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1.
Article in English | MEDLINE | ID: mdl-38837727

ABSTRACT

PURPOSE OF REVIEW: Adenomyosis is a common cause of abnormal uterine bleeding (AUB), dysmenorrhea, and pelvic pain. Definitive diagnosis and treatment have historically been by uterine histopathology at time of hysterectomy; however, advances in imaging have supported earlier diagnosis and subsequent conservative treatment. This review aims to update the evidence supporting the uterine-sparing, procedural management options with a focus on clinical outcomes. RECENT FINDINGS: Uterine artery embolization (UAE), radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), percutaneous microwave ablation (PMWA), and adenomyomectomy are minimally invasive interventions proven to be effective in reducing AUB and dysmenorrhea due to adenomyosis. Symptom improvement is associated with a decrease in uterine volume. Studies support the use of alternative treatment options given the overall low rates of symptom recurrence and reintervention. Combination therapy may be more effective than monotherapy. SUMMARY: This review provides the current evidence for use of alternative treatment options for adenomyosis. Access to ablative therapies in the USA is limited and primarily off label, given lack of FDA approval. High-quality prospective and randomized controlled trials are needed in order to further delineate treatment comparisons, efficacy, safety, and ideal patient selection for these treatments. More data are needed to assess safety and utility in those desiring future fertility.

2.
bioRxiv ; 2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38774633

ABSTRACT

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the first exon of the huntingtin gene (HTT). Oligonucleotide therapeutics, such as short interfering RNA (siRNA), reduce levels of huntingtin mRNA and protein in vivo and are considered a viable therapeutic strategy. However, the extent to which they silence HTT mRNA in the nucleus is not established. We synthesized siRNA cross-reactive to mouse (wild-type) Htt and human (mutant) HTT in a di-valent scaffold and delivered to two mouse models of HD. In both models, di-valent siRNA sustained lowering of wild-type Htt, but not mutant HTT mRNA expression in striatum and cortex. Near-complete silencing of both mutant HTT protein and wild-type Htt protein was observed in both models. Subsequent fluorescent in situ hybridization (FISH) analysis shows that di-valent siRNA acts predominantly on cytoplasmic mutant HTT transcripts, leaving clustered mutant HTT transcripts in the nucleus largely intact in treated HD mouse brains. The observed differences between mRNA and protein levels, exaggerated in the case of extended repeats, might apply to other repeat-associated neurological disorders.

3.
Nucleic Acids Res ; 2024 May 10.
Article in English | MEDLINE | ID: mdl-38726879

ABSTRACT

Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of a target gene within the central nervous system (CNS). However, an siRNA modality capable of simultaneously modulating gene pairs would be invaluable for treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, the parameters and scaffold considerations for multi-targeting nucleic acid modalities in the CNS are undefined. Here, we propose a framework for designing unimolecular 'dual-targeting' divalent siRNAs capable of co-silencing two genes in the CNS. We systematically adjusted the original CNS-active divalent siRNA and identified that connecting two sense strands 3' and 5' through an intra-strand linker enabled a functional dual-targeting scaffold, greatly simplifying the synthetic process. Our findings demonstrate that the dual-targeting siRNA supports at least two months of maximal distribution and target silencing in the mouse CNS. The dual-targeting divalent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g. Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting divalent siRNAs against each gene. This work enhances the potential for CNS modulation of disease-related gene pairs using a unimolecular siRNA.

4.
Article in English | MEDLINE | ID: mdl-38809185

ABSTRACT

OBJECTIVE: To determine the effect of a single intraoperative dose of dexamethasone on the risk of postoperative reflux (POR) in horses undergoing small intestinal surgery and to investigate its association with incisional complications and short-term survival. DESIGN: Retrospective cohort study over an 11-year period (2008-2019). SETTING: UK-based private referral center. ANIMALS: Two hundred and forty client-owned horses >6 months of age undergoing exploratory laparotomy for treatment of a small intestinal lesion. INTERVENTIONS: Ninety-seven horses received a single intraoperative dose of dexamethasone (0.1 mg/kg, IV). MEASUREMENTS AND MAIN RESULTS: Of 97 horses that received dexamethasone, 52 (53.6%) required small intestinal resection. Of 143 horses that did not receive dexamethasone, small intestinal resection was performed in 78 (54.5%). A total of 70 horses (29%) developed POR. There was no difference in the risk of POR between horses that received dexamethasone (25/97; 26%) and those that did not (45/143; 31%, P = 0.34). Risk factors associated with the development of POR included small intestinal resection (odds ratio [OR]: 4.55, 95% confidence interval [CI]: 2.27-9.11, P < 0.001), a PCV >40% 24 hours postoperatively (OR: 4.11, 95% CI: 2-8.45, P < 0.001), and a WBC count >10 × 109/L on admission (OR: 3.29, 95% CI: 1.47-7.41, P = 0.004). Dexamethasone was not associated with the odds of POR. Horses undergoing repeat laparotomy had a higher risk of incisional infection (OR: 8.07, 95% CI: 1.98-32.81, P = 0.004). Dexamethasone administration was not associated with incisional infection. The development of POR was negatively associated with short-term survival (OR: 0.07, 95% CI: 0.03-0.17, P ≤ 0.001). Dexamethasone administration was not retained in the final multivariable model for survival. CONCLUSIONS: Intraoperative dexamethasone was not associated with the development of POR in this study population, nor did it have an effect on postoperative survival or incisional infection in horses undergoing surgical management of small intestinal disease.


Subject(s)
Dexamethasone , Horse Diseases , Intestine, Small , Laparotomy , Postoperative Complications , Animals , Horses , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Retrospective Studies , Horse Diseases/surgery , Female , Male , Laparotomy/veterinary , Laparotomy/adverse effects , Intestine, Small/surgery , Postoperative Complications/veterinary , Cohort Studies , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Intestinal Diseases/veterinary , Intestinal Diseases/surgery
5.
Article in English | MEDLINE | ID: mdl-38541285

ABSTRACT

Indigenous people in Montana are disproportionately affected by chronic illness (CI), a legacy of settler colonialism. Existing programs addressing CI self-management are not appropriate because they are not consonant with Indigenous cultures in general and the Apsáalooke culture specifically. A research partnership between the Apsáalooke (Crow Nation) non-profit organization Messengers for Health and Montana State University co-developed, implemented, and evaluated a CI self-management program for community members. This article examines qualitative and quantitative program impacts using a pragmatic cluster randomized clinical trial design with intervention and waitlist control arms. The quantitative and qualitative data resulted in different stories on the impact of the Báa nnilah program. Neither of the quantitative hypotheses were supported with one exception. The qualitative data showed substantial positive outcomes across multiple areas. We examine why the data sets led to two very different stories, and provide study strengths and limitations, recommendations, and future directions.


Subject(s)
American Indian or Alaska Native , Indians, North American , Self-Management , Humans , Chronic Disease , Community-Based Participatory Research/methods
6.
iScience ; 27(4): 109413, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38510117

ABSTRACT

Human physiology is highly susceptible to frameshift mutations within coding regions, and many hereditary diseases and cancers are caused by such indels. Presently, therapeutic options to counteract them are limited and, in the case of direct genome editing, risky. Here, we show that release factor 1 (eRF1) from Euplotes, an aquatic protist known for frequent +1 frameshifts in its coding regions, can enhance +1 ribosomal frameshifting at slippery heptameric sequences in human cells without an apparent requirement for an mRNA secondary structure. We further show an increase in frameshifting rate at the premature termination sequence found in the HEXA gene of Tay-Sachs disease patients, or a breast cancer cell line that harbors a tumor-driving frameshift mutation in GATA3. Although the overall increase in frameshifting would need further improvement for clinical applications, our results underscore the potential of exogenous factors, such as Eu eRF1, to increase frameshifting in human cells.

7.
Vet Rec Open ; 10(2): e74, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37927814

ABSTRACT

Background: During the COVID-19 pandemic, equine health care in the UK may have been adversely affected due to mandated changes in the delivery of veterinary healthcare and the potential for reduced health-seeking behaviour. Methods: Electronic patient records (EPRs) were analysed to describe veterinary activity for all equids under the active care of 20 veterinary practices in the UK in the 12 months before and after the introduction of the first UK lockdown. Pre-pandemic and pandemic levels of clinical activity were compared. Further comparisons of care, including immediate management and treatment, were made following a detailed review of EPRs from randomly selected subsets of equids under care in four time periods. Results: All measures of activity and face-to-face interaction were lower in the early pandemic period than in the equivalent pre-pandemic period. Compared to pre-pandemic, the early pandemic was associated with a decrease in prophylactic care and non-urgent diagnostic imaging and an increase in systemic non-steroid anti-inflammatory prescription. Convenience sampling of veterinary practices may have limited the generalisability of the findings. The quality of EPRs was variable. Conclusions: While equine veterinary activity was significantly disrupted in the early pandemic period, there was a rapid return to pre-pandemic levels of activity. Subsequent lockdowns appeared to have had little effect on veterinary care.

8.
Article in English | MEDLINE | ID: mdl-37947547

ABSTRACT

Treatment fidelity remains underreported in health intervention research, particularly among Indigenous communities. One explanation for this gap is the lack of culturally consonant strategies listed in the National Institutes of Health (NIH) Behavior Change Consortium (BCC) treatment fidelity framework, the gold standard for understanding and measuring fidelity. This paper focuses on the development and implementation of a culturally consonant treatment fidelity support plan across two of the five BCC fidelity areas, provider training and treatment delivery, within a chronic illness self-management program for the Apsáalooke (Crow) Nation. Our team selected and adapted strategies from, and added strategies to, the BCC framework, that centered on relational accountability and the Apsáalooke culture. To be culturally consonant, we approached treatment fidelity as supporting Aakbaabaaniilea (Apsáalooke program facilitators) rather than monitoring them. This resulted in the development of a fifth treatment fidelity area: building and fostering relationships. We propose that fidelity to relational accountability is the foundation of successful programs in Indigenous communities. This suggests an important shift from tracking what was conducted in an intervention to prioritizing how things were conducted. We encourage others to view the BCC framework as a starting point in developing fidelity strategies that are consonant with local cultures.


Subject(s)
Health Services, Indigenous , Self-Management , United States , Humans , Behavior Therapy , Chronic Disease , National Institutes of Health (U.S.)
9.
J Sleep Res ; 32(6): e14031, 2023 12.
Article in English | MEDLINE | ID: mdl-37654128

ABSTRACT

The inherent nature of personality serves as a predisposing, and possible maintaining, factor of insomnia. However, methodological differences limit the ability to draw causal conclusions regarding the specific traits involved in the aetiology of the disorder. This systematic review of the relationship between insomnia and personality provides a narrative synthesis of the literature to date. Here, we identified N = 76 studies meeting the inclusion/exclusion criteria. The outcomes reliably evidenced the experience of insomnia to be associated with personality traits that are typically considered to be negative or maladaptive in nature. More specifically, insomnia was related to neuroticism, introversion, perfectionistic doubts and concerns, elevated personal standards, negative affect, social inhibition and avoidance, hysteria, hypochondriasis, psychasthenia, impulsive behaviour, anger, hostility, and psychopathic tendencies, schizotypal and borderline traits, reduced conscientiousness and self-directedness, and negatively perceived perception of the self. Several studies examined the role that personality plays in predicting the treatment efficacy and adherence of CBTi. Moving forward, longitudinal research, methodological consistency, the mediating role of treatment outcomes and adherence, and clinical and population representative samples should be prioritised. Methodological strengths and limitations of the literature are discussed alongside the next steps that should be taken to advance our understanding of the literature.


Subject(s)
Sleep Initiation and Maintenance Disorders , Humans , Personality , Neuroticism
10.
Adv Cancer Res ; 160: 17-60, 2023.
Article in English | MEDLINE | ID: mdl-37704288

ABSTRACT

Since the discovery of tyrosine phosphorylation being a critical modulator of cancer signaling, proteins regulating phosphotyrosine levels in cells have fast become targets of therapeutic intervention. The nonreceptor protein tyrosine phosphatase (PTP) coded by the PTPN11 gene "SHP2" integrates phosphotyrosine signaling from growth factor receptors into the RAS/RAF/ERK pathway and is centrally positioned in processes regulating cell development and oncogenic transformation. Dysregulation of SHP2 expression or activity is linked to tumorigenesis and developmental defects. Even as a compelling anti-cancer target, SHP2 was considered "undruggable" for a long time owing to its conserved catalytic PTP domain that evaded drug development. Recently, SHP2 has risen from the "undruggable curse" with the discovery of small molecules that manipulate its intrinsic allostery for effective inhibition. SHP2's unique domain arrangement and conformation(s) allow for a truly novel paradigm of inhibitor development relying on skillful targeting of noncatalytic sites on proteins. In this review we summarize the biological functions, signaling properties, structural attributes, allostery and inhibitors of SHP2.


Subject(s)
Neoplasms , Humans , Phosphotyrosine , Neoplasms/drug therapy , Carcinogenesis , Cell Differentiation , Cell Transformation, Neoplastic
11.
Sci Data ; 10(1): 621, 2023 09 13.
Article in English | MEDLINE | ID: mdl-37704598

ABSTRACT

Despite existing wellbeing services, university students remain particularly vulnerable to mental health difficulties. Therefore, this study was designed to provide a comprehensive assessment of the prevalence of psychiatric symptoms by using well validated scales with robust psychometric properties. More specifically, the current data provides crucial information concerning the prevalence of anxiety, depression, mania, insomnia, stress, suicidal ideation, psychotic experiences and loneliness amongst a sample of N = 1408 UK university students. A cross-sectional online questionnaire-based study was implemented. Online recruitment for this dataset began on September 17th, 2018, and ended on the 30th July 2019. Eight validated measures were used: Generalized Anxiety Disorder Scale; Patient Health Questionnaire; The Mood Disorder Questionnaire; The Sleep Condition Indicator; The Perceived Stress Scale; Suicidal Behaviours Questionnaire-Revised; The Prodromal Questionnaire 16 (PQ-16); and the University of California Loneliness Scale. The dataset is available to other researchers and is provided on figshare. Information concerning the data records, usage notes, code availability and technical validation are presented. Finally, we present demographic information concerning psychiatric symptom prevalence.


Subject(s)
Mania , Sleep Initiation and Maintenance Disorders , Humans , Anxiety/epidemiology , Cross-Sectional Studies , Depression/epidemiology , Loneliness , Prevalence , Sleep Initiation and Maintenance Disorders/epidemiology , Students , Suicidal Ideation , United Kingdom/epidemiology , Universities
13.
J Immunother Cancer ; 11(6)2023 06.
Article in English | MEDLINE | ID: mdl-37321663

ABSTRACT

BACKGROUND: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αß, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. METHODS: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1-4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107-1×109 T4+ T-cells, administered without prior lymphodepletion. RESULTS: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. CONCLUSIONS: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.


Subject(s)
Head and Neck Neoplasms , Receptors, Chimeric Antigen , Humans , Squamous Cell Carcinoma of Head and Neck/therapy , Interleukin-4 , Neoplasm Recurrence, Local , Immunotherapy , Head and Neck Neoplasms/drug therapy
15.
Nutr Clin Pract ; 38(2): 216-239, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36917007

ABSTRACT

When an enteral feeding tube (EFT) is placed, it is not always known how long this nutrition support intervention will be needed. As a result, the type of device the patient originally has placed may not match the function it is required to serve or the lifestyle needs of the patient throughout their enteral nutrition journey. Medicare considers an EFT a prosthetic device, as it is replacing a permanently inoperable or nonfunctioning organ. If we think about an EFT the same way we think about a prosthetic limb, one that needs to be customized to meet all of the patient's functional and lifestyle needs, we can also begin to think beyond the procedure room and carefully consider a variety of factors that impact the patient at home receiving enteral nutrition. Proper fit, function, and style is essential in order for the patient to have a positive relationship with their EFT, contributing to their successful home enteral nutrition experience. Clinicians who care for these patients in any setting and in any capacity would benefit from enhancing their understanding of available EFT options, their design components, and available methods of placement. Many home care and outpatient clinicians adopt the role of patient advocate as it relates to a patient's enteral nutrition journey, and this expanded knowledge could be used to benefit the patient by improving their overall enteral nutrition experience and ultimately their relationship with their "prosthetic."


Subject(s)
Enteral Nutrition , Gastrostomy , Aged , United States , Humans , Enteral Nutrition/methods , Gastrostomy/methods , Jejunostomy , Medicare , Intubation, Gastrointestinal/methods
16.
Brain Behav ; 13(4): e2959, 2023 04.
Article in English | MEDLINE | ID: mdl-36922902

ABSTRACT

AIMS: Childhood trauma has been associated with adult psychosocial outcomes linked to social exclusion. However, the strength of these associations in the general population is unknown. The emergence of the UK Biobank, with rich phenotypic characterization of the adult population, affords the exploration of the childhood determinants of adult psychopathology with greater statistical power. The current study aims to explore (1) the associations between childhood trauma and social exclusion in adulthood and (2) the role that self-reported loneliness and symptoms of distress play in the associations. METHODS: This study was an analysis of 87,545 participants (mean [± SD] age = 55.68 [7.78], 55.0% female, 97.4% White) enrolled in the UK Biobank. Childhood trauma was determined by the five-item Childhood Trauma Screener. Current loneliness and symptoms of anxiety (Generalized Anxiety Disorder Scale-7) and depression (Patient Health Questionnaire-9) were also entered in analyses. Outcomes were "limited social participation," "area deprivation," "individual deprivation," and "social exclusion" from a previously determined dimensional measure of social exclusion in the UK Biobank. RESULTS: Hierarchical multiple regression models indicated small associations between childhood trauma and social exclusion outcomes, explaining between 1.5% and 5.0% of the variance. Associations weakened but remained significant when loneliness, anxiety, and depression were entered in the models; however, anxiety symptoms demonstrated a negative association with "individual deprivation" and "social exclusion" in the final models. Depression was most strongly associated with "individual deprivation," "area deprivation," and "social exclusion" followed by childhood trauma. Loneliness was most strongly associated with "limited social participation." CONCLUSIONS: Experiences of childhood trauma can increase the propensity for adulthood social exclusion. Loneliness and symptoms of depression attenuate but do not eliminate these associations. Anxiety symptoms have a potentially protective effect on the development of "individual deprivation." Findings add to the growing body of literature advocating for trauma-informed approaches in a variety of settings to help ameliorate the effects of childhood trauma on adult psychosocial outcomes. Further research, however, is required.


Subject(s)
Adverse Childhood Experiences , Loneliness , Adult , Humans , Female , Middle Aged , Male , Loneliness/psychology , Mental Health , Biological Specimen Banks , Depression/psychology , Anxiety/psychology , Anxiety Disorders , United Kingdom/epidemiology
17.
Equine Vet J ; 55(5): 808-819, 2023 Sep.
Article in English | MEDLINE | ID: mdl-36199158

ABSTRACT

BACKGROUND: Judicious antimicrobial use (AMU) is important for preserving therapeutic effectiveness. Large-scale studies of antimicrobial prescribing can provide clinical benchmarks and help identify opportunities for improved stewardship. OBJECTIVES: To describe systemic AMU in UK equine practice and identify factors associated with systemic and Category B (third and fourth generation cephalosporins, quinolones and polymixins) AMU. STUDY DESIGN: Retrospective cohort. METHODS: Anonymised electronic patient records (EPRs) for all equids attended by 39 UK veterinary practices between 1 January and 31 December 2018 were collected via the VetCompass programme. Systemic antimicrobial prescriptions were identified using electronic keyword searches. Indications for AMU were determined through manual review of a randomly selected subset of EPRs. The types and frequency of systemic antimicrobials prescribed and indications were summarised using descriptive statistics. Mixed-effects logistic regression was used to evaluate practice- and horse-related risk factors. RESULTS: Systemic antimicrobials were prescribed to 12 538 (19.5%, 95% confidence interval [CI]: 19.2%-19.8%) of 64 322 equids attended in 2018. Category B antimicrobials were prescribed to 1.9% (95% CI: 1.8%-2.0%) of attended equids and in 8.9% (95% CI: 8.5%-9.4%) of antimicrobial courses. Bacteriological culture was performed in 19.1% (95% CI: 17.1%-21.3%) of Category B antimicrobial courses. The most commonly prescribed antimicrobial classes were potentiated sulphonamides (50.2% of equids receiving antimicrobials) and tetracyclines (33.5% of equids receiving antimicrobials). Integumentary disorders were the most common reason for systemic AMU (40.5% of courses). Urogenital disorders were the most common reason for Category B AMU (31.1% of courses). Increased odds of systemic and Category B AMU were observed in equids <1 year compared with those aged 5-14 years. Breed was associated with AMU, with odds of systemic and Category B AMU highest in Thoroughbreds and Thoroughbred crosses. MAIN LIMITATIONS: Convenience sample of practices may limit generalisability. CONCLUSIONS: Empirical use of Category B antimicrobials remains commonplace.


Subject(s)
Anti-Infective Agents , Horses , Animals , Retrospective Studies , Anti-Bacterial Agents/therapeutic use , United Kingdom
18.
bioRxiv ; 2023 Dec 19.
Article in English | MEDLINE | ID: mdl-38187561

ABSTRACT

Di-valent short interfering RNA (siRNA) is a promising therapeutic modality that enables sequence-specific modulation of a single target gene in the central nervous system (CNS). To treat complex neurodegenerative disorders, where pathogenesis is driven by multiple genes or pathways, di-valent siRNA must be able to silence multiple target genes simultaneously. Here we present a framework for designing unimolecular "dual-targeting" di-valent siRNAs capable of co-silencing two genes in the CNS. We reconfigured di-valent siRNA - in which two identical, linked siRNAs are made concurrently - to create linear di-valent siRNA - where two siRNAs are made sequentially attached by a covalent linker. This linear configuration, synthesized using commercially available reagents, enables incorporation of two different siRNAs to silence two different targets. We demonstrate that this dual-targeting di-valent siRNA is fully functional in the CNS of mice, supporting at least two months of maximal target silencing. Dual-targeting di-valent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g., Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting di-valent siRNAs against each gene. This work potentiates CNS modulation of virtually any pair of disease-related targets using a simple unimolecular siRNA.

19.
Am J Vet Res ; 84(2)2022 Dec 19.
Article in English | MEDLINE | ID: mdl-36520648

ABSTRACT

OBJECTIVE: To evaluate the time-course of ampicillin-sulbactam and percentage of time that its concentration is above a given MIC (T% > MIC) in dogs with septic peritonitis when delivered as either a continuous infusion (CI) or intermittent infusion (II). ANIMALS: 11 dogs with septic peritonitis. PROCEDURES: Dogs were randomized to receive ampicillin-sulbactam as either CI or II. Continuous infusions were delivered as a 50 mg/kg bolus IV followed by a rate of 0.1 mg/kg/min. Intermittent infusions were administered as 50 mg/kg IV q8h. Serum ampicillin-sulbactam concentrations were measured at hours 0, 1, 6, and every 12 hours after until patients were transitioned to an oral antimicrobial equivalent. All other care was at the discretion of the attending clinician. Statistical analysis was used to determine each patient's percentage of time T% > MIC for 4 MIC breakpoints (0.25, 1.25, 8, and 16 µg/mL). RESULTS: No dogs experienced adverse events related to ampicillin-sulbactam administration. Both CI and II maintained a T% > MIC of 100% of MIC 0.25 µg/mL and MIC 1.25 µg/mL. The CI group maintained a higher T% > MIC for MIC 8 µg/mL and MIC 16 µg/mL; however, these differences did not reach statistical significance (P = .15 and P = .12, respectively). CLINICAL RELEVANCE: This study could not demonstrate that ampicillin-sulbactam CI maintains a greater T% > MIC in dogs with septic peritonitis than II; however, marginal differences were noted at higher antimicrobial breakpoints. While these data support the use of antimicrobial CI in septic and critically ill patients, additional prospective trials are needed to fully define the optimal doses and the associated clinical responses.


Subject(s)
Ampicillin , Peritonitis , Animals , Prospective Studies , Ampicillin/therapeutic use , Sulbactam/therapeutic use , Peritonitis/drug therapy , Peritonitis/veterinary , Infusions, Intravenous/veterinary
20.
J Minim Invasive Gynecol ; 29(12): 1344-1351, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36162768

ABSTRACT

STUDY OBJECTIVE: The primary objective was to quantify postoperative opioid use after laparoscopic surgery for endometriosis or pelvic pain. The secondary objective was to identify patient characteristics associated with greater postoperative opioid requirements. DESIGN: Prospective, survey-based study in which subjects completed 1 preoperative and 7 postoperative surveys within 28 days of surgery regarding medication usage and pain control. SETTING: Tertiary care, academic center. PATIENTS: A total of 100 women with endometriosis or pelvic pain. INTERVENTIONS: Laparoscopic same-day discharge surgery by fellowship-trained minimally invasive gynecologists. MEASUREMENTS AND MAIN RESULTS: A total of 100 patients were recruited and 8 excluded, for a final sample size of 92 patients. All patients completed the preoperative survey. Postoperative response rates ranged from 70.7% to 80%. The mean number of pills (5 mg oxycodone tablets) taken by day 28 was 6.8. The average number of pills prescribed was 10.2, with a minimum of 4 (n = 1) and maximum of 20 (n = 3). Previous laparoscopy for pelvic pain was associated with a significant increase in postoperative narcotic use (8.2 vs 5.6; p = .044). Hysterectomy was the only surgical procedure associated with a significant increase in postoperative narcotic use (9.7 vs 5.4; p = .013). There were no difference in number of pills taken by presence of deep endometriosis or pathology-confirmed endometriosis (all p >.36). There was a trend of greater opioid use in patients with diagnoses of self-reported chronic pelvic pain, anxiety, and depression (7.9 vs 5.7, p = .051; 7.7 vs 5.2, p = .155; 8.1 vs 5.6, p = .118). CONCLUSION: Most patients undergoing laparoscopic surgery for endometriosis and pelvic pain had a lower postoperative opioid requirement than prescribed, suggesting surgeons can prescribe fewer postoperative narcotics in this population. Patients with a previous surgery for pelvic pain, self-reported chronic pelvic pain syndrome, anxiety, and depression may represent a subset of patients with increased postoperative opioid requirements.


Subject(s)
Endometriosis , Laparoscopy , Opioid-Related Disorders , Humans , Female , Analgesics, Opioid/therapeutic use , Pain, Postoperative/drug therapy , Pain, Postoperative/etiology , Prospective Studies , Pelvic Pain/drug therapy , Pelvic Pain/etiology , Pelvic Pain/surgery , Endometriosis/complications , Endometriosis/surgery , Endometriosis/drug therapy , Laparoscopy/methods
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