Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy.

Objective: Few clinical studies have assessed real-world abrupt transitioning between insomnia medications. This study assessed strategies for directly transitioning patients from zolpidem tartrate (ZOL) immediate/extended release to the dual orexin receptor antagonist, lemborexant (LEM). Methods: This randomized, open-label, multicenter study (Study 312; E2006-A001-312) enrolled 53 adults age ≥18 years with insomnia disorder and ≥1-month history of intermittent (3-4 nights/week) or frequent (≥5 nights/week) ZOL use. Subjects recorded their ZOL use in a 3-week Pretreatment Phase, followed by a 2-week Treatment Phase (TRT; Titration) during which ZOL was discontinued. Intermittent ZOL users transitioned to LEM 5 mg (LEM5), Cohort 1, and frequent ZOL users were randomized 1:1 to LEM5, Cohort 2A, or LEM 10 mg (LEM10), Cohort 2B. One dose adjustment was permitted during the TRT. Subjects completing the TRT could continue LEM in the 12-week Extension Phase (EXT). The primary outcome was proportion of subjects who successfully transitioned and remained on LEM at the end of the TRT. Results: Most subjects (43 [81.1 %]) successfully transitioned to LEM (9 [90 %], 17 [81.0 %], and 17 [77.3 %] in Cohorts 1, 2A, and 2B, respectively). By the end of the EXT, 66.7 % in Cohort 1 and 60.0 % in Cohort 2A up-titrated to LEM10, whereas 41.2 % in Cohort 2B down-titrated to LEM5; 61.0 % were receiving LEM10 at study end. At the end of the TRT, more subjects taking LEM reported that it helped them return to sleep after waking, compared with those taking ZOL (71.7 % vs. 49.1 %). There were no important differences between treatments regarding how subjects reported feeling as they fell asleep. Most of the treatment-emergent adverse events with LEM were mild in severity. Conclusions: Most subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated.

Efficacy of the triple-combination SM-1 in a 5-h phase advance transient insomnia model.

Thomas Dahl, PO Box 404, Guilford, CT 06437 USA. Email: tadahl@outlook.com. The objectives of the study were to demonstrate the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia. Randomized, double-blind, placebo-controlled cross-over study utilizing a 5-h phase advance model of transient insomnia. Subjects were 85 healthy adults reporting a history of transient insomnia, with an average age of 38.9 years. Both SM-1 and placebo were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time determined by polysomnography. Secondary endpoints included wakefulness after sleep onset, latency to persistent sleep, number of awakenings, subjective total sleep time and subjective sleep onset latency, total sleep time by quarters of the night, subjective number of awakenings, and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale, Digit Symbol Substitution Test, and predischarge evaluation (tandem gait and Romberg tests). SM-1 provided an increase of 94.4 min in total sleep time over placebo (p < 0.0001). Wakefulness after sleep onset, subjective total sleep time, subjective sleep onset latency, and total sleep time in the first quarter of the night also showed significant improvement. SM-1 was well-tolerated with both type and frequency of adverse events being comparable to placebo, and no residual sleepiness upon awakening (i.e., after 8 h). SM-1 provided a robust and statistically significant increase in total sleep time compared to placebo in a circadian model of transient insomnia, without evidence of next-day impairment.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator.

RATIONALE: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. OBJECTIVES: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). METHODS: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. RESULTS: In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. CONCLUSIONS: Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

Mango (Mangifera indica L.): a magnificent plant with cancer preventive and anticancer therapeutic potential.

Mangifera indica L. (mango), a long-living evergreen plant belonging to the Anacardiaceae family, has been cultivated for thousands of years in the Indian subcontinent for its excellent fruits which represent a rich source of fiber, vitamin A and C, essential amino acids, and a plethora of phytochemicals. M. indica is extensively used in various traditional systems of medicine to prevent and treat several diseases. The health-promoting and disease-preventing effects of M. indica are attributed to a number of bioactive phytochemicals, including polyphenols, terpenoids, carotenoid and phytosterols, found in the leaf, bark, edible flesh, peel, and seed. M. indica has been shown to exhibit various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, antidiabetic, antiobesity, and anticancer effects. There are a few studies conducted that have indicated the nontoxic nature of mango constituents. However, while there are numerous individual studies investigating anticancer effects of various constituents from the mango tree, an up-to-date, comprehensive and critical review of available research data has not been performed according to our knowledge. The purpose of this review is to present a comprehensive and critical evaluation of cancer preventive and anticancer therapeutic potential of M. indica and its phytochemicals with special focus on the cellular and molecular mechanisms of action. The bioavailability, pharmacokinetics, and safety profile of individual phytocomponents of M. indica as well as current limitations, challenges, and future directions of research have also been discussed.

Skull Abnormalities in Cadavers in the Gross Anatomy Lab.

BACKGROUND: The skull encompasses and houses one of the most important organs in the body-the brain-and like all tissues in the body, it is comprised of living cells that are constantly remodeling as this maintains the strength and homeostasis of the bone. In the present study, abnormal bone growth patterns were observed and the possible causes of said findings were investigated in multiple cadaver skulls dissected during head and neck anatomy courses at Detroit Mercy Dental over the past year. There are many factors, both intrinsic and extrinsic, with differences in stimulation to the skull resulting in skull abnormalities. Materials and Methods. For this study, skull abnormalities were examined from 65 formalin-embalmed cadaver heads, obtained from the Gross Anatomy Laboratory at the University of Detroit Mercy School of Dentistry between the years 2016 and 2019. We have recorded the age, sex, and previous chief medical issues of all lab specimens used in the study. Skulls were later evaluated for possible indications of bone disease such as hypertosis frontalis interna (HFI) or Paget's disease. RESULTS: Among the sixty-five specimens provided to the Detroit Mercy Dental cadaver lab, 19 specimens (29%) were found to present with irregular, undulating, thickening of the frontal bone internal surface. The findings located on the skulls closely resembled the gross anatomic appearance of HFI or Paget's disease; however, a conclusive diagnosis of these skull abnormalities cannot be made without a pathologist biopsy and radiological examination. Twelve of the nineteen specimens that displayed possible bone disease, approximating 63% prevalence, were females; their ages ranged from 68 to 95 years old. Thus, seven of the nineteen specimens exhibiting features of skull abnormalities, approximating 36% prevalence, were males with ages ranging from 70 to 103 years old. In addition, five of these nineteen specimens collected (26% prevalence) had been diagnosed with neurological disorders, including Alzheimer's, dementia, depression, and Parkinson's disease. In the current study, the proportion of specimens exhibiting skull abnormalities was higher compared to the overall prevalence observed in previous studies. CONCLUSION: Possible causes of observed anatomical abnormalities in the skull of cadavers of a gross anatomy laboratory were investigated, and it was determined that hypertosis frontalis interna (HFI) may contribute to such abnormalities. This is a condition that affects bone growth in the frontal skull. Our numbers of skull abnormalities were higher than previous studies and might be due to the fact that HFI was predominately present as an incidental finding during imaging of postmenopausal females or observed postmortem in cadavers. In addition, Paget's disease or hormonal imbalances could also result in similar features, and thus cannot be ruled out as a plausible cause. Paget's disease causes the bone to deposit at a faster rate than normal, which will result in thick and brittle bone. Studies that will involve further examination of new cadavers for the presence of HFI is needed, either using biopsy specimens and/or radiological examination to explore possible causes for the abnormal bone growth in the frontal bone.

Efficacy of SM-1 in a transient insomnia model.

OBJECTIVES: The objectives of this study were primarily to assess the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia and secondarily, to assess the contribution of diphenhydramine to the combination. METHODS: Randomized, double-blind, placebo-controlled three-way cross-over study with a 5-hr phase advance. Subjects were 39 healthy adults reporting a history of transient insomnia. All treatments (SM-1, SM-1 without diphenhydramine, or placebo) were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time (TST) determined by polysomnography. Secondary endpoints included wakefulness after sleep onset (WASO), latency to persistent sleep, number of awakenings (NAW), subjective TST (sTST) and sleep latency (sSL), TST, and NAW by quarters of the night and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale digit symbol substitution test, and subject-reported alertness level. RESULTS: SM-1 provided an increase of 126.7 min in TST over placebo (p < .001). WASO, sTST, sleep quality, and sSL also showed significant improvement. Diphenhydramine demonstrated a significant (p = .014) contribution of 43.7 min to TST. SM-1 was well-tolerated with type and frequency of adverse events comparable with placebo, and no residual sleepiness upon awakening after 8 hr. CONCLUSIONS: SM-1 provided a robust and statistically significant increase in TST compared with placebo in a circadian model of transient insomnia, without evidence of next-day impairment. Diphenhydramine contributed to the effect.

The Anatomical Nature of Dental Paresthesia: A Quick Review.

Dental paresthesia is loss of sensation caused by maxillary or mandibular anesthetic administration before dental treatment. This review examines inferior alveolar block paresthesia symptoms, side effect and complications. Understanding the anatomy of the pterygomandibular fossa will help in understanding the nature and causes of the dental paresthesia. In this review, we review the anatomy of the region surrounding inferior alveolar injections, anesthetic agents and also will look also into the histology and injury process of the inferior alveolar nerve.

Direct Syn Addition of Two Silicon Atoms to a C≡C Triple Bond by Si-Si Bond Activation: Access to Reactive Disilylated Olefins.

A catalytic intramolecular silapalladation of alkynes affords, in good yields and stereoselectively, syn-disilylated heterocycles of different chemical structure and size. When applied to silylethers, this reaction leads to vinylic silanols that undergo a rhodium-catalyzed addition to activated olefins, providing the oxa-Heck or oxa-Michael products, depending on the reaction conditions.

Infraorbital Foramen and Pterygopalatine Fossa Location in Dry Skulls: Anatomical Guidelines for Local Anesthesia.

PURPOSE: The aim of the study was to locate the infraorbital foramen (IOF) in relation to the infraorbital margin (IOM) for proper injections of local anesthetics in skull specimens. Another aim was to determine the depth of needle penetration into pterygopalatine fossa through the greater palatine canal (GPC). MATERIALS AND METHODS: 102 skull halves were used to measure the distances between (1) IOF and IOM and (2) IOF and alveolar ridge of maxilla at second premolar. Needles were inserted and bent at a 45° angle, passing through the GPC at the level of hard palate. The depth of the tip of needle emerging out of GPC into pterygopalatine fossa was measured. RESULTS: The mean distance between IOF and IOM was 6.46 ± 1.57 mm on the right side and 6.74 ± 1.72 mm on the left. The mean distance between IOF and alveolar bone process of the maxilla at second premolar was 29.07 ± 3.58 mm on the right side and 29.39 ± 3.78 mm on the left. The mean depth of penetration of the needle into the pterygopalatine fossa was similar on both sides. CONCLUSIONS: Proper identification of IOF and pterygopalatine fossa is of great significance during local anesthesia injections, due to their close proximity to vital anatomic structures.

Internal Occipital Crest Misalignment with Internal Occipital Protuberance: A Case Report of Posterior Cranial Fossa Anatomic Variations.

During gross anatomy head and neck laboratory session, one dissection group observed an abnormal anatomic variation in the posterior cranial fossa of a 94-year-old male cadaver. The internal occipital crest was not aligned with internal occipital protuberance and groove for superior sagittal sinus. It seemed that the internal occipital protuberance was shifted significantly to the right side. As a result the skull was overly stretched in order to connect with the internal occipital ridge. These internal skull variations of occipital bone landmarks can influence the location of adjacent dural venous sinuses and possibly influence cerebrospinal fluid flow. Similar anatomical anomalies have been attributed to presence of hydrocephalus and abnormalities in cisterna magna.

Use of High-Definition Audiovisual Technology in a Gross Anatomy Laboratory: Effect on Dental Students' Learning Outcomes and Satisfaction.

Laboratory cadaver dissection is essential for three-dimensional understanding of anatomical structures and variability, but there are many challenges to teaching gross anatomy in medical and dental schools, including a lack of available space and qualified anatomy faculty. The aim of this study was to determine the efficacy of high-definition audiovisual educational technology in the gross anatomy laboratory in improving dental students' learning outcomes and satisfaction. Exam scores were compared for two classes of first-year students at one U.S. dental school: 2012-13 (no audiovisual technology) and 2013-14 (audiovisual technology), and section exams were used to compare differences between semesters. Additionally, an online survey was used to assess the satisfaction of students who used the technology. All 284 first-year students in the two years (2012-13 N=144; 2013-14 N=140) participated in the exams. Of the 140 students in the 2013-14 class, 63 completed the survey (45% response rate). The results showed that those students who used the technology had higher scores on the laboratory exams than those who did not use it, and students in the winter semester scored higher (90.17±0.56) than in the fall semester (82.10±0.68). More than 87% of those surveyed strongly agreed or agreed that the audiovisual devices represented anatomical structures clearly in the gross anatomy laboratory. These students reported an improved experience in learning and understanding anatomical structures, found the laboratory to be less overwhelming, and said they were better able to follow dissection instructions and understand details of anatomical structures with the new technology. Based on these results, the study concluded that the ability to provide the students a clear view of anatomical structures and high-quality imaging had improved their learning experience.

Attitudes towards the resuscitation of periviable infants: a national survey of American Muslim physicians.

AIM: To examine the associations between American Muslim physicians' characteristics and intended behaviours towards resuscitation of 22- and 23-week gestation infants. METHODS: This national survey of physician members of the Islamic Medical Association of North America inquired about physician religiosity, their practice of referring to Islamic resources for bioethical guidance, their preferred model of patient-doctor decision-making and the perceived importance of quality-of-life determinations with respect to medical decision-making. Four vignettes described birth of a 22- and a 23-week gestation infant. Respondents were given estimated survival data for each and asked whether they would attempt resuscitation. RESULTS: A total of 255 of 626 responses received. About 51% and 85% of respondents believed that a 22- and a 23-week gestation infant should be resuscitated, respectively. If parents opposed resuscitation, 44% (22 weeks) and 46% (23 weeks) of respondents still endorsed resuscitating. Respondents who were more religious, referred more often to Islamic bioethical resources and did not believe that quality-of-life determinations were tied to life's value had greater odds of endorsing resuscitation in many of the scenarios. CONCLUSION: American Muslim physicians have high rates of support for delivery room resuscitation of periviable infants. Their intended behaviour appears to associate with religious values.

Intramolecular carbolithiation of heterosubstituted alkynes: an experimental and theoretical study.

A series of heterosubstitued alkynes was successfully submitted to the intramolecular carbolithiation of their triple bond. We show that the addition is stereoselective because of the control exerted by the terminal substituent X on the geometry of the transition state. A complementary DFT study suggests that the addition is anti when a strong Li-X interaction occurs.

In vitro correlation of the level of inferior alveolar canal with CBCT imaging.

PURPOSE: The aim was to correlate the level of the inferior alveolar canal on cadaver specimens and as evaluated with three-dimensional radiographic cone-beam computed tomography (CBCT) imaging. METHODS: Twenty-one skulls with intact mandibles (42 inferior alveolar canals) were imaged with an I-CAT Cone-Beam 3D Imaging System and multi-planar reformatted images obtained were scored to assess the level of the canal (Level I, Level II, and Level III). The mandibles were later dissected and level of the canal was directly visualized, scored, and further correlated with results from CBCT imaging. RESULTS: There was no difference in the level of the inferior alveolar canal between the dissected cadaver specimen and CBCT images. Also, there was no statistically significant difference in the level of the canal among the gender assigned to the specimens and corresponding CBCT images. There were no statistical differences in the level of the canal (cadaver specimen vs. CBCT) between the left and right sides of the specimens, as studied individually. CONCLUSION: Our study indicates that there is close correlation of the level of the inferior alveolar canal between cadaver specimens and CBCT images. Well-designed studies would be required to further validate the findings in this study.

Carbolithiation of chloro-substituted alkynes: a new access to vinyl carbenoids.

The intramolecular carbolithiation of a series of chloro-substituted alkynes leads to exocyclic alkylidene carbenoids of which both nucleophilic and electrophilic characters can be drove. A sole stereoselective 5-exo-dig addition takes place, probably because of a strong and persisting Li-Cl interaction arising before the transition state.

Antiproliferative effect of hepatitis C virus on mitogen-stimulated peripheral blood mononuclear cells: potential role in viral persistence in Egyptian patients.

OBJECTIVES: We aimed to study the effect of hepatitis C virus (HCV) and sera of chronic HCV patients on phytohemagglutinin (PHA)-stimulated normal donor PBMCs and to study the effect of chronic HCV infection on some cytokine profile. SUBJECTS AND METHODS: (3)H-Thymidine uptake was utilized to study effect of pelleted virus and patients sera on PBMCs proliferation in vitro. The study included 337 Egyptian chronic liver patients from Ain Shams University Hospitals and 90 healthy control subjects. The patients' group included chronic hepatitis C (250 subjects), and other chronic liver diseases (87 subjects). All subjects' sera were subjected to RT-PCR for HCV RNA detection, IL-4, IL-1beta, and TNF-alpha measurement by EIA, and biochemical measurement of ALT and albumin. RESULTS: Treatment of PHA-stimulated normal donor PBMCs with pelleted virus led to decrease (dose response) in their rate of proliferation. This was partially reversed after addition of HCV RNA positive patients' sera. HCV RNA positive patients were significantly higher in IL-4 and ALT, and lower in IL-1beta and albumin than HCV RNA negative patients. CONCLUSION: HCV infection suppresses early immune response. This leads to increased IL-4 Th2 cytokine.

Pattern of medical diseases and determinants of prognosis of hospitalization during 2005 Muslim pilgrimage Hajj in a tertiary care hospital. A prospective cohort study.

OBJECTIVE: To document the pattern of medical diseases necessitating admission in a tertiary care hospital during Muslim pilgrimage (Hajj). To assess the risk factors associated with mortality during hospitalization. METHODS: The study was conducted at Al Noor Specialist Hospital, a 550-bed tertiary care teaching hospital, in Makkah, KSA. The participants included all Hajj patients admitted in the Department of Medicine in a 5-week period (January 3 to February 6, 2005) during the 2005 (1425 AH) Hajj. Information about demographics; past medical history; pre-Hajj functional status; presence of language barrier and translator availability; diagnosis for admission and complications during hospitalization including mortality was obtained prospectively using a standardized form. RESULTS: Six hundred and eighty-nine patients, belonging to 49 countries, with mean age of 62 years and male:female ratio of 1.8:1 were admitted. Two hundred-twenty (31.9%) had diabetes mellitus, 256 (37.2%) had hypertension, 219 (31.8%) had cardiac disease, and 103 (14.9%) patients had chronic lung disease. Of the 449 (65.2%) patients assessed, 284 (63.2%) patients had language barrier, and translator was not available for 152 (53.5%) of them. Pre-Hajj functional status assessment of 240 patients showed that 20 (8.3%) required assistance in performing activities of daily living (ADL), and 40 (16.7%) could not walk for half kilometer without difficulty. Common causes of morbidity were: 235 (34.1%) cardiovascular, 137 (19.9%) infectious and 85 (12.3%) neurological diseases. One hundered and fourteen (16.5%) patients died, with the common causes being pneumonia (28 patients), acute coronary syndrome (21), and stroke (20). The risk factors associated with higher mortality were older age (65 +/- 1 versus 61 +/- 0.6 years, p=0.008), prior history of chronic lung disease (crude odds ratio, 1.81, p=0.034), dependence in any ADLs (4.90, p=0.025), inability to ambulate for half kilometer without difficulty (4.17, p=0.017) and non-availability of translator for patients with language barrier (5.51, p<0.0001). CONCLUSION: Most patients were elderly with high prevalence of chronic medical disorders. Non-infectious diseases accounted for most morbidity and mortality. Pre-Hajj functional assessment should be carried out to identify patients at high risk of mortality. Provision of translator services for patients with language barrier is essential to improve future outcomes.