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1.
BMC Psychiatry ; 24(1): 506, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39014363

ABSTRACT

BACKGROUND: Asians and Asian Americans have the lowest rate of mental health service utilization (25%) in the US compared to other racial/ethnic groups (39 - 52%), despite high rates of depression, anxiety, and suicidal ideation. The lack of culturally-responsive mental health trainings hinders access to mental health services for these populations. We assessed the mental health priorities of Asian communities in Greater Boston and evaluated cultural responsiveness of the Mental Health First Aid (MHFA), a first-responder training teaching participants skills to recognize signs of mental health and substance use challenges, and how to appropriately respond. METHODS: This is community-based participatory research with the Boston Chinatown Neighborhood Center (BCNC), Asian Women For Health (AWFH), and the Addressing Disparities in Asian Populations through Translational Research (ADAPT) Coalition. We conducted focus groups with community-based organization staff and community members to assess mental health priorities of Asian populations in Boston, MA. We then evaluated the utility and cultural-responsiveness of the English-language MHFA for Asian populations through pre- and post-training questionnaires and focus groups with community participants. Paired t-tests were used to evaluate questionnaire responses. Thematic analysis was used to analyze interviews. RESULTS: In total, ten staff and eight community members participated in focus groups, and 24 community members completed the MHFA and pre- and post-training questionnaires. Common mental health challenges in the Asian communities reported by participants were loneliness, high stigma around mental illnesses, academic pressure, and acculturation stress. Compared to pre-training, MHFA participants demonstrated lower personal mental health stigma (p < 0.001) and higher mental health literacy (p = 0.04) post-training. Participants also noted the lack of data statistics and case studies relevant to Asian populations in the training, and desired the training be offered in languages spoken by Asian ethnic subgroups (e.g., Chinese, Vietnamese). CONCLUSION: Cultural-responsiveness of the MHFA for Asian populations could be improved with the inclusion of data and case studies that capture common mental health challenges in the Asian communities and with translation of the MHFA to non-English languages predominant in Asian communities. Increasing the cultural relevance and language accessibility of the MHFA could facilitate wider adoption of these trainings across communities and help to reduce mental health stigma and gaps in literacy and service utilization.


Subject(s)
Asian , Community-Based Participatory Research , Emigrants and Immigrants , Focus Groups , Humans , Boston , Female , Asian/psychology , Adult , Male , Emigrants and Immigrants/psychology , Middle Aged , First Aid/methods , Mental Disorders/ethnology , Mental Disorders/therapy , Mental Health Services , Cultural Competency , Mental Health/ethnology , Culturally Competent Care
2.
Cancer Discov ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38959428

ABSTRACT

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

3.
MMWR Surveill Summ ; 73(5): 1-44, 2024 07 11.
Article in English | MEDLINE | ID: mdl-38980822

ABSTRACT

Problem/Condition: In 2021, approximately 75,000 persons died of violence-related injuries in the United States. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) on violent deaths that occurred in 48 states, the District of Columbia, and Puerto Rico in 2021. Results are reported by sex, age group, race and ethnicity, method of injury, type of location where the injury occurred, circumstances of injury, and other selected characteristics. This report introduces additional incident and circumstance variables, which now include child victim-specific circumstance information. This report also incorporates new U.S. Census Bureau race and ethnicity categories, which now account for more than one race and Native Hawaiian or other Pacific Islander categories and include updated denominators to calculate rates for these populations. Period Covered: 2021. Description of System: NVDRS collects data regarding violent deaths from death certificates, coroner and medical examiner records, and law enforcement reports. This report includes data collected for violent deaths that occurred in 2021. Data were collected from 48 states (all states with exception of Florida and Hawaii), the District of Columbia, and Puerto Rico. Forty-six states had statewide data, two additional states had data from counties representing a subset of their population (31 California counties, representing 64% of its population, and 13 Texas counties, representing 63% of its population), and the District of Columbia and Puerto Rico had jurisdiction-wide data. NVDRS collates information for each violent death and links deaths that are related (e.g., multiple homicides, homicide followed by suicide, or multiple suicides) into a single incident. Results: For 2021, NVDRS collected information on 68,866 fatal incidents involving 70,688 deaths that occurred in 48 states (46 states collecting statewide data, 31 California counties, and 13 Texas counties), and the District of Columbia. The deaths captured in NVDRS accounted for 86.5% of all homicides, legal intervention deaths, suicides, unintentional firearm injury deaths, and deaths of undetermined intent in the United States in 2021. In addition, information was collected for 816 fatal incidents involving 880 deaths in Puerto Rico. Data for Puerto Rico were analyzed separately. Of the 70,688 deaths, the majority (58.2%) were suicides, followed by homicides (31.5%), deaths of undetermined intent that might be due to violence (8.2%), legal intervention deaths (1.3%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force acting in the line of duty, excluding legal executions), and unintentional firearm injury deaths (<1.0%). The term "legal intervention" is a classification incorporated into the International Classification of Diseases, Tenth Revision, and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement.Demographic patterns and circumstances varied by manner of death. The suicide rate was higher for males than for females. Across all age groups, the suicide rate was highest among adults aged ≥85 years. In addition, non-Hispanic American Indian or Alaska Native (AI/AN) persons had the highest suicide rates among all racial and ethnic groups. Among both males and females, the most common method of injury for suicide was a firearm. Among all suicide victims, when circumstances were known (84.4%), suicide was most often preceded by a mental health, intimate partner, or physical health problem or by a recent or impending crisis during the previous or upcoming 2 weeks. The homicide rate was higher for males than for females. Among all homicide victims, the homicide rate was highest among persons aged 20-24 years compared with other age groups. Non-Hispanic Black or African American (Black) males experienced the highest homicide rate of any racial or ethnic group. Among all homicide victims, the most common method of injury was a firearm. When the relationship between a homicide victim and a suspect was known, the suspect was most frequently an acquaintance or friend for male victims and a current or former intimate partner for female victims. Homicide most often was precipitated by an argument or conflict, occurred in conjunction with another crime, or, for female victims, was related to intimate partner violence. Nearly all victims of legal intervention deaths were male, and the legal intervention death rate was highest among men aged 30-34 years. The legal intervention death rate was highest among AI/AN males, followed by Black males. A firearm was used in the majority of legal intervention deaths. When circumstances were known, the most frequent circumstances reported for legal intervention deaths were as follows: the victim used a weapon in the incident and the victim had a substance use problem (other than alcohol use). Other causes of death included unintentional firearm injury deaths and deaths of undetermined intent. Unintentional firearm injury deaths were most frequently experienced by males, non-Hispanic White (White) persons, and persons aged 15-24 years. These deaths most frequently occurred while the shooter was playing with a firearm and were precipitated by a person unintentionally pulling the trigger. The rate of deaths of undetermined intent was highest among males, particularly among AI/AN and Black males, and among adults aged 30-54 years. Poisoning was the most common method of injury in deaths of undetermined intent, and opioids were detected in nearly 80% of decedents tested for those substances. Interpretation: This report provides a detailed summary of data from NVDRS on violent deaths that occurred in 2021. The suicide rate was highest among AI/AN and White males, whereas the homicide rate was highest among Black males. Intimate partner violence precipitated a large proportion of homicides for females. Mental health problems, intimate partner problems, interpersonal conflicts, and acute life stressors were primary precipitating circumstances for multiple types of deaths examined. Public Health Action: Violence is preventable, and data can guide public health action. NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in developing, implementing, and evaluating programs, policies, and practices to reduce and prevent violent deaths. NVDRS data can be used to enhance prevention efforts into actionable strategies. States or jurisdictions have used their Violent Death Reporting System (VDRS) data to guide suicide prevention efforts and highlight where additional focus is needed. For example, North Carolina VDRS program data have played a significant role in expanding activities related to firearm safety and injury prevention. The program served as a primary data source for partners, which led to the creation of the Office of Violence Prevention in the state, focusing on combatting firearm-related deaths. In Maine, the VDRS provided data on law enforcement officer suicides that were used to help support a bill mandating mental health resiliency and awareness training in the state's law enforcement training academy, along with plans for similar training addressing mental health, substance use, and alcohol problems among corrections officers. In addition, states and jurisdictions have also used their VDRS data to examine factors related to homicide in their state or jurisdiction. For example, Georgia VDRS collaborated with the City of Atlanta Mayor's Office of Violence Reduction to develop two public dashboards that not only offer comprehensive data on violent deaths but also present data on the geographic distribution of populations disproportionately affected by violence to help inform violence prevention interventions.


Subject(s)
Cause of Death , Homicide , Population Surveillance , Suicide , Violence , Humans , Puerto Rico/epidemiology , Puerto Rico/ethnology , Child , Female , Adolescent , Violence/statistics & numerical data , Violence/ethnology , United States/epidemiology , Male , Adult , Middle Aged , Young Adult , Aged , Child, Preschool , Infant , Homicide/statistics & numerical data , Homicide/ethnology , Suicide/statistics & numerical data , Suicide/ethnology , District of Columbia/epidemiology , Wounds and Injuries/mortality , Wounds and Injuries/ethnology , Age Distribution , Sex Distribution , Ethnicity/statistics & numerical data , Aged, 80 and over
4.
Nat Commun ; 15(1): 4833, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844821

ABSTRACT

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.


Subject(s)
Regeneration , Single-Cell Analysis , Transcriptome , Humans , Animals , Regeneration/genetics , Mice , Saccule and Utricle/metabolism , Saccule and Utricle/cytology , Neuroma, Acoustic/genetics , Neuroma, Acoustic/metabolism , Neuroma, Acoustic/pathology , Ear, Inner/metabolism , Ear, Inner/cytology , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/genetics , Male , Hair Cells, Vestibular/metabolism , Female , Gene Expression Profiling
5.
Cell ; 187(13): 3236-3248.e21, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38772369

ABSTRACT

Leveraging AAVs' versatile tropism and labeling capacity, we expanded the scale of in vivo CRISPR screening with single-cell transcriptomic phenotyping across embryonic to adult brains and peripheral nervous systems. Through extensive tests of 86 vectors across AAV serotypes combined with a transposon system, we substantially amplified labeling efficacy and accelerated in vivo gene delivery from weeks to days. Our proof-of-principle in utero screen identified the pleiotropic effects of Foxg1, highlighting its tight regulation of distinct networks essential for cell fate specification of Layer 6 corticothalamic neurons. Notably, our platform can label >6% of cerebral cells, surpassing the current state-of-the-art efficacy at <0.1% by lentivirus, to achieve analysis of over 30,000 cells in one experiment and enable massively parallel in vivo Perturb-seq. Compatible with various phenotypic measurements (single-cell or spatial multi-omics), it presents a flexible approach to interrogate gene function across cell types in vivo, translating gene variants to their causal function.


Subject(s)
Gene Regulatory Networks , Single-Cell Analysis , Animals , Female , Humans , Mice , Cerebral Cortex/metabolism , Cerebral Cortex/cytology , CRISPR-Cas Systems/genetics , Dependovirus/genetics , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Genetic Vectors/metabolism , Mice, Inbred C57BL , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Neurons/metabolism , Neurons/cytology , Single-Cell Analysis/methods , Transcriptome/genetics , Cell Line , Transcription, Genetic
7.
J Commun Healthc ; : 1-9, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38695767

ABSTRACT

BACKGROUND: The COVID-19 pandemic introduced a myriad of changes that negatively impacted resident physicians' well-being. Communication from program leadership may mitigate resident stress during times of crisis, yet literature supporting this premise is scant, and best communication practices remain uncertain. This qualitative study aimed to identify stressors to residents and explore the influence of residency program leadership's communication on emotional stress during the COVID-19 pandemic. METHODS: Informed by Kotter's 8-step management model to support resident well-being, this qualitative study used grounded theory methods to interview 25 residents from three training programs (Pediatrics, Internal Medicine, and Medicine-Pediatrics) on a single academic medical campus from May-September 2020. Four investigators coded the data using the constant comparative analysis. Sampling continued until reaching thematic saturation. Codes were built using an iterative approach and organized into themes. Discrepancies were resolved by consensus discussion among investigators. RESULTS: Residents described increased stress levels, the all-consuming nature of COVID-19, mixed emotions about their role as healthcare providers, new coping mechanisms, and changes to their education and work environment that impacted stress. Communication from leadership to residents during the pandemic varied. Effective communication helped mitigate stress; perceived suboptimal communication exacerbated stress. Who was communicating, methods of communication, and content of communication influenced resident stress. CONCLUSIONS: The COVID-19 pandemic introduced new stressors and challenges to residents. The perception of leadership communication played a critical role in mitigating or exacerbating resident stress. We propose a communication framework ("Who? What? Where? When? How?") that residency leadership can utilize during times of crisis.

9.
bioRxiv ; 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38746193

ABSTRACT

Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "don't eat me" signaling axis between CD47 (ligand) and SIRPα (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRPα. Expression of the gene encoding the protein is required for bacteria to bind SIRPα or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRPα. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.

10.
Mar Pollut Bull ; 203: 116446, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38703627

ABSTRACT

Perfluorooctanesulfonic acid (PFOS) is detected in estuarine environments, where salinity levels fluctuate regularly. We investigated the effects of salinity on the toxicity of PFOS in embryos and larvae of Cyprinodon variegatus. We crossed six PFOS treatments (0, 1-10,000 µg/L) with two salinities (10, 30 ppt). Larvae exposed to the highest concentration of PFOS under high salinity accumulated over twice the amount of PFOS compared to larvae maintained under low salinity. Embryonic survival was unaffected by PFOS, salinity, or their interaction. PFOS delayed time to hatch and increased salinity reduced time to hatch regardless of PFOS treatment; however, no salinity by PFOS interactions were observed. Conversely, PFOS and salinity interacted in the larval stage, with decreased survival at 30 ppt salinity. This is one of the first studies evaluating interactive effects of PFOS and high salinity and highlights the importance of assessing PFAS toxicity across life stages.


Subject(s)
Alkanesulfonic Acids , Fluorocarbons , Larva , Salinity , Water Pollutants, Chemical , Animals , Fluorocarbons/toxicity , Alkanesulfonic Acids/toxicity , Water Pollutants, Chemical/toxicity , Larva/drug effects , Estuaries , Killifishes/physiology , Embryo, Nonmammalian/drug effects
11.
JCI Insight ; 9(10)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38652538

ABSTRACT

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here, we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, though the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Hypoxia-Inducible Factor 1, alpha Subunit , Liver , Manganese , Polycythemia , Animals , Polycythemia/metabolism , Polycythemia/genetics , Mice , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Liver/metabolism , Manganese/metabolism , Manganese/toxicity , Manganese/deficiency , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Humans , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Erythropoietin/metabolism , Erythropoietin/genetics , Mice, Knockout , Male , Hepatocytes/metabolism
12.
Curr Opin Cardiol ; 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38606620

ABSTRACT

PURPOSE OF REVIEW: The no-touch technique is an established method to harvest the saphenous vein (NT-SV), which is the most commonly used conduit in coronary artery bypass grafting. Herein, we summarize the foundational evidence, as well as highlight recent innovations and ongoing clinical trials involving NT-SV. RECENT FINDINGS: Through preservation of perivascular tissue for atraumatic handling and omission of manual distension, the NT-SV maintains endothelial nitrous oxide synthase levels and experiences less vascular smooth muscle cell activation, which translates to slower progression of atherosclerosis and less size mismatch of the graft and target vessel. These biomolecular advantages allow NT-SV to provide superior graft patency compared to conventional skeletonized saphenous vein and approximating that of the radial artery. Nonetheless, the clinical benefits of NT-SV for mortality and reduction in major adverse cardiac and cerebrovascular events are insufficiently studied in the long-term. The drawback of NT-SV is the short-term harvest site complications, which may potentially be addressed by the advent of endoscopic no-touch technique. SUMMARY: NT-SV is a promising conduit, and its role will be further clarified in upcoming clinical trials and as follow-up lengthens. However, conduit selection and harvest technique should ultimately be personalized to the individual patient.

13.
bioRxiv ; 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38585815

ABSTRACT

The application of allele-specific gene editing tools can expand the therapeutic options for dominant genetic conditions, either via gene correction or via allelic gene inactivation in situations where haploinsufficiency is tolerated. Here, we used allele-targeted CRISPR/Cas9 guide RNAs (gRNAs) to introduce inactivating frameshifting indels at a single nucleotide variant in the COL6A1 gene (c.868G>A; G290R), a variant that acts as dominant negative and that is associated with a severe form of congenital muscular dystrophy. We expressed spCas9 along with allele-targeted gRNAs, without providing a repair template, in primary fibroblasts derived from four patients and one control subject. Amplicon deep-sequencing for two gRNAs tested showed that single nucleotide deletions accounted for the majority of indels introduced. While activity of the two gRNAs was greater at the G290R allele, both gRNAs were also active at the wild-type allele. To enhance allele-selectivity, we introduced deliberate additional mismatches to one gRNA. One of these optimized gRNAs showed minimal activity at the WT allele, while generating productive edits and improving collagen VI matrix in cultured patient fibroblasts. This study strengthens the potential of gene editing to treat dominant-negative disorders, but also underscores the challenges in achieving allele selectivity with gRNAs.

14.
Mol Ther Nucleic Acids ; 35(2): 102178, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38617974

ABSTRACT

Collagen VI-related dystrophies (COL6-RDs) are a group of severe, congenital-onset muscular dystrophies for which there is no effective causative treatment. Dominant-negative mutations are common in COL6A1, COL6A2, and COL6A3 genes, encoding the collagen α1, α2, and α3 (VI) chains. They act by incorporating into the hierarchical assembly of the three α (VI) chains and consequently produce a dysfunctional collagen VI extracellular matrix, while haploinsufficiency for any of the COL6 genes is not associated with disease. Hence, allele-specific transcript inactivation is a valid therapeutic strategy, although selectively targeting a pathogenic single nucleotide variant is challenging. Here, we develop a small interfering RNA (siRNA) that robustly, and in an allele-specific manner, silences a common glycine substitution (G293R) caused by a single nucleotide change in COL6A1 gene. By intentionally introducing an additional mismatch into the siRNA design, we achieved enhanced specificity toward the mutant allele. Treatment of patient-derived fibroblasts effectively reduced the levels of mutant transcripts while maintaining unaltered wild-type transcript levels, rescuing the secretion and assembly of collagen VI matrix by reducing the dominant-negative effect of mutant chains. Our findings establish a promising treatment approach for patients with the recurrent dominantly negative acting G293R glycine substitution.

15.
Plast Reconstr Surg ; 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38640068

ABSTRACT

BACKGROUND: With aging, repetitive contraction of the platysma leads to an increase in platysma prominence (PP) characterized by the accentuation of vertical neck bands and blunting of the jawline's contour. METHODS: This multicenter, double-blind, phase 2 study evaluated onabotulinumtoxinA (onabotA) treatment in adults with Moderate to Severe PP. Participants were randomized to receive 1 treatment of onabotA low dose (LD), onabotA high dose (HD), or placebo, and were followed for 4 months. Efficacy endpoints were the achievement of a ≥ 1-grade improvement on both the left and right sides at Day 14 at maximum contraction as assessed by the investigator (primary) or by participants (secondary) using validated scales. Safety was evaluated throughout. RESULTS: Participants in the modified intent-to-treat population (N = 164) had a mean age of 50 years; 95.1% were female and 93.9% were White. The primary endpoint was met for both onabotA groups, with investigator-assessed ≥ 1-grade improvement in 77.8% (LD) and 88.2% (HD) vs 12.0% (placebo) of participants on Day 14 (P < 0.0001 vs placebo). Based on participant self-assessment, 75.9% (LD) and 88.2% (HD) vs 18.0% (placebo) achieved ≥ 1-grade improvement on Day 14 (P < 0.0001 vs placebo). Most treatment-related adverse events (AEs) were procedure-related, transient, and mild in severity. The most frequent onabotA-related AE was neck muscle weakness, reported in the HD group. CONCLUSIONS: OnabotA was effective in improving the appearance of PP based on both investigators' and participants' ratings. Treatment was well tolerated.

16.
Biomed Opt Express ; 15(4): 2561-2577, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38633084

ABSTRACT

To improve particle radiotherapy, we need a better understanding of the biology of radiation effects, particularly in heavy ion radiation therapy, where global responses are observed despite energy deposition in only a subset of cells. Here, we integrated a high-speed swept confocally-aligned planar excitation (SCAPE) microscope into a focused ion beam irradiation platform to allow real-time 3D structural and functional imaging of living biological samples during and after irradiation. We demonstrate dynamic imaging of the acute effects of irradiation on 3D cultures of U87 human glioblastoma cells, revealing characteristic changes in cellular movement and intracellular calcium signaling following ionizing irradiation.

17.
Parkinsonism Relat Disord ; 123: 106971, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38631081

ABSTRACT

INTRODUCTION: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg. METHODS: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits. RESULTS: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05). CONCLUSION: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes.


Subject(s)
Antiparkinson Agents , Levodopa , Oxadiazoles , Parkinson Disease , Sleep , Humans , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Parkinson Disease/complications , Male , Female , Double-Blind Method , Middle Aged , Aged , Sleep/drug effects , Sleep/physiology , Antiparkinson Agents/therapeutic use , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/pharmacology , Levodopa/pharmacology , Levodopa/administration & dosage , Oxadiazoles/pharmacology , Oxadiazoles/administration & dosage , Oxadiazoles/therapeutic use , Carbidopa/pharmacology , Carbidopa/administration & dosage , Drug Combinations , Wakefulness/drug effects , Wakefulness/physiology
19.
J Pediatr Health Care ; 38(4): 564-573, 2024.
Article in English | MEDLINE | ID: mdl-38483355

ABSTRACT

INTRODUCTION: The global prevalence of exclusive breastfeeding for 6 months is 48%. This analysis examined the relationship between infant and maternal morbidity symptoms and the interruption of exclusive breastfeeding. METHODS: Data from a cohort study among women living in a peri-urban community in Peru were used. Data were collected during pregnancy, birth, and the first 6 months postpartum among 179 dyads... RESULTS: After the first month, interruption of exclusive breastfeeding was almost twofold (adjusted odds ration [aOR] = 1.99, 95% confidence interval [CI]: 1.14, 3.45) more likely among infants with symptoms (e.g., diarrhea, cough) than those without. Maternal morbidity symptoms (e.g., gastrointestinal, respiratory) and breast problems were positively associated with interruption of exclusive breastfeeding throughout the first 6 months (aOR = 1.77, 95% CI: 1.11, 2.82 and aOR = 3.23, 95% CI: 1.84, 5.69, respectively). DISCUSSION: Mother-infant dyads often experience illness symptoms that are not contraindications to breastfeeding. Health professionals need to reinforce that exclusive breastfeeding should continue during illness.


Subject(s)
Breast Feeding , Humans , Breast Feeding/statistics & numerical data , Breast Feeding/psychology , Peru/epidemiology , Female , Prospective Studies , Infant , Adult , Infant, Newborn , Pregnancy , Mothers/psychology , Mothers/statistics & numerical data , Young Adult
20.
R Soc Open Sci ; 11: 231348, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38544561

ABSTRACT

People form social evaluations of others following brief exposure to their voices, and these impressions are calibrated based on recent perceptual experience. Participants adapted to voices with fundamental frequency (f o; the acoustic correlate of perceptual pitch) manipulated to be gender-typical (i.e. masculine men and feminine women) or gender-atypical (i.e. feminine men and masculine women) before evaluating unaltered test voices within the same sex. Adaptation resulted in contrastive aftereffects. Listening to gender-atypical voices caused female voices to sound more feminine and attractive (Study 1) and male voices to sound more masculine and attractive (Study 2). Studies 3a and 3b tested whether adaptation occurred on a conceptual or perceptual level, respectively. In Study 3a, perceivers adapted to gender-typical or gender-atypical voices for both men and women (i.e. adaptors pitch manipulated in opposite directions for men and women) before evaluating unaltered test voices. Findings showed weak evidence that evaluations differed between conditions. In Study 3b, perceivers adapted to masculinized or feminized voices for both men and women (i.e. adaptors pitch manipulated in the same direction for men and women) before evaluating unaltered test voices. In the feminized condition, participants rated male targets as more masculine and attractive. Conversely, in the masculinized condition, participants rated female targets as more feminine and attractive. Voices appear to be evaluated according to gender norms that are updated based on perceptual experience as well as conceptual knowledge.

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