (H&E) stains revealed histologic changes in the COVID-19 samples, most notably multifocal endothelial cell swelling and degeneration plus microvascular thrombi. Distribution of SARS-CoV2 RNA and nucleocapsid protein expression was investigated by qRT-PCR and in situhybridization (ISH). Trace amounts of viral RNA and no nucleocapsid protein were detected in the COVID-19 hearts. However, 7/11 COVID-19 hearts were positive for viral spike protein. Further validation by immunohistochemistry (IHC) showed that viral spike protein was detected in all 11 COVID-19 hearts. Co-expression analysis revealed that viral spike protein localized mostly to the ACE2+ interstitial macrophages/pericytes that were activated as evidenced by increased IL6 and TNFα expression. Previously, we identified a novel arrhythmia mechanism wherein inflammation-induced vascular endothelial dysfunction triggers cardiomyocyte structural remodeling, particularly of intercalated disc (ID) components including connexin-43 (Cx43) gap junctions and NaV1.5 sodium channels, and thereby promotes arrhythmias. We therefore investigated ID structure in our human samples. Both Cx43 and NaV1.5 showed marked lateral migration in myocytes of COVID-19 hearts, consistent with previous experiments with inflammatory insults in murine hearts. These findings suggest that the viral spike protein, and not direct infection by SARS-CoV2, results in the pathophysiology of cardiac dysfunction in fatal COVID-19.

The purpose of this study was to evaluate the efficiency of the plication of the anterior rectus sheath during abdominoplasty and the anatomical characteristics of patients with recurrence.

The aim of this paper is to demonstrate the effectiveness of the calculation method, which takes into consideration the electrostatic ligands field as well as the the magnetic interactions. Our calculations method based on crystal field (CEF) together with the Zeeman effect in one Hamiltonian and allows calculating many of the temperature dependencies of the magnetic and electronic properties of the rare earth compounds. The result of the calculations shows the accuracy of the approach even for the intermetallic compounds. The obtained results for calculations of the compounds of the family in RERu2Si2 (RE – rare-earth element) are fully confirmed the experimental data such as: the easy magnetic direction of all the analyzed compounds, the thermal dependencies of magnetic properties; in particular the giant magnetocrystalline anisotropy of PrRu2S2 with the calculated anisotropy field BA>400T, in-plain anisotropy of ErRu2Si2, the cause of difficulty in magnetic ordering of compounds TmRu2Si2 and YbRu2Si2 as well as effects and dependencies not foreseen before. In this paper we have put together the elementary calculated magnetic properties for the chosen compounds of RERu2Si2 in the paramagnetic region. All Calculations are on the basis of the calculating computer package BIREC 1.51.

ABSTRACTPosaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P= 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P= 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P= 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.

Genaconazole (SCH 39304) is a potent triazole antifungal agent that is active both orally and topically. Genaconazole is a racemic mixture which contains 50% of the RR (SCH 42427) and 50% of the SS (SCH 42426) enantiomers. The RR isomer accounts for most of the antifungal activity of genaconazole. Serum concentrations of the RR and SS enantiomers were analyzed by a chiral HPLC method which involved extraction of serum with organic solvent followed by separation on a Cyclobond I column and quantification by UV absorbance at 205 nm. The bioavailability and pharmacokinetic profiles of the two enantiomers after oral administration of the racemate (genaconazole) were very similar in cynomolgus monkeys. In rats following dosing with genaconazole, the RR enantiomer had a lower Cmaxand a longer t1/2than the SS enantiomer, while the AUC(I) values of the two enantiomers were similar. Based on chiral HPLC analysis, there was no evidence for the inversion of the RR to the SR isomer, or of the SS to the SR isomer, indicating that there was no chiral inversion of the RR or SS enantiomers in either species. Genaconazole at 20 mg/kg and the RR (SCH 42427) enantiomer at 10 mg/kg had very similar serum concentration–time profiles and Cmax, AUC(I), and t1/2values for the RR enantiomer in both rats and monkeys, indicating that the two treatments were equivalent with respect to the bioavailability of the RR enantiomer. Chirality 14:436–441, 2002. © 2002 Wiley‐Liss, Inc.

Calmodulin facilitates normal sodium channel (NaV) inactivation, necessary to prevent proarrhythmic late sodium current (INa). Previous studies have implicated NaV1.6 dysfunction in late INa-mediated arrhythmias. Therefore we investigated NaVdysregulation by arrhythmogenic CaM mutant D96V. Chinese hamster ovarycells expressing NaV1.6 were transfected with either WT- or D96V-CaM. STED microscopy revealed enlarged NaV1.6 clusters in cells receiving D96V-CaM relative to WT. Therefore we explored NaV1.6 remodeling in transgenic mice with cardiac-specific expression of D96V-CaM (cD96V). Confocal microscopy confirmed expression of NaV1.6 and FLAG-tagged D96V-CaM in a striated pattern along with RyR2 in cD96V hearts, consistent with T-tubular localization. STORM microscopy enabled the quantitative assessment of NaV1.6 clustering. In both WT and cD96V hearts, ~50% of NaV1.6 clusters localized <100 nm from RyR2. However, NaV1.6 density within these regions increased 67% in cD96V relative to WT. We probed the functional impact of this surprising remodeling using SICM-guided “smart” patch clamp recording of NaV activity from T-tubule openings. The number of NaVs as well as frequency of late NaV1.6 burst openings were significantly increased in cD96V myocytes relative to WT (Fig 1). Previous work implicates aberrant late NaV1.6 activity in proarrhythmic Ca2+ mishandling. Indeed, STORM revealed significant enrichment of NCX near NaV1.6 in both WT and cD96V. Consistent with these data cD96V myocytes displayed larger, more frequent Ca2+ sparks relative to WT. This effect was reversed by cardiac-specific NaV1.6 knockout. To our knowledge, this is the first report of proarrhythmic cardiac structural remodeling secondary to a defect in calmodulin, which may shed mechanistic insight into calmodulinopathy.

Calmodulin (CaM) mutants are associated with severe arrhythmias (calmodulinopathy). While dysregulation of Ca2+handling proteins (RyR2, CaV1.2) are known mediators of calmodulinopathy, the role of Na+channels (NaVs) remains unclear. Interestingly, effects on CaV1.2 do not fully explain action potential (AP) prolongation by the long QT syndrome CaM mutant D96V. We investigated NaVdysregulation by D96V-CaM and its arrhythmogenic impact.In wild-type (WT) murine cardiomyocytes (CM) dialysis of D96V-CaM (6.5 μM) via a patch pipette prolonged AP, induced early and delayed afterdepolarizations (EADs and DADs) and increased Ca2+waves compared to WT-CaM. The effects of D96V-CaM were abrogated by a NaV1.6 blocker, 4,9-anhydrotetrodotoxin (4,9ahTTX, 300 nM; Fig. 1A). Dialysis of D96V-CaM dysregulated inactivation of 4,9ahTTX-sensitive Na+current (INa) promoting late INain WT murine CM (Fig. 1B) and in Chinese Hamster Ovary(CHO) cells expressing NaV1.6 but not NaV1.5. D96V-CaM, but not WT-CaM, also promoted late INain human induced pluripotent stem cell (iPSC)-derived ventricular myocytes, underscoring translational relevance (Fig. 1C). To examine the arrhythmia potential of NaV1.6 dysregulation by D96V-CaM, we generated mice with cardiac-specific expression of D96V-CaM (cD96V; tgD96V-CaM x β-MHC-Cre). cD96V mice exhibited increased late INaand Ca2+waves resembling those in D96V-CaM-dialyzed WT CMs. In vivocD96V mice evidenced prolonged QTc intervals and ventricular tachycardia (VT) during bradycardia (carbachol 0.5 mg/kg intraperitoneal). Cardiac-specific NaV1.6 knockout protected cD96V mice from impaired INainactivation and arrhythmogenic Ca2+waves on cellular level as well as long QT and VT in vivo(Fig. 1D, E).In summary, D96V-CaM promotes arrhythmias by dysregulating NaV1.6 and thereby, facilitating aberrant Ca2+release. Importantly, NaV1.6 may be a therapeutic target for management of CaM-related arrhythmias.

Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis)by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.

Background:Characteristics of the aging face include not only senescence and flaccidity of the skin, but also sagging of deeper tissues, especially in the fascial and fatty layers. Objective:This study was undertaken to evaluate the different surgical approaches to the aging face, specifically the techniques available for correction of the prominent nasolabial fold, which is a significant sign of facial aging. Methods:Through a total of 7446 cases in more than 40 years of experience in the surgical correction of the aging face, the senior author has emphasized the importance of the repositioning of the skin and the facial soft tissues. After appropriate treatment of the superficial musculoaponeurotic system (SMAS) and the malar fat pad has been completed, adequate placement of the skin flaps is done by rotation, as described in the round-lifting technique, rather than by direct traction. The anatomic basis of this correction is discussed. Results:Traction of the SMAS was found to soften the appearance of the nasolabial fold to varying degrees, but other complementary procedures such as collagen injection or fat grafting often were necessary to achieve a more satisfactory correction. Durability of nasolabial fold correction with simple SMAS traction varied with each individual and his or her unique aging process. Simple traction of the SMAS did not include treatment of the fascial fatty layer. The senior author has included the treatment of the fascial fatty layer in his standard rhytidectomy over the last 2 years, with improved aesthetic results. Again, long-term correction by this technique is related to the aging process, and the final result was deemed superior to treatment of the SMAS alone. Direct excision of the nasolabial fold was performed in patients ranging from 35 to 60 years of age who had extremely prominent folds. In these very select cases, the results were considered satisfactory to both the surgeon and patient, with correction of the fold and acceptable scars. Conclusions:There is as yet no ideal solution for the surgical correction of the naso-labial fold component of the aging face. However, all of the techniques described are considered safe and have precise indications. It should be stressed to the patient that the nasolabial fold is part of the anatomy of the face and that the goal of treatment is to soften the appearance of the fold, not to eliminate it completely.

To determine the penetration of ceftibuten into various respiratory tissues and fluids.

The pharmacokinetics of intravenously administered recombinant human interleukin‐10 (rHuIL‐10) were evaluated in 18 subjects with creatinine clearances (Clcr) between 2.7 and 116.7 mL/min/1.73m2. Serum samples for rHuIL‐10 were obtained over a 48‐hour period after a single 25 μg/kg IV bolus infusion. AUC, total body clearance (Clp), and steady‐state volume of distribution (Vdss) were derived by compartmental methods. Analysis of serum concentrations showed statistically significant group differences for log‐transformed AUC and original scale Clp (p < 0.01). The AUC and effective half‐life increased, while the mean Clp of rHuIL‐10 decreased as renal function declined. A linear relationship between AUC and Clcr as well as Clp and Clcr demonstrates that the disposition of rHuIL‐10 is altered in subjects with renal insufficiency. No serious adverse events were noted.

This article describes, the process used by nurse executives at four freestanding rehabilitation facilities to implement and validate an interactive patient classification system. The research process involved defining critical indicators, measuring workloads by level of staff, and validating the number of care hours for the levels of patient classification. The database enabled the four consortium members to share their knowledge, resources, and costs of implementing a patient classification system, and it provides a benchmark of rehabilitation services. The study data are being used in making staffing decisions, preparing and defending budgets, and identifying the cost of care by disability classification.

The dermocartilaginous ligament of the nose, as first described by the senior author, has been shown to influence the equilibrium of the dorsumtip relationship. In some noses, this is manifested by a residual convexity after routine rhinoplastic management of the osteocartilaginous structures. The anatomic findings are reported, and surgical considerations are analyzed. A system of classification based on the thickness of the ligament has been shown to be helpful in the intraoperative evaluation of this structure. Plast. Reconstr. Surg.95 790, 1995.

Interleukin-10 inhibits T-lymphocyte activation and proliferation and lipopolysaccharide-induced monocyte production of proinflammatory cytokines. Fifty-four healthy volunteers received single doses of recombinant human interleukin-10 (1.0, 2.5, 5.0, 10, 25, or 50 μg/kg) or placebo by subcutaneous injection (randomized double-blind assignment). Clinical adverse events were infrequent at doses below 50 μg/kg (five of six subjects had mild flu-like syndrome). Mean serum interleukin-10 concentrations were dose related. The mean terminal-phase half-life ranged from 2.7 to 4.5 hours, and the apparent volume of distribution ranged from 0.70 to 1.35 L/kg. Hematologic changes included transient mild to moderate increases of neutrophil counts, decreases of lymphocyte counts, and a delayed decrease of platelet counts. Recombinant human interleukin-10 significantly suppressed production of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α by whole blood stimulated ex vivo with Escherichia coli lipopolysaccharide.

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40‐mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration‐time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration‐time curves. For loratadine, the plasma Cmaxwas 30.5 ng/mL at 1.0 hour after dosing and the milk Cmaxwas 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk‐plasma AUC ratio was 1.2 and 4.2 μg of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmaxwas 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmaxwas 16.0 ng/mL, which was in the 4 to 8‐hour collection interval. Through 48 hours, the mean milk‐plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 μg of descarboethoxyloratadine (7.5 μg loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 μg loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4‐kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis. An estimated “worst‐case” dose (i.e., the maximum dose that could be expected under any circumstances) of loratadine and descarboethoxyloratadine to an infant was calculated to be only 1.1% of the adult loratadine dose on a mg/kg basis. The adult dose has been reported to be safe and well tolerated, so it is unlikely that this dose presents a hazard to infants.

The effect of a high‐fat breakfast on the bioavailability of the components of an extended‐release tablet containing 10 mg loratadine in the immediate‐release coating and 240 mg pseudoephedrine sulfate in the extended‐release core was studied in 24 healthy male volunteers in a single‐dose, two‐way crossover study. The drug was administered after a 10‐hour overnight fast or within 5 minutes of consuming a standardized high‐fat breakfast. Serial blood samples were collected over a 48‐hour period, and plasma was analyzed for loratadine and its active metabolite descarboethoxyloratadine (DCL), and pseudoephedrine. For pseudoephedrine, maximum concentration (Cmax) and area under the concentration—time curve extrapolated to infinity (AUC0‐∞) were similar after both treatments, indicating no relevant food effect on the bioavailability of pseudoephedrine. Also, the absorption profiles of pseudoephedrine (from Wagner‐Nelson analysis) were similar for the fed and fasted treatments, indicating no apparent differences in absorption. Plasma concentration—time profiles and values for Cmaxand AUC0‐∞of DCL were similar for the two treatments, indicating no relevant food effect on the pharmacokinetics of DCL. In contrast, for loratadine, administration with food resulted in a significantly increased mean Cmax(53%) and AUC from time zero to the final quantifiable sample (AUCtf) (76%). However, the resultant Cmaxand AUC of loratadine under fed conditions were well below those previously obtained at steady‐state after multiple‐dose administration of loratadine (40 mg/day) that were shown to be safe and well‐tolerated in several clinical studies. The effect of food on the bioavailability and pharmacokinetic profiles of the components of a combination loratadine/pseudoephedrine extended‐release tablet is not likely to be clinically significant.