Selective detection of azelnidipine in pharmaceuticals via carbon dot mediated spectrofluorimetric method: A green approach.

A spectrofluorimetric method using fluorescent carbon dots (CDs) was developed for the selective detection of azelnidipine (AZEL) pharmaceutical in the presence of other drugs. In this study, N-doped CDs (N-CDs) were synthesized through a single-step hydrothermal process, using citric acid and urea as precursor materials. The prepared N-CDs showed a highly intense blue fluorescence emission at 447 nm, with a photoluminescence quantum yield of ~21.15% and a fluorescence lifetime of 0.47 ns. The N-CDs showed selective fluorescence quenching in the presence of all three antihypertensive drugs, which was used as a successful detection platform for the analysis of AZEL. The photophysical properties, UV-vis light absorbance, fluorescence emission, and lifetime measurements support the interaction between N-CDs and AZEL, leading to fluorescence quenching of N-CDs as a result of ground-state complex formation followed by a static fluorescence quenching phenomenon. The detection platform showed linearity in the range 10-200 µg/ml (R2 = 0.9837). The developed method was effectively utilized for the quantitative analysis of AZEL in commercially available pharmaceutical tablets, yielding results that closely align with those obtained from the standard method (UV spectroscopy). With a score of 0.76 on the 'Analytical GREEnness (AGREE)' scale, the developed analytical method, incorporating 12 distinct green analytical chemistry components, stands out as an important technique for estimating AZEL.

Comprehensive insights into herbal P-glycoprotein inhibitors and nanoformulations for improving anti-retroviral therapy efficacy.

The worldwide HIV cases were 39.0 million (33.1-45.7 million) in 2022. Due to genetic variations, HIV-1 is more easily transmitted than HIV-2 and favours CD4 + T cells and macrophages, producing AIDS. Conventional HIV drug therapy has many drawbacks, including adherence issues leading to resistance, side effects that lower life quality, drug interactions, high costs limiting global access, inability to eliminate viral reservoirs, chronicity requiring lifelong treatment, emerging toxicities, and a focus on managing infections. Conventional dosage forms have bioavailability issues due to intestinal P-glycoprotein (P-gp) efflux, which can reduce anti-retroviral drug efficacy and lead to resistance. Use of phyto-constituents with P-gp regulating actions has great benefits for semi-synthetic modification to create formulations with greater bioavailability and reduced toxicity, which improves drug effectiveness. Lipid-based nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, polymer-based nanocarriers, and inorganic nanoparticles may inhibit P-gp efflux. Employing potent P-gp inhibitors within nanocarriers as a Trojan horse approach can enhance the intracellular accumulation of anti-retroviral drugs (ARDs), which are substrates for efflux transporters. This technique increases oral bioavailability and offers lower-dose options, boosting HIV patient compliance and lowering costs. Molecular docking of the inhibitor with P-gp may anticipate optimum binding and function, allowing drug efflux to be minimised.

Exploring the potential of P-glycoprotein inhibitors in the targeted delivery of anti-cancer drugs: A comprehensive review.

Due to the high prevalence of cancer, progress in the management of cancer is the need of the hour. Most cancer patients develop chemotherapeutic drug resistance, and many remain insidious due to overexpression of Multidrug Resistance Protein 1 (MDR1), also known as Permeability-glycoprotein (P-gp) or ABCB1 transporter (ATP-binding cassette subfamily B member 1). P-gp, a transmembrane protein that protects vital organs from outside chemicals, expels medications from malignant cells. The blood-brain barrier (BBB), gastrointestinal tract (GIT), kidneys, liver, pancreas, and cancer cells overexpress P-gp on their apical surfaces, making treatment inefficient and resistant. Compounds that compete with anticancer medicines for transportation or directly inhibit P-gp may overcome biological barriers. Developing nanotechnology-based formulations may help overcome P-gp-mediated efflux and improve bioavailability and cell chemotherapeutic agent accumulation. Nanocarriers transport pharmaceuticals via receptor-mediated endocytosis, unlike passive diffusion, which bypasses ABCB1. Anticancer drugs and P-gp inhibitors in nanocarriers may synergistically increase drug accumulation and chemotherapeutic agent toxicity. The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted.

Exploration of multifaceted molecular mechanism of angiotensin-converting enzyme 2 (ACE2) in pathogenesis of various diseases.

Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.

Meeting Youth Where They Live: How to Use a QR Code in Safety Planning.

When in extreme distress, it is difficult to remember the coping strategies and resources available to you. The purpose of a safety plan is to make it easier for individuals to make wise choices in moments of crisis. By virtue of this, we should strive to have safety plans as easy and convenient to use as possible. The Stanley-Brown safety plan is a template for this style of intervention and has been adapted and adopted in numerous institutions.1 A pillar of this intervention is ready-at-hand contact information for mental health agencies and crisis resources. Although the classic paper safety plan remains an invaluable tool, integration of digital resources may be necessary to meet our young patients "where they live."2 Generation Z are "digital natives" with great fluency and comfort with smart devices. Expansion of the audio-only National Suicide Prevention Lifeline to the audio, SMS, and Web-based instant messaging capabilities of the 988 Crisis & Suicide Lifeline recognizes this shift.3 At the University of Michigan, we developed a quick response (QR) code to save these resources directly onto youths' smartphones.

Enhanced Adoption of Measurement-Based Care in a Psychiatry Outpatient Clinic After High-Reliability Process Changes.

OBJECTIVE: This study examined the impact of high-reliability changes to how measurement-based care questionnaires were administered to patients on rates of questionnaire completion. METHODS: Medical record data were abstracted from 44,305 adult outpatient return visits to a psychiatry outpatient clinic within two 10-month periods (before and after process changes were implemented). Linear mixed models tested the change in questionnaire completion rates and the interaction effects between time and age, sex, and race. RESULTS: Patient completion of questionnaires increased by 79% after process changes. Women were more likely to complete questionnaires regardless of the process. After process changes, older patients and White patients were more likely to complete questionnaires. CONCLUSIONS: High-reliability process changes to measurement-based care questionnaire administration were associated with higher questionnaire completion rates. Racial, age, and sex disparities in questionnaire completion rates were notable and deserve attention in future measurement-based care implementation efforts.

Ethyl Methane Sulfonate and Sodium Azide-Mediated Chemical and X-ray-Mediated Physical Mutagenesis Positively Regulate Peroxidase 1 Gene Activity and Biosynthesis of Antineoplastic Vinblastine in Catharanthus roseus.

Catharanthus roseus synthesizes bioactive therapeutic metabolites, known as monoterpenoid indole alkaloids (MIAs), including antineoplastic vinblastine and vincristine, which have high global demand, and antihypertensive ajmalicine, a serpentine. However, the in planta biosynthesis and accumulation of these phytopharmaceuticals are very low, attributed to their high cytotoxicity in the plant. Considering the low in planta concentration and over-harvesting of plant resources, biotechnological interventions have been undertaken to enhance the production of MIAs in plant systems. The present study was carried out to mutation through chemical and physical mutagenesis with sodium azide, ethyl methane sulfonate and X-rays, respectively, on C. roseus to determine their possible effects on the transcriptional modulation of MIA biosynthetic pathways in planta. The chemical mutagenesis resulted in delayed seed pod development in mutated C. roseus plants, with distinct leaf morphology and flower color. However, X-ray mutagenesis resulted in pollen-less sterile flowers. An HPLC analysis confirmed the higher catharanthine, vindoline and vinblastine content in sodium azide and X-ray mutants, and was further supported by higher PRX1 transcript levels estimated through real-time PCR analysis. The transcription factors WRKY1 and ORCA2 were found negatively regulated along with major MIA pathway genes in chemical mutants and their M1 generation, but showed positive regulation in X-ray M0 mutants. The induced mutagenesis of C. roseus provides a prospective strategy to modulate plant transcriptomes and enhance the biosynthesis of pharmaceutically important antineoplastic vinblastine in the plant.

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Narirutin-rich fraction from grape fruit peel protects against transient cerebral ischemia reperfusion injury in rats.

Objective: Ischemic stroke is one of the leading causes of disability in adults worldwide. The present study was aimed to evaluate the efficacy of Narirutin-rich fraction (NRF), obtained from grape fruit peel, on cerebral ischemia/reperfusion injury in rats.Methods: Male Wistar rats (180-200 g) were subjected to bilateral carotid artery occlusion for 30 min followed by reperfusion for 24 h to induce cerebral ischemia/reperfusion injury. NRF (150, 300 mg/kg, oral) was administered for 7 days continuously before animals were subjected to ischemia/reperfusion injury. Various behavioral tests (for measurement of motor coordination, locomotor activity, and spatial memory), biochemical parameters (lipid peroxidation, superoxide dismutase, and catalase activity), and histopathological alterations were assessed.Results: Seven-day NRF (150 and 300 mg/kg) pretreatment significantly improved neurobehavioral alterations and histological findings as compared to the disease control group. Further NRF treatment significantly reduced oxidative damage as indicated by improved lipid peroxidation, superoxide dismutase, and catalase activity as compared to disease control animals.Conclusion: The present study demonstrated the protective effect of NRF against cerebral ischemia/reperfusion injury in rats. The results suggest that NRF can be a potential pretreatment option against cerebral ischemia/reperfusion injury.

Going Virtual During a Pandemic: An Academic Psychiatry Department's Experience with Telepsychiatry.

Background: The novel coronavirus pandemic (COVID-19) led healthcare providers, including mental health providers, across the U.S. to swiftly shift to telemedicine. Objectives: This shift gave our Department of Psychiatry a chance to better understand key challenges and opportunities vis-à-vis virtual mental healthcare. We aimed to obtain provider feedback on the use of telepsychiatry and to learn from the provider perspective about patient experiences with video visits. This information will be used to inform the telemedicine strategy at a systems level within our psychiatry department, our academic health system, as well as the field of telemedicine as a whole. Design and Sample: A 22-item online questionnaire comprising 16 quantitative and six qualitative items was distributed to providers currently using video visits to provide care. Results: A total of 89 mental health providers completed the questionnaire. Outcomes demonstrated that while providers perceive challenges associated with virtual care (e.g., fatigue, technology-related issues, and age-related concerns), they also recognize a number of benefits to themselves and their patients (e.g., convenience and increased access). Overall, provider satisfaction, comfort, and willingness to use telepsychiatry was high. Conclusions: The vast majority of providers adapted quickly to the use of virtual platforms; many endorse advantages that suggest virtual care will continue to be a modality they provide in the future, post-COVID-19. It will be important to continue to evaluate aspects of virtual care that may limit clinical assessments and to optimize use to improve access, convenience, and cost-efficiency of mental healthcare delivery.

Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior.

The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Improved 3D-QSAR Prediction by Multiple Conformational Alignments and Molecular Docking Studies to Design and Discover HIV-I Protease Inhibitors.

BACKGROUND: Inhibition of HIV-I protease enzyme is a strategic step for providing better treatment in retrovirus infections, which avoids resistance and possesses less toxicity. OBJECTIVES: In the course of our research to discover new and potent protease inhibitors, 3D-QSAR (CoMFA and CoMSIA) models were generated using 3 different alignment techniques, including multifit alignment, docking based and Distill based alignment for 63 compounds. Novel molecules were designed from the output of this study. METHODS: A total of 3 alignment methods were used to generate CoMFA and CoMSIA models. A Distill based alignment method was considered a better method according to different validation parameters. A 3D-QSAR model was generated and contour maps were discussed. The biological activity of designed molecules was predicted using the generated QSAR model to validate QSAR. The newly designed molecules were docked to predict binding affinity. RESULTS: In CoMFA, leave one out cross-validated coefficient (q2), conventional coefficient (r2) and predicted correlation coefficient (r2Predicted) values were found to be 0.721, 0.991 and 0.780, respectively. The best obtained CoMSIA model also showed significant cross-validated coefficient (q2), conventional coefficient (r2) and predicted correlation coefficient (r2Predicted) values of 0.714, 0.987 and 0.721, respectively. Steric and electrostatic contour maps generated from CoMFA and hydrophobic and hydrogen bond donor and hydrogen bond acceptor contour maps from CoMSIA models were used to design new and bioactive protease inhibitors by incorporating bioisosterism and knowledge-based structure-activity relationship. CONCLUSION: The results from both these approaches, ligand-based drug design and structure-based drug design, are adequate and promising to discover protease inhibitors.

Microwave ablation: How we do it?

Minimally invasive techniques such as Image guided thermal ablation are now widely used in the treatment of tumors. Microwave ablation (MWA) is one of the newer modality of thermal ablation and has proven its safety and efficacy in the management of the tumors amenable for ablation for primary and metastatic diseases. It is used in the treatment of primary and secondary liver malignancies, primary and secondary lung malignancies, renal and adrenal tumors and bone metastases. We wanted to share our initial experience with this newer modality. In this article we will describe the mechanism and technique of MWA, comparison done with RFA, advantages and disadvantages of MWA along with pre procedure workup, post procedure follow-up and review of literature.

Implementing Measurement-Based Care in Various Practice Settings.

Measurement-based care (MBC) is recognized as a valuable component to maximize quality in psychiatric care; however, actual use of MBC by practitioners is poor. A host of implementation barriers have been noted, and are likely significant contributors to this poor adoption. Many of these barriers are related to work-flow issues that can be managed or mitigated by appropriate infrastructure considerations. This article offers an overview of the continuum of infrastructures to support MBC in clinical practice, delineating the tradeoffs between these infrastructures, and then identifying specific experience-based strategies for addressing several major patient-, provider-, and organization-level barriers to MBC implementation.

The effect of a computerized best practice alert system in an outpatient setting on metabolic monitoring in patients on second-generation antipsychotics.

WHAT IS KNOWN AND OBJECTIVE: Metabolic syndrome is a well-documented adverse effect of second-generation antipsychotics (SGAs). Patients with metabolic syndrome are at an increased risk of potentially fatal cardiovascular events, including myocardial infarction and stroke. This elevated risk prompted the creation of a national guideline on metabolic monitoring for patients on SGAs in 2004. However, monitoring practices remained low at our clinic. To address this concern, a clinical decision support system was developed to alert providers of monitoring requirements. The purpose of this study is to determine the effect of the best practice alert (BPA), and to assess the impact of provider and patient characteristics on metabolic laboratory (lab) order rates. METHODS: A retrospective chart review was conducted at a large outpatient psychiatric clinic. Data were collected from all adult patients who were prescribed an SGA and triggered the BPA (indicating lab monitoring is needed for the patient). Data collection included a variety of patient, provider and alert variables. The primary outcome was a composite of fasting blood glucose (FBG), haemoglobin A1c (HbA1c) and/or fasting lipid panel order rates. Secondary outcomes included the rate of valid response, which considered appropriate reasons for not ordering labs (ie monitoring already completed during recent primary care visit), as well as order rates of individual labs. RESULTS AND DISCUSSION: Data from 1112 patients were collected and analysed. Patients with a thought disorder diagnosis had significantly more labs ordered than those without. No other patient factors affected order rates. Resident psychiatrists and nurse practitioners ordered significantly more labs and had significantly more valid responses than attending psychiatrists. An active alert, which fired during medication order entry, was associated with a higher rate of lab ordering and valid response compared to a passive alert, which fired whenever a prescribing healthcare provider opened the chart. WHAT IS NEW AND CONCLUSION: Prescribers may associate metabolic syndrome with schizophrenia or with use of SGAs specifically in thought disorders, even though these medications pose a risk for all indications. Higher rates of monitoring by resident physicians may have been due to spending more time with patients during the encounter and in documentation. Lastly, the active BPA was an effective tool to increase metabolic monitoring in patients taking SGAs. Continued education on the importance of regular metabolic monitoring should be implemented for all providers.

Development of the National Network of Depression Centers Mood Outcomes Program: A Multisite Platform for Measurement-Based Care.

OBJECTIVES: Mood disorders are among the most burdensome public health concerns. The National Network of Depression Centers (NNDC) is a nonprofit consortium of 26 leading clinical and academic member centers in the United States providing care for patients with mood disorders, including depression and bipolar disorder. The NNDC has established a measurement-based care program called the Mood Outcomes Program whereby participating sites follow a standard protocol to electronically collect patient-reported outcome assessments on depression, anxiety, and suicidal ideation in routine clinical care. This article describes the approaches taken to develop and implement the program. METHODS: Since 2015, eight pilot sites have implemented the program and followed more than 10,000 patients. This pilot study presents descriptive statistics based on the first 24-month period of data collection. RESULTS: In this sample, 58.6% of patients with bipolar disorder (N=849) and 57.5% of patients with unipolar depression (N=3,998) remained symptomatic at follow-up. Lifetime rates of planned or actual suicide attempts were high, ranging from 27.6% for patients with unipolar mood disorders to 33.5% for patients with bipolar disorder. Men, unmarried individuals, and those with comorbid anxiety had a poorer longitudinal course. This initial snapshot of clinical burden is consistent with public health data indicating that mood disorders are severely debilitating. CONCLUSIONS: This study demonstrates the potential of the Mood Outcomes Program to create a nationwide "learning health system" for mood disorders. This goal will be further realized as the program expands in reach and scope across additional NNDC sites.

The Michigan Child Collaborative Care Program: Building a Telepsychiatry Consultation Service.

This column describes the establishment of the Michigan Child Collaborative Care (MC3), a statewide telepsychiatry consultation program that provides support to primary care providers (PCPs) in meeting the mental health needs of youths and perinatal women. The MC3 program provides cost-effective, timely, remote consultation to primary care providers in an effort to address the lack of access and scarcity of resources in child, adolescent, and perinatal psychiatry. Data from 10,445 service requests are summarized. Common diagnoses included attention-deficit hyperactivity disorder, mood disorders, anxiety disorders, and autistic spectrum disorders, with many cases (58%) deemed moderate to severe. Co-occurring psychological trauma was suspected in 9% of service requests. Partnerships, stakeholder roles, PCP engagement, and workflow integration are highlighted as keys to the program's success.

Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.

The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.

Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder.

Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 × 10-11) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.

Partnerships with Primary Care for the Treatment of Preschoolers.

This article reviews mental health access issues relevant to preschool children and data on this population obtained through the Michigan Child Collaborative Care Program (MC3). The MC3 program provides telephonic consultation to primary care physicians (PCPs) in 40 counties in Michigan and video telepsychiatric consultation to patients and families. Attention-deficit/hyperactivity disorder and disruptive behavioral disorders are frequent initial presenting diagnoses, but autism spectrum disorders, parent-child relational issues, trauma, and posttraumatic stress disorder should also be considered. Collaborative care programs provide promising ways to promote access to child psychiatric services when these services are distant to local PCP offices.