The Effectiveness of Preventative Interventions to Reduce Mental Health Problems in at-risk Children and Young People: A Systematic Review of Reviews.

Mental health problems are the leading cause of childhood disability worldwide, resulting in poor outcomes for children and young people that persist into adulthood. It is essential that those young people most at risk of developing mental health problems receive effective preventative interventions. Whilst there have been a number of systematic reviews which have examined the effectiveness of secondary prevention interventions for specific groups of children and young people, or to address identified mental health concerns, no review has engaged with the breadth of this literature. We conducted a systematic review of systematic reviews to map this complex field of secondary preventative interventions and identify effective interventions to prevent mental health problems in children and adolescents aged 3-17 years. The review protocol was registered on PROSPERO. We searched five electronic databases from inception to February 2023. The certainty of the evidence was appraised using the AMSTAR 2. We included 49 unique systematic reviews each including between 2 and 249 (mean 34) unique studies; the majority of which were reviews which included only or mostly randomised controlled trials (70%). The reviews examined selective interventions (defined as interventions which are delivered to sub-group populations of young people at increased risk of mental health problems) (n = 22), indicated interventions (defined as interventions which target young people who are found to have pre-clinical symptoms) (n = 15) or a synthesis of both (n = 12). The certainty of the evidence in the reviews was rated as high, (n = 12) moderate (n = 5), low (n = 9) and critically low (n = 23). We found evidence to support both selective and indicated interventions in a range of populations and settings, with most of this evidence available for children and young people in their mid-years (6-10 years) and early adolescence (11-13 years). There was a large body of evidence suggesting that resilience enhancing, cognitive behaviour therapy-based and psychoeducational interventions for children who experience adversity, or those with subclinical externalising problems may offer promise. Early selective interventions for a subpopulation of children and young people who have experienced adversity which combines risk reduction and resilience enhancing approaches directed at children and their families may be effective at reducing mental health problems.

Barriers to Accessing Primary Dental Care in Adults with Alcohol Dependence: A Qualitative Study.

BACKGROUND: People with alcohol dependence (AD) frequently experience oral health problems, but their dental attendance is poor, with limited evidence to the reasons why from their perspective. OBJECTIVE: To explore perceived barriers, motivators, and facilitators to accessing primary dental care in people with AD. METHODS: Qualitative study consisting of remote one-to-one and group semistructured interviews with a convenience sample of adults with lived experience of AD in northern England. Data were audio-recorded, transcribed, and coded. A reflexive thematic analysis method was used; use of COM-B model informed data interpretation. RESULTS: Twenty adults with lived experience of AD participated in 18 one-to-one interviews and 1 group interview (of 3 participants). Barriers to access were fear and physical, social, and environmental factors (physical effects of AD, financial barriers, nonprioritization of oral health). Motivators to access were pain and prioritization of oral health. Facilitators to access were patterns of alcohol use (i.e., sobriety) and dental service provision within recovery services. CONCLUSIONS: Fear of "the dentist" is a major barrier to accessing dental care, and pain is the primary motivator, among people with AD, although neither are unique to this population. Fear and physical, social, and environmental barriers to access contribute to problem-oriented attendance, which negatively affect oral health outcomes. Opportunity to facilitate attendance increases when a person is in remission from AD through their physical capabilities improving. Increasing capability and opportunity can influence attendance beyond the automatic motivation of pain. Provision of dental care within recovery services could facilitate access to care. Understanding the "web of causation" is key to developing any intervention to improve dental access in people with AD. Further research is needed from the perspective of other adult populations with lived experience of AD, as well as of dental professionals, to gain deeper insight into barriers, facilitators, and possible solutions. KNOWLEDGE TRANSFER STATEMENT: The results of this study can help dental professionals understand factors affecting access to primary care in people with alcohol dependence to provide knowledge that may reduce stigma surrounding the disease. Results also demonstrate areas for intervention development for public policy.

In vitro hypoxic cytotoxicity of nitroimidazoles: uptake and cell cycle phase specificity.

The hypoxic cytotoxicity of four different 2-nitroimidazoles of similar electron affinities but different lipophilicities was compared using EMT6/Ro mouse mammary tumor cells in exponential growth phase in severely (less than 20 ppm) hypoxic conditions. The relative cytotoxicities were misonidazole (MISO) = desmethylmisonidazole (9963) greater than SR-2508 much greater than SR-2555 indicating that the compounds with the lowest lipophilicity were less cytotoxic. The rates of uptake of these compounds were MISO greater than 9963 greater than SR-2508 = SR-2555. These data together with comparisons of the amounts of cell-associated compounds indicate that the similarity in toxicity of MISO and 9963 can be related to a general similarity in their pharmacokinetics, but that other unknown factors must be considered to explain the relative toxicity of SR-2508 and SR-2555. In other experiments, EMT6/Ro cells synchronized using centrifugal elutriation were most sensitive in hypoxia to MISO at the late G1--early S phase of the cell cycle. These data indicate the importance of considering cellular and subcellular distribution of these nitroimidazoles as well as possible cell cycle specificity for cytotoxicity in interpreting relative effectiveness of different compounds in responses of mixed populations of cells in cultures or tumors.

Cytotoxicity of hypoxic cell sensitizers in multicell spheroids.

Multicell tumor spheroids of EMT6/Ro cells were used to evaluate the cytotoxicity of several hypoxic cell sensitizers. The number of clonogenic cells per spheroid was determined after different exposure periods and concentrations of misonidazole, Ro-05-9963, and SR 2508 which have similar electron affinities. The kinetics of cytotoxicity were similar for each drug and the clonogenic fraction was reduced by about 0.5 to a plateau level after 24 hours at 3.0 mM for spheroids grown in 20% O2. Extended exposure periods caused additional cytotoxicity for both Ro-05-9963 and SR 2508. Lower concentrations (0.5 mM) of these sensitizers were not cytotoxic even in spheroids grown in low concentrations of oxygen (2.5% O2) to increase the hypoxic fraction. However, at cytotoxic concentrations (3.0 mM) spheroids grown in this low oxygen concentration exhibited almost twice as much cytotoxicity. No cytotoxicity was produced at 3.0 mM misonidazole in small spheroids without necrotic centers and hypoxic cells. In addition to being cytotoxic, continuous exposure of spheroids to high concentrations (3.0 mM) of misonidazole were cytostatic. The spheroid experiments were predictive of the relative effectiveness of the different sensitizers for EMT6/Ro tumors in vivo but the rate and extent of cytotoxicity was greater in tumors especially at low concentrations. In both spheroids and tumors there was little change in growth rate after 24 hours or single intraperitoneal exposures respectively, even with concentrations which reduced the clonogenic fraction by 0.9. This was related to a rapid repopulation of cells and increase in growth fraction after misonidazole cytotoxicity. Addition of adriamycin immediately after misonidazole cytotoxicity resulted in an apparent supra-additive overall response. The significance of these results for interpretation of tumor properties and responses in vivo and for tumor therapy were discussed.

Evidence for the presence of secondary calcium phosphate in bone and its stabilization by acid production.

Calvaria from three 4-day-old chicks were incubated in a variety of buffers to study the parameters controlling the equilibration of bone with its supporting fluid environment. Strong inferential chemical evidence was obtained for the presence in viable bone of some calcium phosphate phase of high solubility apparently governed by the Ksp of CaHPO4-2H2O. In dead bone, this phase underwent spontaneous conversion to a higher Ca/P ratio. In viable bone the soluble phase appeared to be stabilized by the metabolic production of acid (lactate) as revealed by the effects of selective inhibitors.

Further studies on the nature of fluid compartmentalization in chick calvaria.

Labeled mannitol and polyethylene glycol (mol. wt. 4000), PEG, were used as space markers to estimate the fluid compartmentalization of calvaria taken from 3-5-day-old chicks. The mannitol results indicated that about 80% of the water in these bones is extracellular. Only a small fraction of this extracellular space was available to the diffusion of polyehtylene glycol. Adsorption studies in vitro and prior incubation of the tissues with hydrolytic enzymes indicated that the phenomenon of exclusion of PEG was primarily physical in nature. The polyethylene polymer is excluded from the water of hydration of the mineral phase. Apparently much of the extracellular water (two-thirds) of bone is in the form of crystal hydration.