Mental health conditions and contraception: current landscape, reproductive health and obstetric outcomes, and clinical guidance.

PURPOSE OF REVIEW: This review presents the epidemiology of mental health conditions among reproductive aged people, common adverse reproductive outcomes, the hormonal profile of contraception and its relationship with psychiatric outcomes, and updated information for clinicians providing contraceptive counselling for this population. RECENT FINDINGS: There is variability among contraceptive behaviours and patterns across those who have mental health conditions, impacting reproductive, psychiatric, and perinatal outcomes. The endocrinology of hormonal contraceptives is well understood, however, the impacts of steroidal hormones on mental health outcomes continue to be less understood. Overall, hormonal contraceptives are safe to use among those with mental health conditions, and among those using selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. Additional considerations are needed when prescribing contraception among people who may be at risk of poor adherence, who use certain classes of antidepressants, antipsychotics, antiepileptics, and who are <6 weeks postpartum. SUMMARY: Barriers to effective contraceptive use should be addressed and myths on negative psychiatric impacts of hormonal contraceptives should be dispelled. Healthcare clinicians should seek out opportunities to become proficient in contraception counselling to improve health outcomes among people with mental health conditions.

Clinical reasoning and hypothesis generation in expert clinical swallowing examinations.

BACKGROUND: A clinical swallow examination (CSE) provides integral information that informs the diagnostic decision-making process within dysphagia management. However, multiple studies have highlighted a high degree of reported variability within the CSE process. It has been hypothesized that such variability may be the result of the clinical reasoning process rather than poor practices. AIMS: To elucidate the nature of expert, speech-language therapists' (SLTs) clinical reasoning during an initial bedside assessment of patients referred for suspected dysphagia in the acute care environment. METHODS & PROCEDURES: An exploratory 'observation of practice' qualitative methodology was used to achieve the aim. Four expert SLTs, from two clinical services, completed CSEs with 10 new referrals for suspected dysphagia. All assessments were video-recorded, and within 30 min of completing the CSE, a video-stimulated 'think aloud' semi-structured interview was conducted in which the SLT was prompted to articulate their clinical reasoning at each stage of the CSE. Three types of concept maps were generated based on this video and interview content: a descriptive concept map, a reasoning map and a hypothesis map. Patterns that consistently characterized the assessment process were identified, including the overall structure; types of reasoning (inductive versus deductive), facts (i.e., clinical information) drawn upon; and outcomes of the process (diagnosis and recommendations). Interview content was examined to identify types of expert reasoning strategies using during the CSE. OUTCOMES & RESULTS: SLTs' approach to clinical assessment followed a consistent structure, with data gathered pre-bedside, during the patient interview and direct assessment before a management recommendation was made. Within this structure, SLTs engaged in an iterative approach with inductive hypothesis-generating and deductive hypothesis-testing, with each decision-making pathway individually tailored and informed by patient-specific facts collected during the assessment. Clinical assessment was primarily geared towards management of an initial acute presentation with less focus on formulating a diagnostic statement. CONCLUSIONS & IMPLICATIONS: Variability in reported dysphagia practice is likely the result of a patient-centred assessment process characterized by iterative cycles of fact-gathering in order to generate and test clinical hypotheses. This has implications for the development of novel assessment tools, as well as professional development and education of novice SLTs. What this paper adds What is already known on the subject CSE practices are reportedly variable, which has led to calls for more stringent, standardized assessment tools. Emerging evidence suggests that this variation is non-random, but may arise from clinical reasoning processes. What this paper adds to existing knowledge We directly observed expert SLTs conducting CSEs and identified patterns in practice that were consistent across all CSEs evaluated. These patterns were consistent in structure, whereas the content of the assessment items varied and was tailored to individual patient presentation. Overall, expert SLTs engaged in balanced cycles of inductive hypothesis generation and deductive hypothesis-testing, a hallmark of good clinical assessment and practice. What are the potential or actual clinical implications of this work? Ensuring quality CSE requires a more nuanced approach that considers the role of clinical reasoning in SLTs' decision-making and the potential unintended negative consequences of standardized assessment tools.

Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an orthologous mouse model of polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models. However, clinical trials with mTOR inhibitors were disappointing largely due to the intolerable extrarenal side effects during long-term treatment with these drugs. Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in ADPKD patients. To overcome this problem, we previously demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and FC-rapa are similarly effective on polycystic kidneys in this model. However, FC-rapa lacks the extrarenal effects of unconjugated rapamycin, in particular immunosuppressive effects. We conclude that folate-conjugation is a promising avenue for increasing the tissue specificity of small-molecule compounds to facilitate very long-term treatment in ADPKD.

Implications of Variability in Clinical Bedside Swallowing Assessment Practices by Speech Language Pathologists.

Speech language pathology (SLP) clinical bedside swallowing assessments (CBSA) are a cornerstone of quality care for patients in acute hospitals who have dysphagia. The CBSA informs clinical diagnosis and decisions regarding further instrumental assessment, and is used to develop a management plan and monitor progress. However, self-report and retrospective research shows that SLPs are highly variable in their use of assessment components considered by experts to be important for quality CBSA, casting doubt on the validity and reliability of CBSA. This prospective study describes the components included by SLPs when designing a standardised evidence based dysphagia assessment protocol for acute care patients and observed patterns of component use. The findings confirm that SLPs use the CBSA for multiple purposes beyond diagnosis of aspiration risk and dysphagia presence/severity. They are highly variable in their use of certain components, but also demonstrate consistent use of a core set. It is apparent that SLPs prioritise the application of clinical reasoning to tailor their CBSA to the patient over following a highly structured item-based protocol. The variability in component use likely reflects a complex clinical reasoning process that draws on a wide variety of information combined with expert knowledge as is also observed in many other medical specialties. Rather than promoting the standardisation of CBSA protocols that constrain SLP practice to strict item-based assessment protocols, consideration should be given to promoting the value and facilitating the clinical reasoning process that supports the utility of the CBSA for diagnosis, patient centred management and treatment planning.

Mifepristone and misoprostol in California pharmacies after modifications to the Risk Evaluation and Mitigation Strategy Program.

In January 2023, the Food & Drug Administration modified the Risk Evaluation and Mitigation Strategy program regulating mifepristone to allow direct dispensation from retail pharmacies. In June 2023, we conducted a random, distributive survey of pharmacies in California using secret shopper methodology to investigate the feasibility of accessing mifepristone. One pharmacy had mifepristone immediately available (<24 hours), and misoprostol availability was limited. Accessibility to misoprostol varied by type of pharmacy (p < 0.01), but not by region. Even in a reproductive freedom state, access to mifepristone and misoprostol from outpatient retail pharmacies remains limited.

ß-hydroxybutyrate recapitulates the beneficial effects of ketogenic metabolic therapy in polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by the formation of fluid-filled renal cysts, loss of mitochondrial function, decreased fatty acid oxidation, increased glycolysis, and likely renal failure. We previously demonstrated that inducing a state of ketosis ameliorates or reverses PKD progression in multiple animal models. In this study, we compare time-restricted feeding and 48-h periodic fasting regimens in both juvenile and adult Cy/+ rats. Both fasting regimens potently prevent juvenile disease progression and partially reverse PKD in adults. To explore the mechanism of fasting, we administered ß-hydroxybutyrate (BHB) to Cy/+ rats and orthologous mouse models of PKD (Pkd1 RC/RC , Pkd1-Ksp:Cre). BHB recapitulated the effects of fasting in these models independent of stereoisomer, suggesting the effects of BHB are largely due to its signaling functions. These findings implicate the use of ketogenic metabolic therapy and BHB supplementation as potential disease modifiers of PKD and point toward underlying mechanisms.

Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease.

Mild reduction in food intake was recently shown to slow polycystic kidney disease (PKD) progression in mouse models, but whether the effect was due to solely reduced calories or some other aspect of the diet has been unclear. We now show that the benefit is due to the induction of ketosis. Time-restricted feeding, without caloric reduction, strongly inhibits mTOR signaling, proliferation, and fibrosis in the affected kidneys in a PKD rat model. A ketogenic diet had a similar effect and led to regression of renal cystic burden. Acute fasting in rat, mouse, and feline models of PKD results in rapid reduction of cyst volume, while oral administration of the ketone ß-hydroxybutyrate (BHB) in rats strongly inhibits PKD progression. These results suggest that cystic cells in PKD are metabolically inflexible, which could be exploited by dietary interventions or supplementation with BHB, representing a new therapeutic avenue to treat PKD.

Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another.