Nontuberculous mycobacteria can cause minimally symptomatic self-limiting infections to progressive and life-threatening disease of multiple organs. Several factors such as increased testing and ...prevalence have made this an emerging infectious disease. Multiple guidelines have been published to guide therapy, which remains difficult owing to the complexity of therapy, the potential for acquired resistance, the toxicity of treatment, and a high treatment failure rate. Given the long duration of therapy, complex multi-drug treatment regimens, and the risk of drug toxicity, therapeutic drug monitoring is an excellent method to optimize treatment. However, currently, there is little available guidance on therapeutic drug monitoring for this condition. The aim of this review is to provide information on the pharmacokinetic/pharmacodynamic targets for individual drugs used in the treatment of nontuberculous mycobacteria disease. Lacking data from randomized controlled trials, in vitro, in vivo, and clinical data were aggregated to facilitate recommendations for therapeutic drug monitoring to improve efficacy and reduce toxicity.
Biofilms are highly tolerant to antibiotics and underlie the recalcitrance of many chronic infections. We demonstrate that mature
biofilms can be substantially sensitized to the treatment by pulse ...dosing of an antibiotic - in this case, oxacillin. Pulse (periodic) dosing was compared to continuous application of antibiotic and was studied in a novel
flow system which allowed for robust biofilm growth and tractable pharmacokinetics of dosing regimens. Our results highlight that a subpopulation of the biofilm survives antibiotic without becoming resistant, a population we refer to as persister bacteria. When oxacillin was continuously present the persister level did not decline, but, importantly, providing correctly timed periodic breaks decreased the surviving population. We found that the length of the periodic break impacted efficacy, and there was an optimal length that sensitized the biofilm to repeat treatment without allowing resistance expansion. Periodic dosing provides a potential simple solution to a complicated problem.
An ordered mesoporous tungsten‐oxide/carbon (denoted as m‐WO3−x‐C‐s) nanocomposite is synthesized using a simple one‐pot method using polystyrene‐block‐poly(ethylene oxide) (PS‐b‐PEO) as a ...structure‐directing agent. The hydrophilic PEO block interacts with the carbon and tungsten precursors (resol polymer and WCl6), and the PS block is converted to pores after heating at 700 °C under a nitrogen flow. The m‐WO3−x‐C‐s nanocomposite has a high Brunauer–Emmett–Teller (BET) surface area and hexagonally ordered pores. Because of its mesoporous structure and high intrinsic density of tungsten oxide, this material exhibits a high average volumetric capacitance and gravimetric capacitance as a pseudocapacitor electrode. In comparison with reduced mesoporous tungsten oxide (denoted as m‐WO3−x‐h), which is synthesized by a tedious hard template approach and further reduction in a H2/N2 atmosphere, m‐WO3−x‐C‐s shows a high capacitance and enhanced rate performance, as confirmed by cyclic voltammetry, galvanostatic charge/discharge measurements, and electrochemical impedance spectroscopy. The good performance of m‐WO3−x‐C‐s is attributed to the high surface area arising from the mesoporous structure, the large interconnected mesopores, and the low internal resistance from the well‐dispersed reduced tungsten oxide and amorphous carbon composite structure. Here, the amorphous carbon acts as an electrical pathway for effective pseudocapacitor behavior of WO3‐x.
An ordered mesoporous tungsten‐oxide/carbon (m‐WO3−x‐C‐s) nanocomposite is synthesized using a block‐copolymer‐assisted one‐pot self‐assembly method. As a pseudocapacitor electrode, m‐WO3−x‐C‐s exhibits a high average volumetric capacitance of 340 F cm−3 and a gravimetric capacitance of 103 F g−1. The amorphous carbon in the m‐WO3−x‐C‐s decreases the internal resistance of m‐WO3−x‐C‐s electrode by facilitating electric conduction.
Youth with anxiety and obsessive-compulsive disorder (OCD) rarely access exposure therapy, an evidence-based treatment. Known barriers include transportation, waitlists, and provider availability. ...Efforts to improve access to exposure require an understanding of the process that families take to find therapists, yet no prior studies have examined parents' perspectives of the steps involved.
Parents of children who have received exposure therapy for anxiety and/or OCD (
) were recruited from a hospital-based specialty anxiety clinic where the majority of their children previously received exposure. Recruitment was ongoing until thematic saturation was reached. Parents completed questionnaires and attended an online focus group during which they were asked to describe each step they took-from recognizing their child needed treatment to beginning exposure. A process map was created and shown in real-time, edited for clarity, and emailed to parents for member checking. Authors analyzed process maps to identify common themes.
Several themes emerged, as visually represented in a final process map. Participants identified a "search-outreach" loop, in which they repeated the cycle of looking for therapists, contacting them, and being unable to schedule an appointment due to factors such as cost, waitlists, and travel time. Parents often did not know about exposure and reported feeling guilty about their lack of knowledge and inability to find a suitable provider. Parents reported frustration that medical providers did not often know about exposure and sometimes dismissed parents' concerns. Participants emphasized the difficulty of navigating the mental health system; many reported that it took years to find an exposure therapist, and that the search was sometimes stalled due to fluctuating symptoms.
A common thread among identified barriers was the amount of burden placed on parents to find treatment with limited support, and the resultant feelings of isolation and guilt. Findings point to several directions for future research, such as the development of parent support groups for navigating the mental health system; enhancing coordination of care between medical and mental health providers; and streamlining referral processes.
Bacterial communities are crucial to soil ecosystems and are known to be sensitive to environmental changes. However, our understanding of how present-day soil bacterial communities remain impacted ...by historic land uses is limited; implications for their functional potential are especially understudied. Through 16S rRNA gene amplicon and shotgun metagenomic sequencing, we characterized the structure and functional potential of soil bacterial communities after land use conversion. Sites converted from pine plantations to dairy pasture were sampled five- and eight-years post conversion. The bacterial community composition and functional potential at these sites were compared to long-term dairy pastures and pine forest reference sites. Bacterial community composition and functional potential at the converted sites differed significantly from those at reference sites (P = 0.001). On average, they were more similar to those in the long-term dairy sites and showed gradual convergence (P = 0.001). Differences in composition and functional potential were most strongly related to nutrients such as nitrogen, Olsen P and the carbon to nitrogen ratio. Genes related to the cycling of nitrogen, especially denitrification, were underrepresented in converted sites compared to long-term pasture soils. Together, our study highlights the long-lasting impacts land use conversion can have on microbial communities, and the implications for future soil health and functioning.
Background Invasive melanoma of the skin is the third most common cancer diagnosed among adolescents and young adults (aged 15-39 years) in the United States. Understanding the burden of melanoma in ...this age group is important to identifying areas for etiologic research and in developing effective prevention approaches aimed at reducing melanoma risk. Methods Melanoma incidence data reported from 38 National Program of Cancer Registries and/or Surveillance Epidemiology and End Results statewide cancer registries covering nearly 67.2% of the US population were used to estimate age-adjusted incidence rates for persons 15-39 years of age. Incidence rate ratios were calculated to compare rates between demographic groups. Results Melanoma incidence was higher among females (age-adjusted incidence rates = 9.74; 95% confidence interval 9.62-9.86) compared with males (age-adjusted incidence rates = 5.77; 95% confidence interval 5.68-5.86), increased with age, and was higher in non-Hispanic white compared with Hispanic white and black, American Indians/Alaskan Natives, and Asian and Pacific Islanders populations. Melanoma incidence rates increased with year of diagnosis in females but not males. The majority of melanomas were diagnosed on the trunk in all racial and ethnic groups among males but only in non-Hispanic whites among females. Most melanomas were diagnosed at localized stage, and among those melanomas with known histology, the majority were superficial spreading. Limitations Accuracy of melanoma cases reporting was limited because of some incompleteness (delayed reporting) or nonspecific reporting including large proportion of unspecified histology. Conclusions Differences in incidence rates by anatomic site, histology, and stage among adolescents and young adults by race, ethnicity, and sex suggest that both host characteristics and behaviors influence risk. These data suggest areas for etiologic research around gene-environment interactions and the need for targeted cancer control activities specific to adolescents and young adult populations.
Background Diffusion-weighted (DW) imaging is useful in detecting tumor in the primary tumor bed in locally advanced rectal cancer (LARC) after neoadjuvant therapy, but its value in detecting ...extramural venous invasion (EMVI) and tumor deposit is not well validated. Purpose To evaluate diagnostic accuracy and association with patient prognosis of viable EMVI and tumor deposit on DW images in patients with LARC after neoadjuvant therapy using whole-mount pathology specimens. Materials and Methods This retrospective study included patients who underwent neoadjuvant therapy and surgery from 2018 to 2021. Innovative five-point Likert scale was used by two radiologists to independently evaluate the likelihood of viable EMVI and tumor deposit on restaging DW MRI scans in four axial quadrants (12 to 3 o'clock, 3 to 6 o'clock, 6 to 9 o'clock, and 9 to 12 o'clock). Diagnostic accuracy was assessed at both the per-quadrant and per-patient level, with whole-mount pathology as the reference standard. Weighted κ values for interreader agreement and Cox regression models for disease-free survival and overall survival analyses were used. Results A total of 117 patients (mean age, 56 years ± 12 SD; 70 male, 47 female) were included. Pathologically proven viable EMVI and tumor deposit was detected in 29 of 117 patients (25%) and in 44 of 468 quadrants (9.4%). Per-quadrant analyses showed an area under the receiver operating characteristics curve of 0.75 (95% CI: 0.68, 0.83), with sensitivity and specificity of 55% and 96%, respectively. Good interreader agreement was observed between the radiologists (κ = 0.62). Per-patient analysis showed sensitivity and specificity of 62% and 93%, respectively. The presence of EMVI and tumor deposit on restaging DW MRI scans was associated with worse disease-free survival (hazard ratio HR, 5.6; 95% CI: 2.4, 13.3) and overall survival (HR, 8.9; 95% CI: 1.6, 48.5). Conclusion DW imaging using the five-point Likert scale showed high specificity and moderate sensitivity in the detection of viable extramural venous invasion and tumor deposits in LARC after neoadjuvant therapy, and its presence on restaging DW MRI scans is associated with worse prognosis. Published under a CC BY 4.0 license.
See also the editorial by Méndez and Ayuso in this issue.
Endometriosis is a chronic inflammatory condition that affects fertility and could be toxic to the ovary. Endometrioma per se and surgical interventions for endometrioma significantly reduce the ...ovarian reserve. Therefore, to prepare for surgical intervention for endometrioma, the high-risk group with decreased ovarian reserve must be considered. There is no evidence to support the use of surgical intervention before in vitro fertilization (IVF) to improve the reproductive outcomes of subsequent IVF in infertile women with advanced-stage endometriosis or endometrioma. As surgical treatment has few benefits, IVF could be recommended immediately for aiding conception in these women. However, the reproductive prognosis of IVF may be worse in the more advanced stages of endometriosis. When dysmenorrhea is severe or when cancer is suspected, surgery prior to IVF may be necessary and justified. When the size of the endometrioma is very large, surgery could be required prior to IVF to facilitate access to follicles during oocyte retrieval or to improve the ovarian response to controlled ovarian stimulation. Prolonged pituitary downregulation in women with surgically diagnosed endometriosis may be helpful to increase the clinical pregnancy rate in subsequent IVF cycles. The purpose of this paper was to review the efficiency and clinical application of the surgical intervention and IVF for infertile women with advanced-stage endometriosis or endometrioma.
The aim of this study was to evaluate the construct validity of the psychosis module of the Mini International Neuropsychiatric Interview version 7.0.2 (MINI-7).
We utilized data collected from 2738 ...participants with a primary psychotic or bipolar disorder. Participants were drawn from two Kenyan sites of a large multi-center neuropsychiatric genetic study. The factor structure of the MINI-7 psychosis items were explored using confirmatory factor analyses (CFA) and Item Response Theory approach, for the full sample and by gender.
The CFA revealed that a 1-factor model provided adequate fit for the MINI-7 psychosis items for the full sample (x2 = 397.92, df = 35, p < .0001; RMSEA = 0.06; CFI = 0.92; TLI = 0.90) as well as for the female (x2 = 185.16.92, df = 35, p < .0001; RMSEA = 0.06; CFI = 0.93; TLI = 0.91) and male groups (x2 = 242.09, df = 35, p < .0001; RMSEA = 0.06; CFI = 0.92; TLI = 0.89). Item thresholds for the full sample, and female and male groups were highest for ‘odd beliefs’ (−1.42, −1.33, and −1.51 respectively) and lowest for ‘visual hallucinations’ (−0.03, −0.04, and −0.01 respectively).
Our study used a hospital-based population, which may have excluded patients with milder psychotic symptoms. Findings may therefore not be generalizable to the community setting.
Our findings indicate good construct validity of the MINI-7 psychosis module, and provides support for use of the tool in diagnosing psychotic disorders in clinical settings in Kenya.
•Diagnosing psychotic disorders in Kenya requires a valid structured tool.•We evaluated the construct validity of the MINI-7 psychosis module.•MINI-7 psychosis module has good construct validity in a clinical sample in Kenya.
Fragment-based lead discovery (FBLD) often relies on flat, aromatic compounds which display undesirable physicochemical properties with limited exit vectors for fragment growth. Herein, we report ...concise synthetic strategies to sp
3
-rich heterocyclic fragments encompassing polar exit vectors poised for fragment-to-lead (F2L) development.
Herein, we present sp
3
-rich fragments, that display optimal physicochemical properties and exit vectors ideal for fragment-based lead discovery.
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