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Bhaskar Rege,1 Jonathan M Meyer2 1Pharmaceutical & Early Stage Clinical Development, Alkermes, Inc., Waltham, MA, USA; 2Department of Psychiatry, University of California, San Diego, CA, USACorrespondence: Bhaskar Rege, Alkermes, Inc., 852 Winter Street, Waltham, MA, 02451, USA, Email Bhaskar.Rege@alkermes.com

Christoph U Correll,1–3 Rakesh Jain,4 Jonathan M Meyer,5 Antonia Periclou,6 Timothy Carrothers,6 Ágota Barabássy,7 Mehul Patel,8 Willie Earley91Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 2Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; 3Charité Universitätsmedizin, Department of Child and Adolescent Psychiatry, Berlin, Germany; 4Texas Tech University School of Medicine – Permian Basin, Department of Psychiatry, Midland, TX, USA; 5University of California, San Diego School of Medicine, Department of Psychiatry, La Jolla, CA, USA; 6Allergan, Department of Clinical Pharmacology, Madison, NJ, USA; 7Department of Medical Affairs, Gedeon Richter Plc, Budapest, Hungary; 8Department of Medical Affairs, Allergan, Madison, NJ, USA; 9Department of Clinical Development, Allergan, Madison, NJ, USACorrespondence: Christoph U CorrellThe Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USATel +1 718 470 4812Email ccorrell@northwell.eduObjective: To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs).Methods: Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan–Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves.Results: The Kaplan–Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6–7 weeks after randomization, compared to the Kaplan–Meier curves for the other AAPs, which showed earlier separation at 1–4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8–34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (

BackgroundCeramide kinase-like protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism.ObjectivesTo determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress.MethodsCERKL expression was determined by RNA-Seq, quantitative polymerase chain reaction and immunohistochemistry. CERKL was knocked down in cSCC cells using small interfering RNA. Sphingolipid content was analysed by liquid chromatography-mass spectrometry. Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin V binding.ResultsCERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL is also expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress.ConclusionsThese findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

BackgroundCeramide Kinase-Like Protein (CERKL) was originally described in retinal tissue. CERKL has been shown to protect cells from oxidative stress, and mutations in CERKL underlie the inherited disease, retinitis pigmentosa. CERKL expression maintains cellular sphingolipids via an unknown mechanism.ObjectivesTo determine whether CERKL is expressed in epidermis and cutaneous squamous cell carcinoma (cSCC) and whether CERKL expression affects cSCC sphingolipid metabolism and susceptibility to oxidative stress.MethodsCERKL expression was determined by RNA-Seq, qPCR and immunohistochemistry. CERKL was knocked down in cSCC cells using siRNA. Sphingolipid content was analyzed by liquid chromatography-mass spectrometry (LC-MS). Oxidative stress was induced by treatment with H2 O2 , and apoptosis was measured using flow cytometry to determine annexin v binding.ResultsCERKL mRNA and protein are highly expressed in actinic keratosis and cSCC in comparison with normal epidermis. CERKL also is expressed in metabolically active epithelial cells in normal hair bulbs and sebaceous glands. CERKL knockdown in cultured cSCC cells reduces cellular sphingolipid content and enhances susceptibility to oxidative stress.ConclusionsThese findings suggest that CERKL may be important in cSCC progression and could lead to novel strategies for prevention and treatment of cSCC.

In this article, we provide information on patient-reported side effects from a cross-section of realworld patients. Specifically, data on side effects were tabulated for patients taking at least one of the following atypical antipsychotic medications: aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone. Approximately 54 percent of the 353 respondents reported having experienced a side effect as a result of taking an atypical antipsychotic medication. Most common side effects mentioned included the following: weight gain/hunger, tiredness/lethargy, and lack of coordination/muscle problems, such as tenderness, twitches, and tremors. Of those experiencing a side effect, less than 25 percent reported this side effect to their physician. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups. [ABSTRACT FROM AUTHOR]

Background: Pretreatment antimicrobial resistance has an important impact on the efficacy of many Helicobacter pylori treatment regimens.Objective: To estimate the prevalence of H. pylori resistance to antimicrobials in the United States, to characterize risk factors associated with H. pylori antimicrobial resistance, and to explore the association between drug utilization and antimicrobial resistance patterns over time.Design: Meta-analysis using patient-level data.Setting: 20 nationwide trials of H. pylori eradication.Patients: 3624 men and women, each of whom contributed one isolate.Measurements: Rates of H. pylori resistance to clarithromycin, metronidazole, and amoxicillin, according to geographic region, age, sex, study year, ethnicity, ulcer status, test method, and study.Results: Overall resistance to clarithromycin, metronidazole, and amoxicillin was 10.1% (95% CI, 9.1% to 11.1% [360 of 3571 patients]), 36.9% (CI, 35.1% to 38.7% [1063 of 2883 patients]), and 1.4% (CI, 1.0% to 1.8% [48 of 3486 patients]), respectively. In multivariable analyses, multiple risk factors were associated with resistance to individual agents. Clarithromycin resistance was significantly associated with geographic region (P = 0.050), older age (P < 0.001), female sex (P < 0.001), inactive ulcer disease (P < 0.001), and study (P = 0.010). Metronidazole resistance was significantly associated with female sex (P < 0.001), earlier year of study enrollment (P = 0.036), Asian ethnicity (P < 0.001), use of an epsilometer test (P = 0.002), and study (P < 0.001). Amoxicillin resistance was low and was not significantly associated with any risk factor. In the 1990s, when rates for use of oral macrolides and metronidazole were relatively stable, clarithromycin resistance rates were stable and metronidazole resistance rates varied.Conclusions: Clinicians should consider risk factors for antimicrobial resistance when deciding which patients should have susceptibility testing and when choosing appropriate H. pylori treatments in the empirical setting. [ABSTRACT FROM AUTHOR]

The in-vitro activities of paromomycin and metronidazole alone or paromomycin and metronidazole plus hydroxymetronidazole (2:1 ratio) were studied against 19 Helicobacter pylori isolates using an in-vitro chequerboard technique. Partial synergy was demonstrated for the majority of isolates (11/19) for both combinations tested. When hydroxymetronidazole was added to the parent compound, the number of metronidazole-sensitive isolates demonstrating synergy increased to 5/12, compared with 1/12 for the combination that did not include the metabolite. In metronidazole-resistant isolates there was a shift from an additive effect to partial synergy for the combination containing hydroxymetronidazole. The in-vitro activity of paromomycin and the synergic effect that is achieved in combination with metronidazole and hydroxymetronidazole render paromomycin suitable for further investigation as a treatment option for H. pylori infection. [ABSTRACT FROM PUBLISHER]

Purpose. Ensuring that all Americans have access to quality oral health care has become the primary focus of local, state, and federal government agencies; and the issue has also been placed on numerous legislative agendas. The purpose of the school-based project at the Southern Illinois University Carbondale (SIUC) Dental Hygiene Program (DHP) was to assist in meeting the goals outlined in the Oral Health in America: The Report of the Surgeon General, Healthy People 2010 (HP 2010), the Illinois Oral Health Plan (IOHP) and A National Call to Action to Promote Oral Health. Dental hygiene (DH) students play a significant role in meeting current access issues. Recent legislation in Illinois has allowed registered dental hygienists (RDHs) to practice under the general supervision of a dentist. Significance. To close the gap in the disparities concerning access to care, DH students have been utilized in multiple settings beyond the traditional and institutionally-based dental hygiene clinic. DH students are being used to staff school-based dental sealant programs as well as safety-net clinics serving a more diverse population including those clients with special needs. Since the students are still matriculating through school, relaxation of the supervision laws have increased the opportunities for those needing the most care to be seen and subsequently treated in facilities or remote sites by DH students who are supervised by the RDH. To date, the Dental Sealant Grant Program (DSGP) at SIUC has seen well over 250 what is considered at-risk, low-income children, placed approximately 400 sealants and has established a referral system for children requiring urgent or routine care through the campus-based Community Dental Center (CDC) and the Illinois Children's Health Foundation (ICHF), which is an extension of the CDC. Both clinics utilize DH students as primary clinicians, supervised by the DH program faculty. This approach to treatment, lends itself to meeting the oral health needs of the population through effective collaborations and partnering with entities within the community that continually seek such services as highlighted in the Surgeon General's Report on Oral Health, in addition to the IOHP. Conclusion: The SIUC DSGP employs the utilization of dental hygiene students under the general supervision of the RDH. The school-based oral health program can serve as one small step towards achieving autonomy in dental hygiene practice. [ABSTRACT FROM AUTHOR]

Background: Spontaneous rupture of the oesophagus is a potentially fatal condition. Symptoms can vary and diagnosis can be challenging., Case Presentation: A woman in her seventies presented to the emergency department with sudden-onset epigastric pain after a meal. A computed tomography (CT) showed signs of oesophageal rupture. Upper gastrointestinal endoscopy revealed an oesophageal rupture, and a stent was placed. The patient developed fever, dyspnoea and hypotension after the procedure. Additional CT revealed increasing pleural effusion, pneumomediastinum and loculaments of air in the peritoneum, and a mediastinal abscess. Laparoscopy with lavage and debridement was performed. A catheter was placed in the abscess and a chest tube in her right hemithorax. The stent was removed after 27 days. Further investigation revealed eosinophil oesophagitis as the likely cause of her oesophageal rupture., Interpretation: This case highlights the importance of early diagnosis and proper treatment of spontaneous oesophageal rupture. Treatment depends on the cause of the rupture and severity of the patient's condition.

Background: Optimal medical therapy (OMT) is a modifiable factor that decreases mortality and cardiovascular events in patients with severe peripheral arterial disease. We hypothesized that preintervention OMT would be associated with improved 1-year reintervention and major adverse limb event (MALE) rates after elective endovascular revascularization for intermittent claudication (IC)., Methods: Using the Vascular Quality Initiative (2010-2020), we identified patients with IC undergoing elective endovascular, hybrid, and open surgical interventions. Preoperative antiplatelet, statin, and nonsmoking status defined OMT components and created three groups: complete (all components), partial (1-2 components), and no OMT. The primary outcome was 1-year reintervention. Secondary outcomes included MALE and factors associated with OMT usage. Multivariable logistic regression generated adjusted odds ratios (aOR)., Results: There were 39,088 patients (14,907 [38.1%] complete, 22,054 [56.4%)] partial, 2127 [5.4%] no OMT) who met our criteria. Patients with any OMT were more frequently older with more cardiovascular diseases and diabetes (P < .0001). Patients without OMT were more likely to be Black or with Medicare or Medicaid (P < .05). Observed 1-year reintervention (5.3% complete OMT, 6.1% partial OMT, 8.3% no OMT; P < .001) and MALE (5.6% complete OMT, 6.3% partial OMT, 8.8% no OMT; P < .001) were decreased by partial or complete OMT compared with no OMT. Complete OMT significantly decreased the adjusted odds of reintervention and MALE by 28% (aOR, 0.72, 95% confidence interval [95% CI], 0.59-0.88) and 30% (aOR, 0.70; 95% CI, 0.58-0.85), respectively, compared with no OMT. Partial OMT decrease the adjusted odds of reintervention and MALE by 24% (aOR, 0.76; 95% CI, 0.63-0.92) and 26% (aOR, 0.74; 95% CI, 0.62-0.89), respectively., Conclusions: Preintervention OMT is an underused, modifiable risk factor associated with improved 1-year reintervention and MALE. Vascular surgeons are uniquely positioned to initiate and maintain OMT in patients with IC before revascularization to optimize patient outcomes., Competing Interests: Disclosures None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The prototype "Oldenburger Logopädie App" (OLA) was designed to support voice therapy for patients with recurrent paresis, such as to accompany homework or as a short-term substitute for regular therapy due to dropouts, such as during the COVID-19 pandemic. The treating speech and language pathologists (SLPs) unlocks videos individually applicable to the respective patients, in which the SLPs instruct the individual exercises. The app can be used without information technology knowledge or detailed instructions., Materials and Methods: The prototype's usability was evaluated through a usability test battery (AttrakDiff questionnaire, System Usability Scale, Visual Aesthetics of Websites Inventory questionnaire) and informal interviews from the perspective of patients and SLPs., Results: The acceptance, usability, user experience, self-descriptiveness, and user behavior of OLA were consistently given and mostly rated as positive. Both user groups rated OLA as practical and easy to use (eg, System Usability Scale: "practical" (agree: ∅ 49.5%), "cumbersome to use" (total: strongly disagree: ∅ 60.0%). However, the monotonous layout of the app and the instructional and exercise videos should be modified in the next editing step. An overview of relevant criteria for a voice therapy app, regarding design and functions, was derived from the results., Conclusion: This user-oriented feedback on the usability of the voice app provides the proof of concept and the basis for the further development of the Artificial intelligence-based innovative follow-up app LAOLA. In the future, it should be possible to support the treatment of all voice disorders with such an app. For the further development of the voice app, the therapeutic content and the effectiveness of the training should also be investigated., Competing Interests: Declaration of Competing Interest Sabrina Habben Schröder declares on behalf of all authors that the manuscript “Requirements for the Acceptance of an App for Voice Therapy—A Usability Report based on the “Oldenburger Logopädie App” (OLA)” is original, has not been fully or partly published before, and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors is responsible for communicating with the other authors about process, submissions of revisions, and final approval of proofs. None declared., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Epigenetic clocks represent molecular evidence of disease risk and aging processes and have been used to identify how social and lifestyle characteristics are associated with accelerated biological aging. However, most research is based on samples of older adults who already have measurable chronic disease., Objective: To investigate whether and how sociodemographic and lifestyle characteristics are associated with biological aging in a younger adult sample across a wide array of epigenetic clock measures., Design, Setting, and Participants: This cohort study was conducted using data from the National Longitudinal Study of Adolescent to Adult Health, a US representative cohort of adolescents in grades 7 to 12 in 1994 followed up for 25 years to 2018 over 5 interview waves. Participants who provided blood samples at wave V (2016-2018) were analyzed, with samples tested for DNA methylation (DNAm) in 2021 to 2024. Data were analyzed from February 2023 to May 2024., Exposure: Sociodemographic (sex, race and ethnicity, immigrant status, socioeconomic status, and geographic location) and lifestyle (obesity status by body mass index [BMI] in categories of reference range or underweight [<25], overweight [25 to <30], obesity [30 to <40], and severe obesity [≥40]; exercise level; tobacco use; and alcohol use) characteristics were assessed., Main Outcome and Measure: Biological aging assessed from banked blood DNAm using 16 epigenetic clocks., Results: Data were analyzed from 4237 participants (mean [SD] age, 38.4 [2.0] years; percentage [SE], 51.3% [0.01] female and 48.7% [0.01] male; percentage [SE], 2.7% [<0.01] Asian or Pacific Islander, 16.7% [0.02] Black, 8.7% [0.01] Hispanic, and 71.0% [0.03] White). Sociodemographic and lifestyle factors were more often associated with biological aging in clocks trained to estimate morbidity and mortality (eg, PhenoAge, GrimAge, and DunedinPACE) than clocks trained to estimate chronological age (eg, Horvath). For example, the β for an annual income less than $25 000 vs $100 000 or more was 1.99 years (95% CI, 0.45 to 3.52 years) for PhenoAgeAA, 1.70 years (95% CI, 0.68 to 2.72 years) for GrimAgeAA, 0.33 SD (95% CI, 0.17 to 0.48 SD) for DunedinPACE, and -0.17 years (95% CI, -1.08 to 0.74 years) for Horvath1AA. Lower education, lower income, higher obesity levels, no exercise, and tobacco use were associated with faster biological aging across several clocks; associations with GrimAge were particularly robust (no college vs college or higher: β = 2.63 years; 95% CI, 1.67-3.58 years; lower vs higher annual income: <$25 000 vs ≥$100 000: β = 1.70 years; 95% CI, 0.68-2.72 years; severe obesity vs no obesity: β = 1.57 years; 95% CI, 0.51-2.63 years; no weekly exercise vs ≥5 bouts/week: β = 1.33 years; 95% CI, 0.67-1.99 years; current vs no smoking: β = 7.16 years; 95% CI, 6.25-8.07 years)., Conclusions and Relevance: This study found that important social and lifestyle factors were associated with biological aging in a nationally representative cohort of younger adults. These findings suggest that molecular processes underlying disease risk may be identified in adults entering midlife before disease is manifest and inform interventions aimed at reducing social inequalities in heathy aging and longevity.

Background: Incretin therapies, comprised of the dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been increasingly utilized for the treatment of type 2 diabetes (T2DM). Previous studies have conflicting results regarding risk of pancreatitis associated with these agents-some suggest an increased risk and others find no correlation. Adverse event reporting systems indicate that incretin therapies are some of the most common drugs associated with reports of pancreatitis., Objectives: This study aimed to compare the odds of developing pancreatitis in veterans with T2DM prescribed an incretin therapy versus thiazolidinediones (TZDs: pioglitazone and rosiglitazone) within the Veterans Health Administration (VHA)., Methods: This was a retrospective cohort study analyzing veterans with T2DM first prescribed an incretin therapy or a TZD between January 1, 2011, and December 31, 2021. A diagnosis of pancreatitis within 365 days of being prescribed either therapy was counted as a positive case. Data was collected and analyzed utilizing VA's Informatics and Computing Infrastructure (VINCI) and an adjusted odds ratio was calculated., Results: The TZD cohort consisted of 42 912 patients compared with the incretin cohort of 304 811 patients. The TZD cohort had a pancreatitis incidence rate of 1.94 cases per 1000 patients. The incretin cohort had a incidence rate of 2.06 cases per 1000 patients. An adjusted odds ratio found no statistical difference of pancreatitis cases between the TZD and incretin cohorts (adjusted odds ratio [AOR] = 0.94, 95% CI [0.75, 1.18])., Conclusion and Relevance: This retrospective cohort study of national VHA data found a relatively low incidence of pancreatitis in both cohorts, and an adjusted odds ratio found no statistical difference of pancreatitis in patients prescribed an incretin therapy compared with a control group. This data adds to growing evidence that incretin therapies do not seem to be associated with an increased risk of developing pancreatitis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Laboratories commonly provide norclozapine concentrations when a plasma clozapine level is requested, but the appropriate use of this information for the treatment of individuals with schizophrenia is not always clear. Particularly vexing is the fact that norclozapine possesses pharmacological properties that are distinct from its parent compound and which contribute to clozapine's efficacy signal, yet the literature focuses primarily on the association of clozapine levels with symptomatic improvement. The purpose of this brief article is to highlight findings with respect to the need to track norclozapine levels, or the ratio of clozapine/norclozapine plasma levels, to optimize efficacy among inadequate responders to clozapine treatment. In addition, there will be a discussion of the specific type of information provided by the clozapine/norclozapine ratio on clozapine's clearance, and how this ratio is sometimes misinterpreted. There is clinical value from to be derived from norclozapine levels and the clozapine/norclozapine ratio for schizophrenia management, and the principles governing use of this information will be distilled into 3 succinct axioms to aid clinicians in managing their clozapine-treated patients with schizophrenia., Competing Interests: Declaration of competing interest Dr. Meyer reports having received speaking or advising fees in the past 24 months from: AbbVie, Alkermes, BioXcel, ITCI, Karuna, Neurocrine, Noven, Otsuka-USA, Sumitomo Pharma (formerly Sunovion) and Teva., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Sleep duration changes across the life course and differs by education in the United States. However, little research has examined whether educational differences in sleep duration change over age-or whether sleep duration trajectories over age differ by education. This study uses a life course approach to analyze American Time Use Survey data (N = 60,908), examining how educational differences in weekday sleep duration change from middle to older adulthood (ages 40-79). For men only, differences in total sleep time between individuals with less than a high school degree and those with more education converge in older adulthood. Results suggest that this leveling is explained by decreasing educational stratification in work hours as men enter older adulthood. Findings highlight the importance of employment for shaping gendered socioeconomic differences in sleep and demonstrate differences by education in how sleep duration changes over age, with possible implications for health disparities.

Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment contributes unique signals that influence cancer growth, immunogenicity, and metastasis. Traditional cancer therapies have limited effectiveness due to off-target effects and poor distribution on bones. As a result, therapies with improved specificity and efficacy for treating bone tumors are highly needed. One of the most promising strategies involves the targeted delivery of pharmaceutical agents to the site of bone cancer by introduction of bone-targeting moieties, such as bisphosphonates or oligopeptides. These moieties have high affinities to the bone hydroxyapatite matrix, a structure found exclusively in skeletal tissue, and can enhance the targeting ability and efficacy of anticancer drugs when combating bone tumors. This review focuses on the engineering of small molecules and proteins with bone-targeting moieties for the treatment of bone tumors., Competing Interests: Declaration of interests X.Z., and H.X. are inventors of patents titled “Bone-specific delivery of polypeptides (EP4281116A1),” “Engineered compositions for bone-targeted therapy (WO2023004348A1),” and “Methods for controlling osteocalcin release (WO2023064802A1).” J.M.B. serves as the Chief Executive Officer of Osteologic Therapeutics, Inc. X.Z., and H.X. are cofounders and Scientific Advisory Board members of Osteologic Therapeutics, Inc., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Albumin knockout (Alb -/- ) mice exhibit a low plasma free fatty acid (FFA) concentration, but it was not known if the suppressed concentration reflects a lower rate of appearance (Ra) of FFA in the circulation (i.e., lower FFA flux) or if the absence of albumin alters the relationship between FFA flux and concentration. For understanding the role of albumin in FFA transport through the bloodstream, it is not sufficient to rely on FFA concentration data alone. Therefore, we developed a method to study FFA kinetics in Alb -/- mice. Using an albumin-free formulation of [U- 13 C]palmitate tracer, serum FFA kinetics were tested in Alb -/- and wild-type (WT) mice. Results indicate that the flux of FFA in serum of Alb -/- mice was significantly lower than in WT mice ( P < 0.05), while albumin deficiency did not alter the relationship between FFA flux and concentration. Next, to test if suppressed lipolysis might have also been involved in the suppressed FFA kinetics, gene expression of a lipolytic enzyme (adipose triglyceride lipase, Atgl) and a marker of lipolysis (phosphorylation of hormone-sensitive lipase, p-HSL) were measured in adipose tissue. In contrast to the low FFA flux in Alb -/- , both Atgl gene expression and p-HSL protein were significantly higher in adipose tissue of Alb -/- than in WT mice ( P < 0.05). Thus, the low FFA flux in Alb -/- appeared to be driven by the absence of albumin's FFA binding functions rather than through regulation of lipolysis, indicating that albumin is an important factor in determining the flux of FFA in circulation. NEW & NOTEWORTHY To improve understanding of the albumin protein's function in vivo, we tested plasma free fatty acid kinetics in albumin knockout mice compared with wild-type mice. Using a new tracer formulation strategy, it was discovered that the appearance rate of free fatty acids in serum is lower in albumin knockout mice than in wild-type mice. The results indicate that albumin is a major controller of free fatty acid kinetics.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually., (© 2024. The Author(s).)

Human herpesvirus type 6 (HHV6) reactivation after haploidentical hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PT-Cy) has been scarcely studied, especially when antithymocyte globulin (ATG) is added to the graft-versus-host disease (GvHD) prophylaxis. We conducted a retrospective cohort study in 100 consecutive patients receiving haploidentical HCT with PT-Cy. We systematically monitored HHV6 DNA loads in blood samples on a weekly basis using quantitative PCR until day +100. The 100-day cumulative incidence of HHV6 reactivation was 54%. Clinically significant HHV6 infections were rare (7%), associated with higher HHV6 DNA loads, and had favorable outcomes after antiviral therapy. The main risk factor for HHV6 reactivation was a low absolute lymphocyte count (ALC) \< 290/µL on day +30 (68% versus 40%, p = 0.003). Adding ATG to PT-Cy did not increase the incidence of HHV6 reactivation (52% with ATG versus 79% without ATG, p = 0.12). Patients experiencing HHV6 reactivation demonstrated delayed platelet recovery (HR 1.81, 95% CI 1.07-3.05, p = 0.026), higher risk of acute grade II-IV GvHD (39% versus 9%, p \< 0.001) but similar overall survival and non-relapse mortality to the other patients. In conclusion, our findings endorse the safety of combining ATG and PT-Cy in terms of the risk of HHV6 reactivation and infection in patients undergoing haploidentical HCT. Patients with a low ALC on day +30 face a higher risk of HHV6 reactivation and may require careful monitoring., Competing Interests: FM reports lecture honoraria from Therakos/Mallinckrodt, Sanofi, JAZZ Pharmaceuticals, Gilead, Novartis, and Bristol Myers Squibb, all outside the submitted work. MM reports grants and lecture honoraria from Janssen, Sanofi, Maat Pharma and JAZZ Pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer, grants from Roche, all outside the submitted work. RD reports research funding from Ligue contre le Cancer, Arthur Sachs, Monahan Foundation, Servier Foundation, Philippe Foundation, DCP AP-HP, honoraria from Novartis and Takeda, non-financial support from Kite Pharma / Gilead, all outside the submitted work. The other authors declare no competing financial interests.

In this theoretical study, we explore the enhancement of sensing capabilities in surface acoustic wave (SAW)-based magnetic field sensors through the integration of engineered phononic crystals (PnCs). We particularly focus on amplifying the interaction between the SAW and magnetostrictive materials within the PnC structure. Through comprehensive simulations, we demonstrate the synchronization between the SAWs generated by IDTs and the resonant modes of PnCs, thereby leading to an enhancement in sensitivity. Furthermore, we investigate the Δ E effect, highlighting the sensor's responsiveness to changes in external magnetic fields, and quantify its magnetic sensitivity through observable changes in the SAW phase velocity leading to phase shifts at the end of the delay line. Notably, our approach yields a magnetic field sensitivity of approximately S~138 °mT for a delay line length of only 77 µm in homogeneous magnetic fields. Our findings underline the potential of PnCs to advance magnetic field sensing. This research offers insights into the integration of engineered materials for improved sensor performance, paving the way for more effective and accurate magnetic field detection solutions.

Introduction: Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved in the United States (US) for the treatment of tardive dyskinesia (TD). There is a paucity of information on the impact of VMAT2 inhibitor treatment on patient social and physical well-being. The study objective was to elucidate clinician-reported improvement in symptoms and any noticeable changes in social or physical well-being in patients receiving VMAT2 inhibitors., Methods: A web-based survey was offered to physicians, nurse practitioners, and physician assistants based in the US who prescribed valbenazine for TD within the past 24 months. Clinicians reported data from the charts of patients who met the inclusion criteria and were allowed to recall missing information., Results: Respondents included 163 clinicians who reviewed charts of 601 VMAT2-treated patients with TD: 47% had TD symptoms in ≥2 body regions, with the most common being in the head or face and upper extremities. Prior to treatment, 93% of patients showed impairment in ≥1 social domain, and 88% were impaired in ≥1 physical domain. Following treatment, among those with improvement in TD symptoms (n = 540), 80% to 95% showed improvement in social domains, 90% to 95% showed improvement in physical domains, and 73% showed improvement in their primary psychiatric condition., Discussion: In VMAT2-treated patients with TD symptom improvement, clinicians reported concomitant improvement in psychiatric disorder symptoms and in social and physical well-being. Regular assessment of TD impact on these types of domains should occur simultaneously with movement disorder ratings when evaluating the value of VMAT2 inhibitor therapy., Competing Interests: Disclosures: JMM has received consulting fees from Acadia Pharmaceuticals, Alkermes, Intra-Cellular Therapies, Karuna, Neurocrine Biosciences, Inc, Otsuka America, Inc, Sunovion Pharmaceuticals, and Teva Pharmaceuticals; has received honoraria from Alkermes, Intra-Cellular, Neurocrine Biosciences, Noven, Sunovion, and Teva for lectures, presentations, speaker bureaus, manuscript writing, or educational events. CC has received research support from Axsome Therapeutics and Harmony Biosciences; has served as a consultant to Corium; has served on the advisory board of Idorsia and Karuna; has received speakers fees from Merck and Sunovion; has received speaker fees and served on the advisory board for Intra-Cellular, Ironshore, and Takeda; has received speaker fees, served as a consultant, and served on the advisory board for AbbVie, Alkermes, Eisai, Jazz, Lundbeck, Janssen, Noven, and Otsuka; has received speaker fees, served as a consultant, served on the advisory board for and has received research support from Acadia, Neurocrine Biosciences, and Teva. His spouse has served on the advisory board of Otsuka. RBB has received research funding from Neurocrine Biosciences. MMP-R has received research grant funding from AI Cure, Millennium Pharmaceuticals, Neurocrine Biosciences, and Takeda. She is a consultant for Alkermes and Neurocrine Biosciences. LL, EGF, and MB, are employees of Neurocrine Biosciences, and EGF is stockholder of Neurocrine Biosciences. CY is a former employee of Neurocrine Biosciences and is now an employee of Reneo Pharmaceuticals. RD is a former employee of Neurocrine Biosciences and is now an employee of UT Health San Antonio. BB is an employee of IQVIA LLC. Neurocrine Biosciences, Inc. provided funding for this study and development of the manuscript., (© 2023 AAPP. The Mental Health Clinician is a publication of the American Association of Psychiatric Pharmacists.)

Black Americans with multiple sclerosis (MS) experience higher levels of disease-related disability compared to White Americans (Marrie et al., 2006). Comorbidities such as depression and anxiety, which are underdiagnosed and undertreated in this population, negatively impact quality of life and treatment outcomes for people living with multiple sclerosis (plwMS) (D'Alisa et al., 2006; Marrie et al., 2009; Stepleman et al., 2014). Acts of discrimination toward Black Americans is associated with stress, which is a contributing factor for depression (Carter, 2017; Nadimpalli, 2015; Williams and Mohammed, 2009). This study compared the severity of multiple sclerosis symptoms amongst Black Americans and White Americans, and whether worsened MS symptoms in Black Americans are associated with increased experiences of discrimination. Data was analyzed from 143 plwMS in the Stress Indicators in Minorities with Multiple Sclerosis (SiMMS) study. Using the Mann-Whitney U test, significant differences were found on the NIH Emotional Distress - Anxiety measure (U = 1466.500, p = 0.045) and NIH Sleep Disturbance measure (U = 1467.000, p = 0.044) between the Black participant and the White participant groups. Discrimination was significantly correlated with both NIH Emotional Distress - Anxiety (r = 0.677, p < .001) and NIH Sleep Disturbance (r = 0.446, p = .007) in Black MS individuals. Additionally, several physiological condition and psychological outcome measures were correlated with the NIH Emotional Distress - Anxiety and NIH Sleep Disturbance measures. This study contributes to literature highlighting the negative impacts of discrimination and race related stress on the physical and mental health of Black Americans., Competing Interests: Declaration of Competing Interest There are no financial or personal interests (across any/all authors) that would affect author objectivity regarding this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: To help reduce relapse rates following alcohol and other drug (AOD) treatment, continuing care interventions have been recommended. Previous continuing care interventions have incorporated telephone and face-to-face sessions to help promote participant engagement. The study was conducted as a randomised controlled feasibility study and examined a call centre delivered continuing care intervention for people leaving residential rehabilitation services., Methods: Participants were attending AOD residential treatment services in NSW, Australia (N = 154). Participants were randomised to either 12- or 4-sessions of continuing care. Follow up assessments were completed at 6-months. The primary outcomes were demand and implementation. Secondary outcomes were AOD use, mental health and physical health at 6-months., Results: Interest in continuing care was high, with 93% of participants approached reporting an interest in being involved. Of the participants who completed the consent and baseline procedures, 29% of people were contacted post residential treatment and randomised. For those people randomised, the average number of sessions completed was 2.78 (SD = 1.65) for the 4-session arm and 4.81 (SD = 4.46) for the 12-session arm. Fidelity to the treatment manual was high. Both treatment arms showed higher complete abstinence at 6-months compared to baseline (12-session OR 28.57 [2.3, 353.8]; 4-session OR 28.11 [3.6, 221.2])., Discussion and Conclusions: A major challenge associated with the call centre approach was re-engaging participants once they left the residential facility and delivering the planned dose of treatment. Further work is required to promote greater uptake of these protocols once people leave residential treatment., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is characterized by symptoms including hallucinations and delusions, apathy, and cognitive impairment, and people with schizophrenia also experience many somatic comorbidities, such as metabolic disturbances, infectious diseases, cardiovascular issues, and respiratory illnesses. For decades, treatment for schizophrenia has focused on antipsychotics (APs) that reduce excess dopamine signaling to the associative striatum, which also blocks dopamine signaling in the dorsal striatum, creating movement disorders. Second-generation APs have a lower propensity to cause drug-induced movement disorders than first-generation APs. Nonetheless, only 1 out of 3 patients respond to any of the available APs; moreover, negative and cognitive symptoms tend to persist, while side effects and long-term risks can contribute to poor outcomes. However, there are new understandings in how to reduce dopamine release both presynaptically and selectively in circuits governing psychotic symptoms. These mechanisms offer a different treatment approach for patients with schizophrenia., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Patients with schizophrenia experience a broad range of detrimental health outcomes resulting from illness severity, heterogeneity of disease, lifestyle behaviors, and adverse effects of antipsychotics. Because of these various factors, patients with schizophrenia have a much higher risk of cardiometabolic abnormalities than people without psychiatric illness. Although exposure to many antipsychotics increases cardiometabolic risk factors, mortality is higher in patients who are not treated versus those who are treated with antipsychotics. This indicates both direct and indirect benefits of adequately treated illness, as well as the need for beneficial medications that result in fewer cardiometabolic risk factors and comorbidities. The aim of the current narrative review was to outline the association between cardiometabolic dysfunction and schizophrenia, as well as discuss the confluence of factors that increase cardiometabolic risk in this patient population. An increased understanding of the pathophysiology of schizophrenia has guided discovery of novel treatments that do not directly target dopamine and that not only do not add, but may potentially minimize relevant cardiometabolic burden for these patients. Key discoveries that have advanced the understanding of the neural circuitry and pathophysiology of schizophrenia now provide possible pathways toward the development of new and effective treatments that may mitigate the risk of metabolic dysfunction in these patients. Novel targets and preclinical and clinical data on emerging treatments, such as glycine transport inhibitors, nicotinic and muscarinic receptor agonists, and trace amine-associated receptor-1 agonists, offer promise toward relevant therapeutic advancements. Numerous areas of investigation currently exist with the potential to considerably progress our knowledge and treatment of schizophrenia., (© 2023. The Author(s).)

The intricate interdependency of device design and fabrication process complicates the development of microelectromechanical systems (MEMS). Commercial pressure has motivated industry to implement various tools and methods to overcome challenges and facilitate volume production. By now, these are only hesitantly being picked up and implemented in academic research. In this perspective, the applicability of these methods to research-focused MEMS development is investigated. It is found that even in the dynamics of a research endeavor, it is beneficial to adapt and apply tools and methods deduced from volume production. The key step is to change the perspective from fabricating devices to developing, maintaining and advancing the fabrication process. Tools and methods are introduced and discussed, using the development of magnetoelectric MEMS sensors within a collaborative research project as an illustrative example. This perspective provides both guidance to newcomers as well as inspiration to the well-versed experts.

Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, and altered PNPLA1 activity is implicated in the pathogenesis of atopic dermatitis and other common skin diseases. To examine the hypothesis that PNPLA1 catalyzes the synthesis of acylceramides and acyl acids, we expressed and partially purified a soluble, truncated form of PNPLA1 in Escherichia coli, (PNPLA1 trun ) along with the related protein PNPLA2 (ATGL, adipose triglyceride lipase) and coactivator CGI-58. Liposomal substrates were incubated with recombinant enzymes for 0.5-24 h and products analyzed by HPLC-UV and LC-MS. Using trilinolein or dilinolein substrates, PNPLA1 trun , like ATGL trun , catalyzed lipolysis and acyltransferase reactions with 2-30% conversion into linoleic acid, monolinolein, and trilinolein. CGI-58 enhanced ATGL-catalyzed lipolysis as previously reported, but transacylase activity was not enhanced with ATGL or PNPLA1. In matching the proposed activity in vivo, PNPLA1 catalyzed acyl transfer from trilinolein and dilinolein donors to omega-hydroxy ceramide, omega-hydroxy glucosylceramide, and omega-hydroxy acid acceptors to form acylceramide, glucosyl-acylceramide, and acyl acid, respectively, albeit with only ∼0.05% conversion of the substrates. Notably, in experiments comparing dilinolein vs. diolein acyl donors, PNPLA1 transferred linoleate with 3:1 selectivity over oleate into acylceramide. These results support the role for PNPLA1 in the synthesis of acylceramides and acyl acids in epidermis and suggest that the enrichment of these lipids with linoleic acid could result from the substrate selectivity of PNPLA1., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of the article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A key requirement in forming the water permeability barrier in the mammalian epidermis is the oxidation of linoleate esterified in a skin-specific acylceramide by the sequential actions of 12R-lipoxygenase, epidermal lipoxygenase-3, and the epoxyalcohol dehydrogenase SDR9C7 (short-chain dehydrogenase-reductase family 7 member 9). By mechanisms that remain unclear, this oxidation pathway promotes the covalent binding of ceramides to protein, forming a critical structure of the epidermal barrier, the corneocyte lipid envelope. Here, we detected, in porcine, mouse, and human epidermis, two novel fatty acid derivatives formed by KOH treatment from precursors covalently bound to protein: a "polar" lipid chromatographing on normal-phase HPLC just before omega-hydroxy ceramide and a "less polar" lipid nearer the solvent front. Approximately 100 μg of the novel lipids were isolated from porcine epidermis, and the structures were established by UV-spectroscopy, LC-MS, GC-MS, and NMR. Each is a C18 fatty acid and hydroxy-cyclohexenone with the ring on carbons C 9 -C 14 in the polar lipid and C 8 -C 13 in the less polar lipid. Overnight culture of [ 14 C]linoleic acid with whole mouse skin ex vivo led to recovery of the 14 C-labeled hydroxy-cyclohexenones. We deduce they are formed from covalently bound precursors during the KOH treatment used to release esterified lipids. KOH-induced intramolecular aldol reactions from a common precursor can account for their formation. Discovery of these hydroxy-cyclohexenones presents an opportunity for a reverse pathway analysis, namely to work back from these structures to identify their covalently bound precursors and relationship to the linoleate oxidation pathway., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)