Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis.

AIMS: The risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates. MATERIALS AND METHODS: We searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication. RESULTS: A total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI]=0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i. CONCLUSIONS: In women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.

Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis.

AIMS: Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes. METHODS: We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A1c over time. RESULTS: Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A1c favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -0.38% (-0.62, -0.15) and -1.14% (-1.53, -0.75) respectively]. There was a significantly greater weight loss favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -2.50 kg (-3.91, -1.09) and -3.19 kg (-3.66, -2.72) respectively]. The proportion of patients achieving glycaemic goals and goal weight loss was greater in semaglutide-treated patients when compared to either other GLP-1RA or DPP-4i. However, semaglutide-treated patients had a significantly higher incidence of gastrointestinal side effects. CONCLUSIONS: While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A1c, semaglutide causes a more potent haemoglobin A1c reduction and greater weight loss when compared to other incretin-based therapies. However, this potent effect of semaglutide was associated with a higher incidence of gastrointestinal side effects. Additional studies are needed to determine whether this marked reduction in both haemoglobin A1c and body weight may translate into improved cardiovascular outcomes.

Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: Our aim was to compare Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) to Dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to metformin. METHODS: We searched for randomized trials comparing SGLT-2i to DPP-4i as add-on therapy to metformin in Type 2 diabetes.We pooled trials reporting outcomes between 12 and 26 weeks together while trials reporting results ≥52 weeks were pooled together. The primary outcomes were the change in haemoglobin A1c (A1c) at ≤26 and ≥52 weeks. Sensitivity analyses were performed according to the dose of SGLT-2i and according to baseline A1c for the primary outcomes. RESULTS: Seven trials met our inclusion criteria. There was a statistically significant reduction in A1c at ≥52 weeks favouring SGLT-2i compared to DPP-4i (MD [95% CI]=-0.11% [-0.20, -0.03]) but no significant difference at ≤26 weeks (MD [95% CI]=-0.05% [-0.16, 0.05]). SGLT-2i caused significantly more weight loss compared to DPP-4i at ≤26 weeks and ≥52 weeks (MD [95% CI]=-2.31kg [-2.66, -1.96] and -2.45kg [-2.83, -2.07], respectively). SGLT-2i treated patients had a significantly more genital infection compared to DPP-4i. On restricting the analysis according to the SGLT-2i FDA-approved dose, only higher doses at ≥52 weeks showed a statistically significant reduction in A1c compared to DPP-4i. On restricting the analysis according to baseline A1c, results favoured DPP-4i if baseline A1c was<8.5%, but favoured SGLT-2i if ≥8.5%. CONCLUSION: While both SGLT-2i and DPP-4i can reduce A1c, SGLT-2i causes a more robust A1c reduction and more weight loss but with more genital infections. Higher doses of SGLT-2i showed more efficacy when compared to DPP-4i; however, this data should be interpreted cautiously given the limited number of trials.

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.

Impaired long-term potentiation in the prefrontal cortex of Huntington's disease mouse models: rescue by D1 dopamine receptor activation.

BACKGROUND: The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs. OBJECTIVE: We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD. METHODS: We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex. RESULTS: We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D(1) dopamine receptor agonist (SKF38393). CONCLUSION: In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction.

Racial disparity in treatment of osteoporosis after diagnosis.

INTRODUCTION: Racial disparities have been identified in a number of areas in clinical medicine. Patients diagnosed with osteoporosis should be treated similarly regardless of race. However, limited data are available on the relative frequency of treatment by race after diagnosis of osteoporosis. METHODS: We analyzed all 739 dual-energy X-ray absorptiometry (DXA) results obtained of women 50 years old and older between 1998 and 2002 at our medical center. Our study sample was 82% Caucasian and 15% African American. Of 353 women who had low bone mineral density on first DXA, we abstracted the electronic and paper medical records to compare treatment rates by race. RESULTS: Of the women diagnosed with osteoporosis or osteopenia, 80.0% and 68.3%, respectively, were started on antiresorptive medications. Of the African American women, 61.9% diagnosed with osteoporosis were started on antiresorptive treatment compared with 83.3% of Caucasian women (p<0.05). African American women with low bone mass were less likely than Caucasian women to be smokers (p<0.05) and use alcohol (p<0.01) but were more likely to be on corticosteroids (p<0.05). No other significant differences were found among treated and nontreated groups that might explain the disparity in treatment. CONCLUSION: A smaller proportion of African American than Caucasian women with osteoporosis received antiresorptive medications after a DXA diagnosis. This significant disparity requires further study in a larger population.

Are some subjects better taught in block rotation? A geriatric experience.

BACKGROUND AND OBJECTIVES: This study characterizes the progress in and effectiveness of learning geriatric medicine during longitudinal and block phases of a family practice residency program. METHODS: A structured second-year geriatric block rotation was added to a residency longitudinal curriculum. To assess learning, a Geriatric Assessment Instrument (GAI) consisting of 50 multiple choice questions was administered to three classes offamily practice residents (n=33)five times during training: entry into the program, beginning of the second year, pre- andpost-geriatric block rotation, and at graduation. Improvement between individual residentfirst- and third-year in-training exam scores in geriatrics of the intervention classes were compared with the four classes that preceded the introduction of the block rotation (n=38). RESULTS: Scores on the GAI improved significantly before and after the rotation but not during any other interval of training during the residency. In-training exam scores improved significantlyfor the classes taught with the block rotation over those without it. CONCLUSIONS: Most of the geriatric learning occurred during the 1-month geriatric block rotation during the residency. In-training geriatric exam scores improved significantly with a geriatric block rotation. The use of structured repetitive learning experiences during the rotation to emphasize the common clinical issues and the skewed exposure to geriatric patients in the random nature of residency clinic and inpatient encounters accountfor this result.

Screening for diabetic retinopathy in rural areas: the potential of telemedicine.

Diabetic retinopathy is a common cause of blindness, and screening can identify the disease at an earlier, more treatable stage. However, rural individuals with diabetes may have limited access to needed eye care. The objective of this project was to demonstrate the feasibility of a diabetic retinopathy screening program using a state-of-the-art nonmydriatic digital fundus imaging system. The study involved a series of patients screened in primary care and public health locations throughout seven predominantly rural counties in eastern North Carolina. Images of each fundus were obtained and sent to a retinal specialist. The retinal specialist reviewed each image, recorded image quality, diagnosed eye disease and made recommendations for subsequent care. Of 193 volunteers with a history of diabetes mellitus, 96.3 percent reported that they were very comfortable or comfortable with the camera. Eighty-five percent of images were rated as good or fair by the retinal specialist. The retinal specialist also reported being very certain or certain of the diagnosis in 84 percent of cases. Image quality correlated highly with the certainty of diagnosis (Spearman's rank order correlation coefficient = 0.79; P < 0.001). The average time since the previous examination by an eye care specialist for diabetic subjects was two years. Approximately 62 percent of diabetic patients had diagnosable eye conditions, the most common of which was diabetic retinopathy (40.9 percent). In this convenience sample, African Americans, despite similar age and disease duration, were more likely to have retinopathy. Digital imaging is a feasible screening modality in rural areas, may improve access to eye care, and may improve compliance with care guidelines for individuals with diabetes mellitus.

Predictors of screening mammography: implications for office practice.

BACKGROUND: The completion of annual screening mammography and other preventive health services among women aged 50 years and older remains an important quality of care indicator. METHODS: A biracial sample of 843 rural women (aged > or =50 years) from a population-based sample reported demographic and preventive health services utilization in the last year including the completion of screening mammography. Bivariate analysis and logistic regression were used to investigate the extent to which completion of other screening examinations, including Papanicolaou (Pap) smears and clinical breast examination, is associated with successful completion of mammography relative to demographic and health service variables. RESULTS: The completion of mammography was associated with age, race, education, health insurance, and the presence of a regular primary care physician, but the strongest predictors were the completion of a clinical breast examination and/or a Pap smear. CONCLUSIONS: Women who receive a clinical breast examination and/or a Pap smear appear far more likely to receive screening mammography, suggesting a synergy in screening services. The relative efficacy of interventions to increase the completion of clinical breast examinations as well as other age-appropriate preventive services during routine office visits or during a single preventive services office visit should be further explored in primary care settings. Residency programs should provide training on the successful incorporation of such services into office practice patterns in an effort to continually improve quality of care.

Pattern of olfactory bulb innervation returns after recovery from reversible peripheral deafferentation.

The olfactory epithelium (OE) is unusual in its ability to regenerate and reinnervate its target, the olfactory bulb (OB), after deafferentation. To address the question of whether olfactory receptor neuron (ORN) axons preserve their topographic organization when they reestablish synaptic contact with the OB, the authors examined the pattern of ORN axon reinnervation into the bulb of adult H-OMP-lacZ-6 transgenic mice during and after recovery from chemical deafferentation. In the H-OMP-lacZ-6 mouse strain, lacZ expression is limited to a subset of ORNs that are distributed bilaterally in the OE and project primarily to a few glomeruli in the ventromedial region of the OB. The OE was lesioned by intranasal irrigation with Triton X-100, and the distribution of 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal)-stained cells was examined in the OE along with beta-galactosidase-immunoreactive (beta-gal-ir) axonal processes in the OB after short (1 week), intermediate (3 week), and long (6-7 weeks) recovery times. One week after the lesion, immunostaining for beta-gal and olfactory marker protein was virtually eliminated in the bulb. After 3 weeks of recovery, beta-gal-containing axons appeared to target many of the same locations innervated in bulbs of unlesioned mice. The region that received the highest density of axonal innervation in controls, however, contained only a few processes at that time. After 6-7 week recovery periods, the pattern of X-gal staining in the OE and beta-gal-ir axons in the OB closely resembled that of unlesioned mice. These results demonstrate that the topographic distribution of ORNs in the OE and the pattern of axon innervation in the OB can be reconstituted after chemical deafferentation.

Changing practices in the use of pneumococcal vaccine.

BACKGROUND AND OBJECTIVES: An important issue facing primary care practices is how to best improve preventive services to patients. We sought to determine if an intervention designed by a continuous quality improvement (CQI) process (reminder sticker and patient education sign in each examining room) or a patient education intervention (sign only) could increase the rate of pneumococcal vaccination. METHODS: These two interventions were administered over a 6-month period in a controlled, prospective study design in a family practice residency program clinic. The study targeted patients ages 65 and older and patients ages 2-64 with diabetes mellitus who had never received the pneumococcal vaccine. The main outcome measure was the vaccination rate in the targeted population. RESULTS: A total of 1,647 patient encounters involving 778 patients were documented during the study period. Overall, the reminder and sign module had higher percentages of pneumococcal vaccination in this target population (20% versus 11% for sign only, versus 7% control). Chi-square analysis revealed a statistically significant difference for this group, compared with placebo, but not for the sign-only group. CONCLUSIONS: An intervention designed from a CQI process to impact the office patterns of primary care physicians can produce measurable changes in pneumococcal vaccination rates.

Targeted deletion of a cyclic nucleotide-gated channel subunit (OCNC1): biochemical and morphological consequences in adult mice.

The olfactory cyclic nucleotide-gated channel subunit 1 (OCNC1) is required for signal transduction in olfactory receptor cells. To further investigate the role of this channel in the olfactory system, the biochemical and morphological consequences of targeted disruption of OCNC1 were investigated in adult mice. Null as compared to wild-type mice had smaller olfactory bulbs, suggesting compromised development of the central target of the receptor cells. Ectopic olfactory marker protein (OMP)-stained fibers localized to the external plexiform layer reflected the relative immaturity of the olfactory bulb in the null mice. The olfactory epithelium of the knock-out mouse was thinner and showed lower expression of olfactory marker protein and growth-associated protein 43, indicating decreases in both generation and maturation of receptor cells. Tyrosine hydroxylase (TH) expression in the olfactory bulb, examined as a reflection of afferent activity, was reduced in the majority of periglomerular neurons but retained in atypical or "necklace" glomeruli localized to posterior aspects of the olfactory bulb. Double label studies demonstrated that the remaining TH-immunostained neurons received their innervation from a subset of receptor cells previously shown to express a phosphodiesterase that differs from that found in most receptor cells. These data indicate that expression of OCNC1 is required for normal development of the olfactory epithelium and olfactory bulb. The robust expression of TH in some periglomerular cells in the OCNC1-null mice suggests that receptor cells innervating these glomeruli may use an alternate signal transduction pathway.

Oral poisonings: guidelines for initial evaluation and treatment.

The initial evaluation and management of poisoned patients should be comprehensive and include an accurate history whenever possible, stabilization of the patient's condition, a physical assessment to evaluate the extent of poisoning and the presence of concurrent conditions, decontamination of the gastrointestinal tract using activated charcoal, gastric lavage, administration of ipecac or irrigation, poison-specific treatment with administration of antidotes when indicated and proper disposition. Consultation with a poison control center is often helpful in assessing and treating these patients.

Lipid and lipoprotein responses to oral combined hormone replacement therapy in normolipemic obese women with controlled type 2 diabetes mellitus.

This study investigated the effects of oral combined hormone replacement therapy (OCHRT) on lipid concentrations and subpopulation distribution of lipoproteins in nine postmenopausal women with type 2 diabetes mellitus and moderate glycemic control. After 16 weeks of continuous daily therapy of conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg, the mean concentration of high-density lipoprotein (HDL) cholesterol showed a statistically significant increase of 16.7%, predominantly in the HDL2 subfraction. No statistically significant changes in mean concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very low-density lipoprotein (VLDL) triglycerides, apolipoprotein A1, or apolipoprotein B were evident. Likewise, no changes were found in the average diameter of VLDL, LDL, or HDL particles; triglyceride concentrations of VLDL subfractions; cholesterol concentrations of LDL subfractions; or chemical composition of plasma LDL. These findings lend further support to the use of OCHRT in postmenopausal women with diabetes to decrease their risk for coronary artery disease.

The effects of variable periods of functional deprivation on olfactory bulb development in rats.

Dramatic alterations occur in the developing olfactory bulb when air flow is reduced through one-half of the nasal cavity. Naris closure on the day after the day of birth (P1) in rats, for example, results in reduced cell survival in the ipsilateral bulb by P20 and a substantial (25%) decrease in bulb size by P30. Almost immediate changes in protein synthesis and cell metabolism are also observed, and one prevalent theory suggests that these changes may be important in specifying which cells are subsequently eliminated. In the present study we used a reversible technique for unilateral naris closure to examine the sensitive period for the effects of olfactory deprivation on bulb size and cell survival. This technique involves the insertion of removable plugs into a rat pup's external naris. We occluded the naris for increasing periods of time (P1-P10, P1-P15, or P1-P20), reared all animals to P30, and measured volumes of bulb laminae. In addition, we examined the duration of naris closure needed to affect cell survival by injecting animals with the thymidine analogue bromodeoxyuridine to label cells born soon after the onset of olfactory deprivation. Results indicate that relatively long periods of naris occlusion (P1-P15 or longer) are required to produce a substantial reduction in experimental bulb size. Cell survival was decreased following olfactory deprivation from P1 to P10, but not after deprivation from P1 to P3. These data support the hypothesis that changes that occur within 48 h of naris closure are not sufficient to affect cell survival.

Effects of unilateral olfactory deprivation in the developing opossum, Monodelphis domestica.

Unilateral naris closure in young rodents leads to striking alterations in the development of the ipsilateral olfactory system. One of the most pronounced effects is a 25% reduction in the size of the experimental olfactory bulb, a change that stems in part from decreased cell survival. Since naris occlusion in rodents alters the system more during development than in adulthood, we investigated the consequences of olfactory deprivation in a species that is born in a very immature state, Monodelphis domestica. In this pouchless marsupial, offspring are born after a short 14-day gestation. In the present study, the thymidine analogue bromodeoxyuridine was used to examine early postnatal neurogenesis in the olfactory bulb. Unlike rats and mice, neurogenesis of the main output neurons (the mitral cells) continues into postnatal life. Unilateral naris closure was begun on postnatal day 4 (P4) or P5 in Monodelphis and continued for 30 or 60 days. Laminar volume measurements revealed a significant reduction in the size of the experimental bulb following 60, but not 30, days of early olfactory deprivation. Mitral cell number estimates indicated a significant reduction after both 30 and 60 days of naris closure. The immaturity of Monodelphis offspring may render the population of mitral cells susceptible to the effects of olfactory deprivation. These findings suggest that afferent activity plays a role in the survival of all bulb neurons, irrespective of cell class.

Olfactory bulb recovery after early sensory deprivation.

Olfactory bulbs retain the ability to acquire new neurons throughout life. Unilateral olfactory deprivation during the first postnatal month in rats results in a dramatic reduction in the size of the experimental olfactory bulb. Part of this reduction is attributable to the death of neurons and glia. To examine the regenerative capacity of the juvenile olfactory bulb, we developed a technique for reversible olfactory deprivation. Reversible blockade from postnatal day 1 (P1) to P20 or P30 results in reduced bulb volume and tyrosine hydroxylase immunostaining, and decreased depth in the olfactory mucosa. In another experiment, normal stimulation was restored for varying periods of time, and experimental and control bulb volumes were measured. Recovery of bulb size occurs after 40 d of normal stimulation. Rats injected with a thymidine analog to label dividing cells during the recovery period revealed that rescue results at least in part from the addition of new neurons and glia. Thus, cells born after the return of normal levels of environmental stimulation can replace some of the neurons and glia that are lost during olfactory deprivation. This system can be used to study mechanisms that underlie neuronal regeneration in the maturing mammalian brain.

Development of the anterior commissure in the opossum: midline extracellular space and glia coincide with early axon decussation.

While the anterior commissure has been shown to be an important route of information transfer in the forebrain, relatively little is known about its anatomical development. Glial substrates and extracellular spaces have been associated with the maturation of other large-fiber tracts, such as the corpus callosum and retinofugal pathway. The present study examined early stages in the maturation of the commissure in the gray short-tailed opossum, Monodelphis domestica. Monodelphis offspring are born after a short 14-day gestation, and, unlike in rats and mice, the anterior commissure develops entirely during the postnatal period. A number of techniques were employed: the carbocyanine dye Dil was used to label early axons in the region, semithin plastic sections were used to examine the extracellular environment of the developing commissure, and immunocytochemistry for glial fibrillary acidic protein (GFAP) was used to characterize glial components. Results suggest that the first commissural fibers that cross the midline pass through a region of large extracellular spaces and may use GFAP-immunoreactive cells and processes as guides during their midline decussation.

NSAIDs revisited: selection, monitoring, and safe use.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are effective analgesic and anti-inflammatory agents, they may have adverse effects on the gastrointestinal, hepatic, renal, pulmonary, and platelet aggregation systems in susceptible patients. Careful consideration of the risks and benefits, judicious dosing, and careful monitoring by the primary care physician are therefore essential. The authors of this article review both the therapeutic and adverse effects of NSAIDs and provide suggestions for safe clinical use.