Risk Factors for Bone Microarchitecture Impairments in Older Men with Type 2 Diabetes - The MrOS Study.

CONTEXT: Impaired bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), may contribute to bone fragility in type 2 diabetes (T2DM) but data on men are lacking. OBJECTIVE: To investigate the association between T2DM and HR-pQCT parameters in older men. METHODS: HR-pQCT scans were acquired on 1794 participants in the Osteoporotic Fractures in Men (MrOS) study. T2DM was ascertained by self-report or medication use. Linear regression models, adjusted for age, race, BMI, limb length, clinic site, and oral corticosteroid use, were used to compare HR-pQCT parameters by diabetes status. RESULTS: Among 1777 men, 290 had T2DM (mean age 84.4 years). T2DM men had smaller total cross-sectional area (Tt.AR) at the distal tibia (p=0.028) and diaphyseal tibia (p=0.025), and smaller cortical area at the distal (p= 0.009) and diaphyseal tibia (p= 0.023). Trabecular indices and cortical porosity were similar between T2DM and non-T2DM. Among men with T2DM, in a model including HbA1c, diabetes duration, and insulin use, diabetes duration ≥ 10 years, compared with <10 years, was significantly associated with higher cortical porosity but with higher trabecular thickness at the distal radius. Insulin use was significantly associated with lower cortical area and thickness at the distal radius and diaphyseal tibia and lower failure load at all three scan sites. Lower cortical area, cortical thickness, total BMD, cortical BMD, and failure load of the distal sites were associated with increased risk of incident non-vertebral fracture in T2DM. CONCLUSIONS: Older men with T2DM have smaller bone size compared to non-T2DM, which may contribute to diabetic skeletal fragility. Longer diabetes duration was associated with higher cortical porosity and insulin use with cortical bone deficits and lower failure load.

Exploring Healthcare Provider Recruitment in a Rural and Frontier Community in Northern Idaho.

Limited U.S. research has been conducted examining factors affecting healthcare provider recruitment in rural settings, necessitating community-level investigations due to community differences. The aim of this study was to explore the factors involved in healthcare provider recruitment in a rural community in Northern Idaho. A retooled version of the Nursing Community Apgar Questionnaire (NCAQ) was used to collect data from 50 healthcare providers to assess items influencing provider recruitment. Items were categorized into five factors: geographic, economic, scope of practice, medical support, and facility and community support classes. Healthcare providers ranked items based on perceived importance and how advantageous or challenging it was to recruitment. A "Community Apgar" score is a composite score calculated using the advantage/challenge and importance scores. In our sample, medical support was rated as the most important class. Additionally, facility and community support was rated as the highest advantage class and had the most impactful Apgar scores, meaning it contained the most important advantage and challenge. Our findings suggest that these classes contain dominant factors related to the recruitment of providers in rural areas. Rural healthcare organizations seeking to improve the recruitment of healthcare providers should consider the potential impact of these factors on their population. Further investigations should be conducted on diverse rural samples across the U.S. to enable comparisons of research findings.

Socioeconomic and Racial/Ethnic Inequalities in Infertility Prevalence, Help-Seeking, and Help Received Since 1995.

BACKGROUND: In the United States, infertility and treatment for infertility are marked by racial/ethnic and socioeconomic inequalities. Simultaneously, biomedical advances and increased public health attention toward preventing and addressing infertility have grown. It is not known, however, whether the racial/ethnic and socioeconomic inequalities observed in infertility prevalence, help-seeking, or help received have changed over time. METHODS: Using National Survey of Family Growth data (1995 through 2017-2019 cycles), this study applied multivariable logistic regression with interaction terms to investigate whether and how racial/ethnic and socioeconomic inequalities in 1) the prevalence of infertility, 2) ever seeking help to become pregnant, and 3) use of common types of medical help (advice, testing, medication for ovulation, surgery for blocked tubes, and artificial insemination) have changed over time. RESULTS: The results showed persisting, rather than narrowing or increasing, inequalities in the prevalence of infertility and help-seeking overall. The results showed persisting racial/ethnic inequalities in testing, ovulation medication use, and surgery for blocked tubes. By contrast, the results showed widening socioeconomic inequalities in testing and narrowing inequalities in the use of ovulation medications. CONCLUSIONS: There is little evidence to suggest policy interventions, biomedical advances, or increased public health awareness has narrowed inequalities in infertility prevalence, treatment seeking, or use of specific treatments.

Microvascular disease not type 2 diabetes is associated with increased cortical porosity: A study of cortical bone microstructure and intracortical vessel characteristics.

Introduction: Fracture risk is elevated in type 2 diabetes (T2D) despite normal or even high bone mineral density (BMD). Microvascular disease (MVD) is a diabetic complication, but also associated with other diseases, for example chronic kidney disease. We hypothesize that increased fracture risk in T2D could be due to increased cortical porosity (Ct.Po) driven by expansion of the vascular network in MVD. The purpose of this study was to investigate associations of T2D and MVD with cortical microstructure and intracortical vessel parameters. Methods: The study group consisted of 75 participants (38 with T2D and 37 without T2D). High-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) of the ultra-distal tibia were performed to assess cortical bone and intracortical vessels (outcomes). MVD was defined as ≥1 manifestation including neuropathy, nephropathy, or retinopathy based on clinical exams in all participants. Adjusted means of outcomes were compared between groups with/without T2D or between participants with/without MVD in both groups using linear regression models adjusting for age, sex, BMI, and T2D as applicable. Results: MVD was found in 21 (55 %) participants with T2D and in 9 (24 %) participants without T2D. In T2D, cortical pore diameter (Ct.Po.Dm) and diameter distribution (Ct.Po.Dm.SD) were significantly higher by 14.6 µm (3.6 %, 95 % confidence interval [CI]: 2.70, 26.5 µm, p = 0.017) and by 8.73 µm (4.8 %, CI: 0.79, 16.7 µm, p = 0.032), respectively. In MVD, but not in T2D, cortical porosity was significantly higher by 2.25 % (relative increase = 12.9 %, CI: 0.53, 3.97 %, p = 0.011) and cortical BMD (Ct.BMD) was significantly lower by -43.6 mg/cm3 (2.6 %, CI: -77.4, -9.81 mg/cm3, p = 0.012). In T2D, vessel volume and vessel diameter were significantly higher by 0.02 mm3 (13.3 %, CI: 0.004, 0.04 mm3, p = 0.017) and 15.4 µm (2.9 %, CI: 0.42, 30.4 µm, p = 0.044), respectively. In MVD, vessel density was significantly higher by 0.11 mm-3 (17.8 %, CI: 0.01, 0.21 mm-3, p = 0.033) and vessel volume and diameter were significantly lower by -0.02 mm3 (13.7 %, CI: -0.04, -0.004 mm3, p = 0.015) and - 14.6 µm (2.8 %, CI: -29.1, -0.11 µm, p = 0.048), respectively. Conclusions: The presence of MVD, rather than T2D, was associated with increased cortical porosity. Increased porosity in MVD was coupled with a larger number of smaller vessels, which could indicate upregulation of neovascularization triggered by ischemia. It is unclear why higher variability and average diameters of pores in T2D were accompanied by larger vessels.

More rapid bone mineral density loss in older men with diabetes: The Osteoporotic Fractures in Men (MrOS) Study.

CONTEXT: Type 2 diabetes mellitus (T2D) is associated with more rapid bone loss in women, but less evidence is available for men or those with prediabetes. OBJECTIVE: To determine whether bone loss rate is affected by diabetes status in older men, we analyzed data from the Osteoporotic Fractures in Men (MrOS) study. METHODS: The multisite MrOS study enrolled 5,994 men aged ≥65 years. Diabetes status was defined by self-report, diabetes medication use, or elevated fasting serum glucose at baseline. Hip bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA) at baseline and a follow-up visit after 4.6 ± 0.4 years. This analysis included 4095 men, excluding those without a follow-up DXA or with unknown diabetes status. Changes in hip BMD in participants with normoglycemia (NG), prediabetes, or T2D, excluding thiazolidinedione (TZD) users, were evaluated using generalized linear models (GLM). Diabetes medication use and BMD loss among those with T2D were also evaluated with GLM. RESULTS: In adjusted models, loss in hip BMD was greater in men with T2D (- 2.23%: 95% CI: -2.54 to -1.91; p<0.001) but not in men with prediabetes (-1.45%; 95% CI -1.63 to -1.26; p=0.33) compared to NG (-1.57%: 95% CI -1.73 to -1.41). Among men with T2D, TZD, insulin and sulfonylurea use were associated with greater hip BMD loss. CONCLUSIONS: Men with T2D, but not prediabetes, experienced an accelerated bone loss compared to participants with normoglycemia. More rapid bone loss predicts increased risk of fractures and mortality in broader populations.

Adaptive Laboratory Evolution of Probiotics toward Oxidative Stress Using a Microfluidic-Based Platform.

Adaptive laboratory evolution (ALE) can be used to make bacteria less susceptible to oxidative stress. An alternative to large batch scale ALE cultures is to use microfluidic platforms, which are often more economical and more efficient. Microfluidic ALE platforms have shown promise, but many have suffered from subpar cell passaging mechanisms and poor spatial definition. A new approach is presented using a microfluidic Evolution on a Chip (EVoc) design which progressively drives microbial cells from areas of lower H2O2 concentration to areas of higher concentration. Prolonged exposure, up to 72 h, revealed the survival of adaptive strains of Lacticaseibacillus rhamnosus GG, a beneficial probiotic often included in food products. After performing ALE on this microfluidic platform, the bacteria persisted under high H2O2 concentrations in repeated trials. After two progressive exposures, the ability of L. rhamnosus to grow in the presence of H2O2 increased from 1 mm H2O2 after a lag time of 31 h to 1 mm after 21 h, 2 mm after 28 h, and 3 mm after 42 h. The adaptive strains have different morphology, and gene expression compared to wild type, and genome sequencing revealed a potentially meaningful single nucleotide mutation in the protein omega-amidase.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Faster sperm selected by rheotaxis leads to superior early embryonic development in vitro.

To understand the impact of sperm speed as they swim against the flow on fertilization rates, we created conditions similar to the female reproductive tract (FRT) on a microfluidic platform for sperm selection. Selected sperm were evaluated based on early development of fertilized embryos. Bovine and human spermatozoa were selected at various fluid flow rates within the device. We found that the speed of bovine spermatozoa increases as the flow rate increases and that the amount of DNA fragmentation index is lowered by increasing the flow rate. Bovine spermatozoa selected by our platform at low (150 µL h-1, shear rate 3 s-1), medium (250 µL h-1, shear rate 5 s-1), and high flow rates (350 µL h-1, shear rate 7 s-1) were used for fertilization and compared to sperm sorted by centrifugation. The samples collected at the highest flow rate resulted in the formation of 23% more blastocysts compared to the control. While selecting for higher quality sperm by increasing the flow rate does result in lower sperm yield, quality improvement and yield may be balanced by better embryonic development.

Impact analysis of regulatory regime options for integrated health care provider networks in the Philippines

Background@#The enactment of the Philippine Universal Health Care (UHC) Act mandates the formation of Integrated Health Care Provider Networks (IHCPN), linking hospitals and health facilities, which includes government and privately-owned primary care providers. While hospitals and some health facilities are already under government regulation, primary care providers have not been subjected to formal licensing requirements. In this changing service delivery model, the possible impact of three regulatory policy options being considered need to be assessed according to the goal of ensuring that health services remain affordable and are of high quality.@*Methodology@#A multi-method approach to regulatory impact analysis (RIA) systematically assessed three regulatory options: 1) one Department of Health (DOH) license per hospital and health facility (status quo); 2) one DOH license for all public hospitals and health facilities within an IHCPN and another for individual private hospitals and health facilities; and 3) one DOH license per individual hospital and health facility, and one DOH certification issued to individual hospitals and health facilities as part of an IHCPN. Information from literature, documents, focus group discussions, and cost analyses were triangulated.@*Results@#Regulators are faced with two main risks: there is no standard for networked health care delivery that could provide a foundation for regulation, and provider participation is voluntary, which could lower the interest of private providers to integrate. The three regulatory options considered these risks. Option 1 requires the least change in regulatory policy, but is expected to increase costs to regulators due to the expansion of licensing and enforcement work covering primary care providers. Option 2 requires the most change in regulatory policy, but may be the least expensive to enforce, especially if all facilities join a network. This can also be preferred in a setting with existing interlocal health zones, and participation in the network by private providers poses the most challenge. Option 3 is a tiered regulatory set up that projects the highest cost to regulators as a result of both establishing new certification standards and guidelines on top of a wider scope for enforcement.@*Conclusion@#This is the first RIA conducted for the Philippine health system, with challenges similar to those experienced in developing countries. Across the three pre-determined regulatory models, the least costly option may not be the easiest to mount and enforce. Implementability appears to be a stronger consideration which seems to be hinged to the option requiring incremental rather than large form of changes.

Platelet Lymphocyte Ratio (PLR) as a predictor of in-hospital outcomes among Acute Ischemic Stroke (AIS) patients in a tertiary hospital

Introduction@#Acute Ischemic Stroke (AIS) is a medical emergency that affects people globally. In the Philippines, it remains as the third leading cause of mortality. This study aims to determine the use of platelet-lymphocyte ratio (PLR) - a simple, economical, and safe tool - as a predictor of in-hospital outcomes in patients with acute ischemic stroke.@*Methods@#A retrospective cross-sectional study was conducted among AIS patients at the Remedios Trinidad Romualdez Hospital (RTRH) Tacloban City, Leyte, Philippines from January 2020 to December 2022. Clinical demographics, laboratory profile, and hospital outcomes were described. Descriptive statistics, Mann-Whitney test, and T-test were utilized to determine the association between PLR and in-hospital outcomes.@*Results and Conclusions@#There were 76 patients enrolled in the study, majority were females (57.9%), and hypertensive (84.2%). Risk factors that are pivotal to the development of AIS were also identified. To note, half of the population presented with unilateral body weakness. Moreover, only 7.9% died due to the disease. Higher PLR levels resulted from an increased platelet count and a decreased lymphocyte count. However, no significant association between PLR levels and AIS outcomes was noted, hence the need for further investigation of these parameters.

Beyond knowledge: Introducing embodied aversion through the case of contraception.

Family planning programs have largely operated at the individual level, seeking to enhance individuals' knowledge of, change attitudes towards, and improve consistent use of efficacious contraception. Social science research has added to these efforts by emphasizing the structural influences that shape individuals' contraceptive attitudes, beliefs, and behaviors. Such work highlights the importance of embodied knowledge which is informed by social contexts and provides individuals with a sense of assuredness in knowing which contraception works well for them (and within their bodies). However, through qualitative analysis of in-depth interviews with 59 self-identified women conducted from 2017 to 2018 across the state of Delaware in the United States, we argue that there is a powerful facet of contraceptive decision-making that lies beyond articulatable, conscious knowledge, which we name "embodied aversion." We draw on affect theory and stigma theory to introduce embodied aversion as an influential feeling and orientation away from implantable and insertable contraceptive methods that arises from internalized stigma around the reproductive body. Embodied aversion overpowers conscious understanding of contraceptive benefits like efficacy, ease of use, and longevity. Our research presents embodied aversion as a missing piece of contraceptive understanding that we argue is vital in more fully conceptualizing experiential dimensions of contraceptive use. Doing so enhances patient-centered care, shared decision-making, and reproductive autonomy.

Diabetes Risk Factors and Bone Microarchitecture as Assessed by High-Resolution Peripheral Quantitative Computed Tomography in Adults With Long-Standing Type 1 Diabetes.

OBJECTIVE: To determine whether type 1 diabetes and its complications are associated with bone geometry and microarchitecture. RESEARCH DESIGN AND METHODS: This cross-sectional study was embedded in a long-term observational study. High-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal and diaphyseal tibia were performed in a subset of 183 participants with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and 94 control participants without diabetes. HbA1c, skin advanced glycation end products (AGEs), and diabetes-related complications were assessed in EDIC participants with >30 years of follow-up. RESULTS: Compared with control participants (aged 60 ± 8 years, 65% female), EDIC participants (aged 60 ± 7 years, diabetes duration 38 ± 5 years, 51% female) had lower total bone mineral density (BMD) at the distal radius (-7.9% [95% CI -15.2%, -0.6%]; P = 0.030) and distal tibia (-11.3% [95% CI -18.5%, -4.2%]; P = 0.001); larger total area at all sites (distal radius 4.7% [95% CI 0.5%, 8.8%; P = 0.030]; distal tibia 5.9% [95% CI 2.1%, 9.8%; P = 0.003]; diaphyseal tibia 3.4% [95% CI 0.8%, 6.1%; P = 0.011]); and poorer radius trabecular and cortical microarchitecture. Estimated failure load was similar between the two groups. Among EDIC participants, higher HbA1c, AGE levels, and macroalbuminuria were associated with lower total BMD. Macroalbuminuria was associated with larger total area and lower cortical thickness at the distal radius. Higher HbA1c and AGE levels and lower glomerular filtration rate, peripheral neuropathy, and retinopathy were associated with deficits in trabecular microarchitecture. CONCLUSIONS: Type 1 diabetes is associated with lower BMD, larger bone area, and poorer trabecular microarchitecture. Among participants with type 1 diabetes, suboptimal glycemic control, AGE accumulation, and microvascular complications are associated with deficits in bone microarchitecture and lower BMD.

Community-guided, autism-adapted group cognitive behavioral therapy for depression in autistic youth (CBT-DAY): Preliminary feasibility, acceptability, and efficacy.

LAY ABSTRACT: Depression in youth is a significant public health problem worldwide, particularly for autistic youth who are over twice as likely to experience depression than their non-autistic peers. Although pathways to depression are complex, emotional reactivity and negative self-esteem are two risk factors for depression in autistic and non-autistic youth. Although autistic youth are more likely to experience depression than their non-autistic peers, psychotherapy options for autistic youth are very limited; community guidance in the development and testing of psychotherapy programs is a promising approach in autism. Therefore, in this study, we designed an autism-adapted CBT-DAY, in collaboration with autistic community members. Specifically, CBT-DAY combined neurodiversity-affirming and cognitive behavioral approaches to target emotional reactivity and self-esteem in youth to improve depressive symptom severity in a group setting across 12 weeks. We examined the preliminary feasibility, acceptability, and efficacy of CBT-DAY in a pilot non-randomized trial. In addition, we implemented a rigorous protocol for assessing, monitoring, and addressing potential harms in this intervention. Results from 24 autistic youth (11-17 years old) suggest that CBT-DAY may be feasible to use in an outpatient clinical setting and generally acceptable to youth and their caregivers. Participation in CBT-DAY may be associated with significant improvements in youth emotional reactivity and self-esteem, as well as depressive symptom severity per self-report only. Exploratory analyses showed that participation in CBT-DAY may also be associated with significant improvements in internalizing symptoms. Findings demonstrate the potential promise of neurodiversity-affirming and cognitive behavioral approaches to treating depressive symptoms in some autistic youth.

Bone Marrow Adiposity Alterations in Type 2 Diabetes Are Sex-Specific and Associated with Serum Lipid Levels.

Type 2 diabetes (T2D) has negative effects on skeletal health. A proposed mechanism of diabetic bone disease connects hyperlipidemia to increased bone marrow adiposity and decreased bone quality. Previous research on Type 1 diabetes reported positive associations between serum lipid levels and marrow adiposity, but no data exist for T2D. In addition, marrow adiposity is sex-dependent in healthy populations, but sex has not been addressed adequately in previous reports of marrow adiposity in T2D. The purpose of this study was to quantify associations of marrow adiposity and composition with T2D status, serum lipid levels, and sex. T2D patients and normoglycemic controls (n = 39/37) were included. Single-voxel magnetic resonance spectroscopy (MRS) was performed at the spine and tibia. Quantitative MRS outcomes of marrow adiposity and composition were calculated. Linear regression models were used to compare MRS outcomes among groups and to evaluate associations of MRS outcomes with serum lipid levels. All analyses were performed on sex-stratified subgroups. Total, unsaturated, and saturated fat content at the spine were lower in T2D participants compared to controls in age-adjusted models; these differences were significant in men but not in women. In our study cohort, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were lower in T2D participants compared to controls. Adjustment for LDL, HDL, and statin use attenuated the association of T2D status with unsaturated fat but not saturated fat in men. Further analysis confirmed significant associations between serum lipid levels and MRS outcomes. Specifically, we found a positive association between LDL cholesterol and total marrow fat in the male T2D group and a negative association between HDL and total marrow fat in the female T2D group. In conclusion, our results suggest that marrow adiposity and composition are associated with lipid levels as well as T2D status, and these relationships are sex-specific. © 2023 American Society for Bone and Mineral Research (ASBMR).

Risk Factors for Flat Anterior Chamber Requiring Intervention After Glaucoma Drainage Implant: A Retrospective Case-Controlled Study.

PURPOSE: To identify risk factors for flat anterior chamber that required additional intervention in the postoperative period (90 days) after uncomplicated Baerveldt Glaucoma Implant (BGI) surgery. DESIGN: Retrospective, matched case-control study. METHODS: A total of 42 cases (eyes) that received BGI at Anne Bates Leach Eye Hospital between February 1, 2011, and January 1, 2019, and that developed flat anterior chamber were included. For each case, we matched 2 controls (84). Variables included sex, diagnosis, diabetes, hypertension, pre- and postoperative glaucoma medications, ocular conditions, and intraocular pressure (IOP). Multivariable conditional logistic regression determined odds ratios (ORs) for independent predictors. RESULTS: Case patients were more likely to be female (69.1% case patients/41.7% controls), to have a history of taking oral carbonic anhydrase inhibitors (CAIs) at tube opening (21.4%/7.1%), to be of another race/ethnicity (11.9%/0.0%), and to have pseudoexfoliation (23.8%/6.0%), and were less likely to be using cholinergic agonists (0.0%/11.9%) at baseline and to have primary open angle glaucoma (42.9%/64.3%). Case patients had greater mean age (75.9/64.9 years), earlier tube opening time (5.6/6.2 weeks), and lower IOP after tube opening (7.2/14.4 mm Hg), but IOP before opening was higher (24.7/19.5 mm Hg). We identified 3 independent predictors: older age (10-year increase OR = 3.59, P < .0001), oral CAI use at tube opening (OR = 5.65, P = .009), and higher IOP prior to tube opening (3 mm Hg increase OR = 1.30, P = .018). CONCLUSION: Risk factors for flat anterior chamber were older age, oral CAIs at tube opening, and higher IOP before tube opening. Strategies to minimize the acute IOP reduction that preceded this complication such as discontinuing oral CAI prior to tube opening may be considered.

The long-term effect of intentional weight loss on changes in bone mineral density in persons with type 2 diabetes: results from the Look AHEAD randomized trial.

Intentional weight loss has been shown to increase bone loss short term but the long-term effects are not known. Data from the Look AHEAD clinical trial shows that a long term intentional weight loss intervention was associated with greater bone loss at the hip in men. PURPOSE: Intentional weight loss has been shown to increase bone loss short term and increase frailty fracture risk, but the long-term effects on bone mineral density (BMD) are not known. METHODS: Data from a subgroup from the Look AHEAD (LA) multicenter, randomized clinical trial was used to evaluate whether a long term intentional weight loss intervention would increase bone loss. In a preplanned substudy, BMD was assessed at 5 of the 16 LA clinical centers using dual-energy X-ray absorptiometry at baseline, year 8, and the observational visit 12.6-16.3 years after randomization (year 12-16). RESULTS: At year 8, bone density loss (%) was greater in the Intensive Lifestyle Intervention (ILI) group compared with the control group (DSE) for the femoral neck (p = 0.0122) but this finding was not observed at the year 12-16 visit. In analyses stratified by gender, bone density loss (%) was greater at the total hip for men in the ILI group than the DSE group at both the year 8 and year 12-16 visits (year 8 p = 0.0263 and year 12-16 p = 0.0062). This finding was not observed among women. CONCLUSION: Long term intentional weight loss was associated with greater bone loss at the hip in men. These results taken with the previously published Look AHEAD data from the entire clinical trial showing increased frailty fracture risk with weight loss in the ILI group suggest that when intentional weight loss is planned, consideration of bone density preservation and fracture prevention strategies is warranted. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00017953. June 21, 2001.

TP53/p53 Facilitates Stress-Induced Exosome and Protein Secretion by Adipocytes.

Besides the secretion of fatty acids, lipolytic stimulation of adipocytes results in the secretion of triglyceride-rich extracellular vesicles and some free proteins (e.g., fatty acid binding protein 4) that, in sum, affect adipose homeostasis as well as the development of metabolic disease. At the mechanistic level, lipolytic signals activate p53 in an adipose triglyceride lipase-dependent manner, and pharmacologic inhibition of p53 attenuates adipocyte-derived extracellular vesicle (AdEV) protein and FABP4 secretion. Mass spectrometry analyses of the lipolytic secretome identified proteins involved in glucose and fatty acid metabolism, translation, chaperone activities, and redox control. Consistent with a role for p53 in adipocyte protein secretion, activation of p53 by the MDM2 antagonist nutlin potentiated AdEV particles and non-AdEV protein secretion from cultured 3T3-L1 or OP9 adipocytes while the levels of FABP4 and AdEV proteins were significantly reduced in serum from p53-/- mice compared with wild-type controls. The genotoxin doxorubicin increased AdEV protein and FABP4 secretion in a p53-dependent manner and DNA repair-depleted ERCC1-/Δ-haploinsufficient mice expressed elevated p53 in adipose depots, along with significantly increased serum FABP4. In sum, these data suggest that lipolytic signals, and cellular stressors such as DNA damage, facilitate AdEV protein and FABP4 secretion by adipocytes in a p53-dependent manner.