Flow photolysis of aryldiazoacetates leading to dihydrobenzofurans via intramolecular C-H insertion.

Flow photolysis of aryldiazoacetates 3-5 leads to C-H insertion to form dihydrobenzofurans 6-8 in a metal-free process, using either a medium pressure mercury lamp (250-390 nm) or LEDs (365 nm or 450 nm) with comparable synthetic outcomes. Significantly, addition of 4,4'-dimethoxybenzophenone 9 results in an increased yield and also alters the stereochemical outcome leading to preferential isolation of the trans dihydrobenzofurans 6a-8a (up to 50% yield), while the cis and trans diastereomers of 6-8 are recovered in essentially equimolar amounts in the absence of a photosensitiser (up to 26% yield).

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations.

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C-H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.

Effects of a Lifestyle Medicine Elective on Self-Care Behaviors in Preclinical Medical Students.

The purpose of this study was to explore the impact of a lifestyle medicine elective on medical students' self-care behaviors. From fall, 2015, through spring, 2017, a lifestyle medicine elective was offered to first and second year medical students. Acquisition of data was approved by the IRB. Students attended four group sessions, two at the beginning and two at the end of the elective. At the first session, information about the effects of lifestyle on mental and physical health was presented. Students completed screening instruments to assess their own physical activity, nutrition, anxiety, and depression. At the next class, students received their scores. They chose one of three focus groups: nutrition, physical activity or stress management and set a specific goal in that area. At the end of the elective, students attended two group sessions, which focused on patient cases. They again completed the screening instruments, and received their scores. They also evaluated the course. Sixty-three students signed the consent form and provided data. Comparison of baseline scores by gender revealed that women had statistically significant higher scores on the depression screener than men, and lower physical activity scores than men. Pre and post elective comparison in the whole group showed statistically significant improvements in nutrition, depression, and anxiety (all p < .05). Further analysis in the focus groups demonstrated that the stress management group's scores on anxiety were significantly improved. The nutrition group significantly lowered their fat consumption and increased their intake of fruits and vegetables (all p < .05). The physical activity group did not significantly increase their daily physical activity, although this analysis was limited by missing data and wide variability. Student evaluations of the course were positive. Medical students are able to make improvements in their own lifestyle behaviors while acquiring information that may be useful in later patient care.

Copper-Mediated, Heterogeneous, Enantioselective Intramolecular Buchner Reactions of α-Diazoketones Using Continuous Flow Processing.

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper-bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

Psychosocial Factors and Comorbidity Associated with Suicide Attempts: Findings in Patients with Bipolar Disorder.

BACKGROUND: Suicidal attempts occur more frequently in patients with bipolar disorder compared to other mood disorders. The goal of this study is to identify psychosocial factors and comorbidity associated with this serious and life-threatening behavior. SAMPLING AND METHODS: Subjects were 121 patients evaluated and treated at a university outpatient psychiatric clinic. The patients' charts were examined to determine history of suicide attempts, demographic and psychosocial variables, and comorbid symptoms. RESULTS: Forty-one percent of the subjects had attempted suicide. Patients who were younger at onset of illness (p = 0.02) and those who had been abused (p = 0.003) were more likely to attempt suicide. Suicide attempts were also more common in subjects with a history of alcohol abuse (p = 0.003) and those with psychotic symptoms (p = 0.02). CONCLUSIONS: Based on the results of this study, it is recommended that increased emphasis be placed on the psychosocial history and comorbid symptoms in patients with bipolar disorder. While asking about previous suicide attempts is the most accurate way to predict suicidal behavior, age of onset, past abuse, and overuse of alcohol may also be helpful. Since suicidal behavior in patients with bipolar disorder is relatively common, intensified efforts to predict this behavior may be life-saving.

Taming tosyl azide: the development of a scalable continuous diazo transfer process.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including ß-ketoesters, ß-ketoamides, malonate esters and ß-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an α-diazocarbonyl in >98% purity without any column chromatography.

A Stress Management Program for Higher Risk Medical Students: Preliminary Findings.

Approximately 10 % of first year medical students have clinically relevant anxiety or depression which may affect academic success and quality of life. This study tested the effects of a stress management intervention on indicators of anxiety, depression and self-efficacy in self-selected first year medical students. Forty two medical students volunteered to participate and provided informed consent. An eight session intervention was offered and focused on building relaxation skills, adaptive coping, and basic nutrition. Anxiety, depression, and self-efficacy were assessed pre and post intervention. This group of students had significantly higher baseline values of depression and anxiety but lower self-efficacy compared to a previous study of medical students at the same institution (p < 0.03). After the intervention, statistically significant improvements were observed in anxiety (p < 0.05), and self-efficacy (p < 0.05), but not in depression. The entering levels of anxiety and depression in this group suggested that these students were at risk for later clinical syndromes. Intervention directed to decreasing the effects of stress was associated with improvement in indicators of distress and may modify the longer term risk.

Development of a continuous process for α-thio-ß-chloroacrylamide synthesis with enhanced control of a cascade transformation.

A continuous process strategy has been developed for the preparation of α-thio-ß-chloroacrylamides, a class of highly versatile synthetic intermediates. Flow platforms to generate the α-chloroamide and α-thioamide precursors were successfully adopted, progressing from the previously employed batch chemistry, and in both instances afford a readily scalable methodology. The implementation of the key α-thio-ß-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts.

Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow.

Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.

A wellness program for first year medical students.

Entering medical students experience distress symptoms due to the demands of the intensive curriculum, adjustment to new environments and increased responsibilities. The purpose of this controlled, randomized study was to determine the effects of a structured wellness program on measures of anxiety, depression and frequency of acute illness in 449 first year medical students. The effects of eight sessions of stress management were compared to a wait list control group. High risk students were identified based on scores on psychological inventories and number of recent life events (WLE). Results showed that depression, anxiety scores and frequency of acute illness were higher in women than in men, and were higher in students with multiple life events. Significant decreases were observed in depression in the intervention group students when WLE was the covariate (p = .045). Further, the high risk group showed consistently lower depression scores after the intervention compared to high risk wait list controls (p = .003), and these changes were maintained at the end of school year. There were no significant changes in anxiety or frequency of acute illness. Wellness programs can be implemented in medical school and may be particularly useful for entering students with elevated psychological distress.

Managing antidepressants in primary care: physicians' treatment modifications.

To examine antidepressant management practices in primary care, patients (N = 148) given an antidepressant for at least one month completed the Beck Depression Inventory (BDI-II), the Patient Health Questionnaire-9 (PHQ-9), and a demographic survey. Participants' mean age was 50.7 yr. and 80% were women. Patients' charts indicated whether physicians had made changes to prescribed antidepressants or dose either 6 wk. before or 6 wk. after study entry. For the 87% of participants whose depression status could be determined, 10% met dysthymic disorder criteria and only 33% had had a medication change in the previous month. Major depressive disorder occurred in 37% but only 18% had had a medication change. Co-existing dysthymic disorder and major depressive disorder were diagnosed in 34%, with 24% receiving a medication change. Participants not receiving a medication change had mean BDI-II scores indicating moderate depression. Lack of antidepressant adjustment suggests physicians may need to monitor depressive symptoms closely using protocols and prompts.

A Naturalistic Study of Outcomes for Durable Remission in Patients With Bipolar Disorder.

OBJECTIVE: Bipolar disorder is a severe mental illness affecting emotional stability, physical health, and quality of life. In a previous study, we identified medications associated with remission in patients with bipolar disorder. The objective of the current study was to determine the status of the patients after 3 additional years, as well as the medications associated with remission. METHODS: Data were extracted from clinical records. The criteria for remission in both the original study and the follow-up were 12 continuous months of euthymia, mild symptoms, and no clinical relapse. Active illness was defined as <12 months of remission. Statistical comparisons were made between the remitted and active illness groups on demographics and medication regimens. RESULTS: The original study contained 121 patients, 52 of whom were available for follow-up. Of the 121 patients from the original study, 53 (43.8%) were remitted for at least 12 months. Follow-up data were available for 19 of those patients, 15 of whom continued in remission while 4 relapsed. Of the 68 patients who were still ill at the end of the first study, follow-up data were available for 33 patients, 18 of whom had achieved remission at the time of follow-up while 15 continued to be ill. Remitted patients were more likely to be receiving a mood stabilizer (P=0.022) or a combination of a mood stabilizer and an antidepressant (P=0.004). CONCLUSIONS: On the basis of our results, mood stabilizers and antidepressants were associated with remission in long-term follow-up. Remission may ultimately be possible for many patients who did not succeed initially.

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O-H Insertion.

Generation of tosyl azide 12 in acetonitrile in flow under water-free conditions using an azide resin and its use in diazo transfer to a series of aryl acetates are described. Successful telescoping with a rhodium acetate-catalyzed O-H insertion has been achieved, thereby transforming the aryl acetate 8 to α-hydroxy ester 10, a key intermediate in the synthesis of clopidogrel 11, without requiring isolation or handling of either tosyl azide 12 or α-aryl-α-diazoacetate 9, or indeed having significant amounts of either present at any point. Significantly, the solution of α-diazo ester 9 was sufficiently clean to progress directly to the rhodium acetate-catalyzed step without any detrimental impact on the efficiency of the O-H insertion. In addition, the rhodium acetate-catalyzed O-H insertion process is cleaner in flow than under traditional batch conditions. Use of the azide resin offers clear safety advantages and, in addition, this approach complements earlier protocols for the generation of tosyl azide 12 in flow; this protocol is especially useful with less acidic substrates.

The influence of reaction conditions on the Diels-Alder cycloadditions of 2-thio-3-chloroacrylamides; investigation of thermal, catalytic and microwave conditions.

The Diels-Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide, sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for stereoselective construction of Diels-Alder cycloadducts.

Coherence between physician diagnosis and patient self reports of anxiety and depression in primary care.

Mood and anxiety disorders complicate the care of patients with physical illness and pose challenges for primary care physicians. This study explored the coherence between a screening tool (PRIME-MD), a standardized questionnaire (Eysenck Personality Inventory), and physician diagnoses of anxiety and depression. Of 165 patients, 29% had diagnoses of depression, 21% had anxiety, and 59% had no mental health diagnosis. Patients who were younger, female, divorced/widowed, or unemployed with minimal education had highest prevalence of anxiety or depression. Scores on the self-report inventories were significantly higher in patients with physician-diagnosed anxiety or depression compared with those without these diagnoses. Medical use and chronic illness were highest in patients with anxiety or depression diagnoses. Despite the statistical agreement between the self-report inventories and physician diagnosis, the coherence among these measures was less than optimal. Use of self report tools is recommended to complement physician understanding of patient symptom description and management of anxiety and depression in primary care.

Effects of wellness programs in family medicine.

The objective of this research was to determine the effects of wellness programs on quality of life and utilization in an academic family medicine practice in two small controlled studies. One offered stress management and problem solving; the second offered a broader wellness intervention. Outcome measures consisted of scores on the Beck Anxiety Inventory, Hamilton Depression Inventory, CES-D (depression), Health Related Quality of Life, SF-12, and the number of office visits in 6 months. Subjects were randomly assigned to intervention or control groups. Statistical analysis compared pre-test and post-test values of the dependent variables between groups. In study one, where the focus was on relaxation, significant differences between groups were observed in anxiety at post-test (p < .03); the intervention group had lower anxiety levels. In study two which had a more general focus, significant group differences were found in days of poor mental health and number of days of depressed mood; the intervention group had fewer days of poor mental health (p < .05) and depression (p < .05) at post-test. No differences were found in utilization in either study. Based on the results of this research, short term wellness programs can be implemented in family practice and are effective in improving quality of life, but not in deceasing utilization in family practice patients. Matching the design of the program to specific patient needs may increase retention and effectiveness.

Segmental odontomaxillary dysplasia presenting with facial hypertrichosis, commissural lip clefting, and hyperlinear palms.

Segmental odontomaxillary dysplasia is a rare disorder that unilaterally affects the maxilla causing facial asymmetry and presenting with hypertrichosis and hypoplastic or missing teeth in the affected area. Lip clefting has only been reported in one other case. We report a case of segmental odontomaxillary dysplasia presenting with hypertrichosis of the face, hyperlinear palms with faint erythema, and commissural lip clefting.

Prescription Drug Monitoring Programs: Relationships Among Program Awareness, Use, and State Mandates.

The inappropriate use of opioids in the United States has increased markedly and has resulted in a tragic loss of lives. To combat this problem, prescription drug monitoring programs (PDMPs) have been instituted in most states. Use of the programs is voluntary for prescribers in some states, whereas in other states it is mandatory. The current study used a self-report survey instrument that was administered to 223 participant physicians. The goal of the study was to compare awareness and use of the PDMP in a state that mandates use (Ohio) with one that does not (North Carolina). Although awareness was not significantly different between respondents from the two states, self-reported use was significantly higher in the state mandating use (Ohio post-mandate vs. Ohio pre-mandate: 64% vs. 51%; χ2 = 15.66, P < .0001; and Ohio post-mandate vs. North Carolina: 64% vs. 42%; χ2 = 12.76, P < .0001). Based on these results, mandating use may be an effective method to increase PDMP utilization.

The patient-physician relationship and medical utilization.

OBJECTIVE: The goal of this study was to (1) explore the relationship between medical utilization and characteristics of the patient-physician relationship and (2) evaluate the relationship between physician perception of patient difficulty, chronic medical problems, and patient somatizing tendencies. METHOD: Patients in an academic family practice center were asked to complete a demographic data sheet, the PRIME-MD Patient Questionnaire, and the Barrett-Lennard Relationship Inventory regarding their relationship with their physicians. Their physicians completed the Difficult Doctor-Patient Relationship Questionnaire. Patient charts were examined for number of office visits and phone calls in the previous year, as well as number of chronic problems and medications. The study was conducted from September 2000 to November 2001. RESULTS: Forms were completed by 165 patients and 20 physicians. Forty-three patients who were approached refused to participate. Patient ratings on the Barrett-Lennard Relationship Inventory were not related to utilization measures. Physician ratings of difficulty were significantly related to phone calls and visits (p < .05), as well as PRIME-MD Patient Questionnaire somatization tendencies (p < .05) but not to number of chronic problems. Patient and physician ratings were not significantly correlated. Gender (p < .001), marital status (p < .04), education (p < .03), and employment status (p < .002) were all related to utilization measures. CONCLUSION: Medical utilization was associated with somatizing tendencies of patients and the physicians' perception of patient difficulty. Physicians rated patients as difficult if they tended to somatize but not if they had a number of chronic problems.