Tag: pubmed

Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2200061119. doi: 10.1073/pnas.2200061119. Epub 2022 Aug 12.

ABSTRACT

DNA looping has emerged as a central paradigm of transcriptional regulation, as it is shared across many living systems. One core property of DNA looping-based regulation is its ability to greatly enhance repression or activation of genes with only a few copies of transcriptional regulators. However, this property based on a small number of proteins raises the question of the robustness of such a mechanism with respect to the large intracellular perturbations taking place during growth and division of the cell. Here we address the issue of sensitivity to variations of intracellular parameters of gene regulation by DNA looping. We use the lac system as a prototype to experimentally identify the key features of the robustness of DNA looping in growing Escherichia coli cells. Surprisingly, we observe time intervals of tight repression spanning across division events, which can sometimes exceed 10 generations. Remarkably, the distribution of such long time intervals exhibits memoryless statistics that is mostly insensitive to repressor concentration, cell division events, and the number of distinct loops accessible to the system. By contrast, gene regulation becomes highly sensitive to these perturbations when DNA looping is absent. Using stochastic simulations, we propose that the observed robustness to division emerges from the competition between fast, multiple rebinding events of repressors and slow initiation rate of the RNA polymerase. We argue that fast rebinding events are a direct consequence of DNA looping that ensures robust gene repression across a range of intracellular perturbations.

PMID:35960846 | DOI:10.1073/pnas.2200061119

J Womens Health (Larchmt). 2022 Aug 12. doi: 10.1089/jwh.2022.0082. Online ahead of print.

ABSTRACT

Objective: To understand the impact of von Willebrand disease (VWD) on women’s health, a retrospective cohort study was conducted using UK Clinical Practice Research Datalink (CPRD) GOLD database and Hospital Episode Statistics (HES) Admitted Patient Care data from 1988 to 2016. Materials and Methods: Hysterectomy and heavy menstrual bleeding (HMB) events were identified by recorded disease/clinical codes and compared in women with and without VWD (matched 1:10 by birth and CPRD record start years [±2 years], and general practice attended). Incidence rates and incidence rate ratios (IRR) were calculated; risks were estimated using the Kaplan-Meier method. Results: HMB was recorded after cohort entry in 388 of 1,335 women (29.1%) with VWD and 1,524 of 12,463 women (12.2%) without VWD. The cumulative incidence of HMB was higher in women with versus without VWD across all ages (p < 0.0001), and irrespective of prior HMB status (p < 0.001). Women with VWD were more likely to have HMB compared with women without VWD; IRR adjusted for age and prior HMB status was 2.74 (95% confidence interval [CI]: 2.44-3.07). Hysterectomy was recorded in 88 of 1,374 women (6.4%) with VWD and 320 of 12,791 women (2.5%) without VWD. The cumulative incidence of hysterectomy was higher for women with versus without VWD (p < 0.0001), and highest among women aged ≥30 years at cohort entry. Women with VWD aged 30 – 39 years were more likely to undergo hysterectomy than women without VWD; IRR adjusted for prior HMB was 3.58 (95% CI: 2.36 – 5.44). Conclusions: These findings highlight the substantial impact of VWD on women’s health.

PMID:35960825 | DOI:10.1089/jwh.2022.0082

J Palliat Med. 2022 Aug 12. doi: 10.1089/jpm.2022.0100. Online ahead of print.

ABSTRACT

Background: Thirty-six states, including Florida, have legalized marijuana for medical and/or recreational use, yet how it is used and perceived by persons with cancer is not well understood. Objectives: The purpose of this study was to identify patterns of use, perceived benefits, and side effects of medical marijuana (MMJ) among cancer patients in Florida. Methods: For this descriptive, cross-sectional study, anyone residing within the state of Florida who was diagnosed or treated for a malignancy within the last five years and had used MMJ was eligible. An online survey containing questions about dosing, side effects, perceived benefits, and barriers to use was used. Descriptive statistics including frequencies, percentages, means, and standard deviations were used to analyze quantitative data. Responses to open-ended questions were coded and categorized. Results: Sleep (n = 112), pain (n = 96), and anxiety (n = 82) were the most common symptoms participants used MMJ to relieve and overall felt it was highly effective. MMJ was well tolerated with a minority (10.3%) reporting any adverse effects. Cost was the most frequent barrier reported by participants (42.8%). A variety of legal, bureaucratic, and system-related barriers were described. Conclusion: Participants perceived MMJ to be helpful in alleviating cancer symptoms. They held negative perceptions of the way MMJ is implemented and integrated into their oncology treatment plan. Enhanced communication and patient/provider education on MMJ are needed to inform patient decision making.

PMID:35960820 | DOI:10.1089/jpm.2022.0100

Photobiomodul Photomed Laser Surg. 2022 Aug;40(8):554-558. doi: 10.1089/photob.2021.0156.

ABSTRACT

Objective: The aim of this study was to determine the thermal effects of diode laser irradiation on titanium implants. Methods: An implant (3.5 × 11 mm) was placed into a bovine bone block. A three-wall intrabony defect was created to simulate peri-implant defect. Two thermocouples were secured to the apical and coronal surfaces to measure temperature changes (ΔT) during irradiation. The block was placed in a 37°C water bath and at room temperature (21°C). The defect was irradiated with different diode lasers (fiber 300 μm), while the coronal part of the implant was slightly emerging from the water. While the laser tip was positioned parallel to the implant, the defect was irradiated for 30 sec at 2 W in continuous and pulsed mode. Twenty laser irradiations were performed for each laser wavelength for assessment of ΔT. The linear mixed model was used for comparative statistics. Results: The 980 nm pulsed laser resulted in the highest ΔT (°C) at the coronal (22.45 ± 2.1/14.15 ± 0.13) and apical level (5.4 ± 0.56/3.56 ± 0.35) when this laser was used in both room temperature and water bath conditions, respectively. Similarly, highest ΔT (p < 0.0001) for the 810 nm was 14.3 ± 1.6/12.51 ± 0.63 and apical 3.42 ± 0.52/2.58 ± 0.25, for the 970 nm was 13 ± 1.4/9.93 ± 0.47 and apical 2.89 ± 0.19/2.01 ± 0.19 compared to the 940 nm laser coronally 10.1 ± 0.6/9.19 ± 0.35 and apically 1.67 ± 0.34/1.80 ± 0.17. The coronal part of the implant surpassed the critical threshold of 10°C when irradiated with each of the lasers in the room temperature conditions. Conclusions: Within the limitations of the study, the 940 nm laser seems to control better the risks of overheating during implant irradiation.

PMID:35960815 | DOI:10.1089/photob.2021.0156

Photobiomodul Photomed Laser Surg. 2022 Aug;40(8):580-588. doi: 10.1089/photob.2022.0045.

ABSTRACT

Objective: The objective of this research is to assess the short-term efficacy of combined erbium-doped: yttrium aluminum and garnet (Er:YAG) and neodymium-doped: yttrium aluminum garnet (Nd:YAG) lasers for the nonsurgical treatment of periodontitis, providing a reliable basis for whether this clinical treatment can be applied in clinical practice. Materials and methods: Thirty patients with periodontitis are chosen for this study. A split-mouth design was used; the left and right quadrants of the oral cavity are randomly assigned to one treatment: combined Er:YAG laser and Nd:YAG laser treatment (laser group) or scaling and root planing (SRP) group. Data on probing depth, clinical attachment level, bleeding index, and subgingival plaque and gingival crevicular fluid samples are collected in the basement, for 1 and 3 months. The levels of red complexes in subgingival plaque and cytokines in gingival sulcus fluid were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results: At 1 and 3 months of follow-up, all clinical parameters in the two groups are significantly improved; there is a statistically remarkable difference between the laser group and SRP group (p < 0.001). Matrix metalloproteinase 8 levels in the laser group are notably lower than those in the SRP group 3 months after treatment (p < 0.001). At any point in time, the levels of red complexes in the laser group showed no additional advantage over those in the SRP group (p > 0.05). Conclusions: Er:YAG laser and Nd:YAG laser combined therapy on periodontitis have advantages in controlling periodontal inflammation and improving clinical symptoms.

PMID:35960814 | DOI:10.1089/photob.2022.0045

Neurosurgery. 2022 Aug 16. doi: 10.1227/neu.0000000000002094. Online ahead of print.

ABSTRACT

BACKGROUND: Temporal lobe epilepsy (TLE) surgery is associated with the best seizure outcome in adults, although its long-term results remain suboptimal. Retrospective pediatric studies suggest better figures whose determinants are poorly understood.

OBJECTIVE: To conduct a systematic review and meta-analysis of studies on the efficacy of TLE surgery in children (age younger than 18 years) and adults.

METHODS: We searched MEDLINE, Embase, and Cochrane Library for TLE surgery original research from January 1, 1990, until May 12, 2020. The outcome measures were seizure freedom since surgery and seizure freedom either at last or longest follow-up. We meta-analyzed the proportion of children and adults achieving either Engel I/International League Against Epilepsy (ILAE) 1 or Engel IA/ILAE 1A outcome by follow-up duration, type of surgery, histopathology, neuroimaging, quality of the studies, and publication period. We used a random effects model with Freeman-Tukey double arcsine transformation of proportions.

RESULTS: From 40 409 records identified, we included 277 studies (30 848 patients). The proportions of patients achieving Engel I/ILAE 1 and Engel IA/ILAE 1A outcomes were 0.74 (95% CI, 0.69-0.78) and 0.61 (0.48-0.74) for children and 0.69 (0.67-0.71) and 0.56 (0.52-0.60) for adults. Histopathology significantly influenced Engel I/ILAE 1 outcome in adults but not in children (P < .0001), while the type of surgery significantly influenced Engel I/ILAE 1 outcome in children but not in adults.

CONCLUSION: The proportion of seizure freedom after TLE surgery was higher in children, although not significantly. Histopathology and the surgical approach can influence seizure outcome, with age-related variability.

PMID:35960753 | DOI:10.1227/neu.0000000000002094

PLoS One. 2022 Aug 12;17(8):e0272638. doi: 10.1371/journal.pone.0272638. eCollection 2022.

ABSTRACT

BACKGROUND: Although chronic pain (CP) is common, little is known about its economic burden in Alberta, Canada.

AIMS: To estimate incremental (as compared to the general population or people without CP) societal (healthcare and lost productivity) costs of CP in Alberta.

METHODS: We applied the prevalence estimated from the Canadian Community Health Survey data to the population retrieved from the Statistics Canada to estimate the number of people with CP in Alberta in 2019. We analyzed the Alberta Health administrative databases to estimate the healthcare costs of person with CP. Finally, we multiplied the number of people with the cost per person.

RESULTS: The prevalence of any CP was 20.1% and of activity-preventing CP was 14.5% among people aged > = 12 years. Incremental cost per person with CP per year was CA$2,217 for healthcare services (among people aged > = 12 years) and CA$8,412 for productivity losses (among people aged 18-64 years). Of the healthcare cost, prescription drugs accounted for the largest share (32.8%), followed by inpatient services (31.0%), outpatient services (13.1%), physician services (9.8%), other services (7.4%), and diagnostic imaging (5.8%). Provincially, total incremental cost of CP ranges from CA$1.2 to 1.7 billion for healthcare services (6% to 8% of total provincial health expenditure); and CA$3.4 to 4.7 billion for productivity losses. Considering costs for long-term care services, the total societal cost of CP in Alberta was CA$6.3 to 8.3 billion per year, reflecting 2.0% to 2.7% of Alberta’s GDP.

CONCLUSIONS: Interventions improving CP prevention and management to reduce this substantial economic burden are urgently needed.

PMID:35960750 | DOI:10.1371/journal.pone.0272638

JAMA Netw Open. 2022 Aug 1;5(8):e2226523. doi: 10.1001/jamanetworkopen.2022.26523.

ABSTRACT

IMPORTANCE: Opioid dosage tapering has emerged as a strategy to reduce harms associated with long-term opioid therapy; however, evidence supporting this approach is limited.

OBJECTIVE: To identify the association of opioid tapering or abrupt discontinuation with opioid overdose and suicide events among patients receiving stable long-term opioid therapy without evidence of opioid misuse.

DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study with a trial emulation approach used a large US claims data set of individuals with commercial insurance or Medicare Advantage who were aged 18 years or older and receiving stable long-term opioid therapy without evidence of opioid misuse between January 1, 2010, and December 31, 2018. Statistical analysis was performed from January 17, 2020, through November 12, 2021.

INTERVENTIONS: Three opioid dosage strategies: stable dosage, tapering (dosage reduction ≥15%), or abrupt discontinuation.

MAIN OUTCOMES AND MEASURES: Time to opioid overdose or suicide event identified from International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes in medical claims over 11 months of follow-up. Inverse probability weighting was used to adjust for baseline confounders. The primary analysis used an intention-to-treat approach; follow-up after assignment regardless of changes in opioid dose was included. A per-protocol analysis was also conducted, in which episodes were censored for lack of adherence to assigned treatment.

RESULTS: A cohort of 199 836 individuals (45.1% men; mean [SD] age, 56.9 [12.4] years; and 57.6% aged 45-64 years) had 415 123 qualifying, long-term opioid therapy episodes; 87.1% of episodes were considered stable, 11.1% were considered a taper, and 1.8% were considered abrupt discontinuation. The adjusted cumulative incidence of opioid overdose or suicide events 11 months after baseline was 0.96% (95% CI, 0.92%-0.99%) with a stable dosage strategy, 1.10% (95% CI, 0.99%-1.22%) with a tapered dosage strategy, and 1.28% (95% CI, 0.93%-1.38%) with an abrupt discontinuation strategy. The risk difference between a taper and a stable dosage was 0.15% (95% CI, 0.03%-0.26%), and the risk difference between abrupt discontinuation and a stable dosage was 0.33% (95% CI, -0.03% to 0.74%). Results were similar using the per-protocol approach.

CONCLUSIONS AND RELEVANCE: This study identified a small absolute increase in risk of harms associated with opioid tapering compared with a stable opioid dosage. These results do not suggest that policies of mandatory dosage tapering for individuals receiving a stable long-term opioid dosage without evidence of opioid misuse will reduce short-term harm via suicide and overdose.

PMID:35960518 | DOI:10.1001/jamanetworkopen.2022.26523

Adv Ther. 2022 Aug 12. doi: 10.1007/s12325-022-02290-3. Online ahead of print.

ABSTRACT

INTRODUCTION: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo.

METHODS: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression.

RESULTS: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments.

CONCLUSIONS: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188).

PMID:35960482 | DOI:10.1007/s12325-022-02290-3

Ann Surg Oncol. 2022 Aug 12. doi: 10.1245/s10434-022-12361-y. Online ahead of print.

ABSTRACT

BACKGROUND: Ductal carcinoma in situ (DCIS) is uncommon and understudied in young women. The objective of this study is to describe clinicopathologic features, treatment, and oncologic outcomes in a modern cohort of women aged ≤ 40 years with DCIS.

PATIENTS AND METHODS: Patients with DCIS were identified from the Young Women’s Breast Cancer Study, a multisite prospective cohort of women diagnosed with stage 0-IV breast cancer at age ≤ 40 years, enrolled from 2006 to 2016. Clinical data were collected from patient surveys and medical records. Pathologic features were examined by central review. Data were summarized with descriptive statistics and groups were compared with χ² and Fisher’s exact tests.

RESULTS: Among the 98 patients included, median age of diagnosis was 38 years; 36 (37%) patients were symptomatic on presentation. DCIS nuclear grade was high in 35%, intermediate in 50%, and low in 15% of lesions; 36% of lesions had comedonecrosis. The majority of patients underwent bilateral mastectomy (57%), 16 (16%) underwent unilateral mastectomy, and 26 (27%) underwent lumpectomy, most of whom received radiation. Few (13%) patients were receiving tamoxifen therapy 1 year postdiagnosis. Over a median follow-up of 8.4 years, six patients (6%) had disease recurrence, including five locoregional and one distant event.

CONCLUSIONS: A high proportion of young women with DCIS underwent mastectomy with or without contralateral prophylactic mastectomy. Although DCIS was frequently symptomatic on presentation and exhibited unfavorable pathologic factors, clinicopathologic features were overall heterogeneous and few recurrences occurred. This underscores the need for careful consideration of treatment options in young women with DCIS.

PMID:35960452 | DOI:10.1245/s10434-022-12361-y