Temporal Trends in Mental Health in the United States by Gender Identity, 2014-2021.

Objectives. To examine the temporal trends in the transgender-cisgender mental health disparity in the United States. Methods. We used 2014-2021 US Behavioral Risk Factor Surveillance System Survey data with logistic and ordinary least squares regression to document temporal trends in the transgender-cisgender disparity in self-reports of the number of poor mental health days in the past month and frequent mental distress. Results. In 2014, cisgender individuals reported a mean average of 3.68 (95% confidence interval [CI] = 3.65, 3.70) poor mental health days compared with a mean average of 5.42 (95% CI = 4.68, 6.16) poor mental health days among transgender respondents. The size of this disparity adjusted by differences in observable characteristics increased by 2.75 days (95% CI = 0.58, 4.91) over the sample period. In 2014, 11.4% (95% CI = 11.3%, 11.5%) of cisgender adults reported frequent mental distress compared with 18.9% (95% CI = 15.9%, 22%) of transgender adults. By 2021, 14.6% (95% CI = 15.9%, 22%) of cisgender adults and 32.9% (95% CI = 30.7%, 35.1%) of transgender adults reported frequent mental distress. Conclusions. Policies are needed to address the worsening mental health of transgender and gender-nonconforming people in the United States. (Am J Public Health. 2024;114(5):523-526. https://doi.org/10.2105/AJPH.2024.307603).

Adverse childhood experiences (ACEs) and mental health by gender identity in the United States, 2019-2021.

OBJECTIVE: To estimate the prevalence of adverse childhood experiences (ACEs) and their association with mental health outcomes in adulthood by gender identity. METHODS: Data come from 2019 to 2021 US Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance System, among 17 states collecting gender identity and ACEs. We estimated the prevalence of ACEs and used Poisson family regression to estimate the association between ACEs and mental health stratified by gender identity. Mental health was assessed as current frequent mental distress and lifetime depression diagnosis. RESULTS: The sample included n = 141,615 adults, 556 of whom identified as gender minority (including transgender or gender non-binary). Gender minority respondents were 18% more likely [95% CI 8% to 29%, p < 0.01] to be exposed to 3 or more ACEs relative to cisgender respondents. Among respondents exposed to 3 or more ACEs, gender minority adults were 25% [95% CI 10% to 43%, p < 0.01] more likely to report current frequent mental distress and 26% [95% CI 14% to 40%, p < 0.01] more likely to report a lifetime depression diagnosis than their cisgender peers. CONCLUSION: Using population-level data, we identified higher prevalence of ACEs among gender minority adults than cisgender adults, and greater associations of ACEs and adverse mental health in adulthood. The prevalence of current and lifetime adverse mental health outcomes increased with higher levels of ACE exposure among cisgender and gender minority respondents. Action by stakeholders at the community, health system, and legislative levels are needed to improve gender minority population health.

Anatomical and Physiological Changes Following Primary Palatoplasty Using "The Buccal Flap Approach".

OBJECTIVE: The purpose of this study was to determine the anatomical differences among selected individuals with a cleft palate repaired using "The Buccal Flap Approach" during primary palatoplasty compared to aged-matched participants without cleft palate. DESIGN: Observational, prospective. SETTING: Two regional hospitals. PARTICIPANTS: A total of 30 adult males consisting of 15 adults born with cleft palate who received the Double Opposing Z-Plasty plus Buccal Flaps (DOZP + BF) repair at the time of primary palatoplasty and no history of secondary speech surgery or orthognathic surgery and 15 adults without a history of cleft palate. INTERVENTIONS: All participants underwent MRI to visualize anatomy. MAIN OUTCOME MEASURES: Ten velopharyngeal and craniofacial anatomical measures. RESULTS: No statistically significant differences between groups were observed for velar thickness, velar length, pharyngeal depth, NSBa angle, SNB angle, or levator veli palatini length. Individuals with the DOZP + BF presented with a greater effective velar length (p < .001), greater effective VP ratio (p < .001), smaller SNA angle (p < .001), and smaller maximal velar stretch (p < .001) compared to the control participants. CONCLUSIONS: This study suggests that adult males who received the DOZP + BF repair at the time of primary palatoplasty and no history of secondary speech surgery or orthognathic surgery present with a longer effective velar length and larger effective VP ratio in comparison to the non-cleft group. Future research is needed to compare patients with and without favorable outcomes from multiple surgical types to fully understand how surgical techniques alter the anatomy.

Clarifying the Cause and Treatment of Paroxysmal Hypertension (Pseudopheochromocytoma).

PURPOSE OF REVIEW: To review the clinical characteristics of paroxysmal hypertension (pseudopheochromocytoma), its previously unsuspected cause, and effective treatment approaches. RECENT FINDINGS: Patients with paroxysmal hypertension experience recurrent, sudden, unprovoked, symptomatic, and severe elevations of blood pressure that occur independently of current stress or perceived emotional distress. Recent findings point to a previously unsuspected psychosomatic etiology, linked in most to a past history of abuse, trauma, or prolonged severe stress, often with repression of pertinent emotions, or to a repressive coping style. Consistent with this understanding, treatment with an antidepressant is thus far the only pharmacologic intervention demonstrated to be effective in preventing recurrent paroxysms, and is effective in most patients. Other treatment approaches are discussed, including medications to acutely lower blood pressure during paroxysms, and, in some cases, the possibility of emotional healing.  Recent findings indicate that paroxysmal hypertension is a psychosomatic disorder frequently linked to a past history of trauma or prolonged severe stress, usually with longstanding repression of pertinent emotions. Data strongly encourage treatment with an antidepressant in patients with recurrent or severe paroxysms. Further studies are needed.

De Novo Design, Solution Characterization, and Crystallographic Structure of an Abiological Mn-Porphyrin-Binding Protein Capable of Stabilizing a Mn(V) Species.

De novo protein design offers the opportunity to test our understanding of how metalloproteins perform difficult transformations. Attaining high-resolution structural information is critical to understanding how such designs function. There have been many successes in the design of porphyrin-binding proteins; however, crystallographic characterization has been elusive, limiting what can be learned from such studies as well as the extension to new functions. Moreover, formation of highly oxidizing high-valent intermediates poses design challenges that have not been previously implemented: (1) purposeful design of substrate/oxidant access to the binding site and (2) limiting deleterious oxidation of the protein scaffold. Here we report the first crystallographically characterized porphyrin-binding protein that was programmed to not only bind a synthetic Mn-porphyrin but also maintain binding site access to form high-valent oxidation states. We explicitly designed a binding site with accessibility to dioxygen units in the open coordination site of the Mn center. In solution, the protein is capable of accessing a high-valent Mn(V)-oxo species which can transfer an O atom to a thioether substrate. The crystallographic structure is within 0.6 Å of the design and indeed contained an aquo ligand with a second water molecule stabilized by hydrogen bonding to a Gln side chain in the active site, offering a structural explanation for the observed reactivity.

Neurogenic hypertension: pathophysiology, diagnosis and management.

Discussions about the cause and treatment of essential hypertension usually focus on mechanisms such as sodium/volume and the renin-angiotensin system. Less often discussed is hypertension driven by the sympathetic nervous system, i.e., neurogenic hypertension. In this review I discuss the pathophysiology of neurogenic hypertension, the controversy of renal versus central origin, the clinical clues that suggest neurogenic hypertension, and the interventions best suited in its treatment. Neurogenic hypertension is most likely to occur in patients with labile or paroxysmal hypertension, but evidence of increased sympathetic tone also suggests a neurogenic component in hypertension in patients with severe or resistant hypertension, chronic renal disease, comorbidities associated with increased sympathetic tone, and ingestion of drugs that stimulate sympathetic tone. The importance of combined alpha- and beta-blockade in pharmacologic treatment and the status of renal denervation are discussed. Although there is much that is unclear in its pathophysiology, recognition of neurogenic hypertension is of considerable clinical importance in individualizing drug therapy and achieving blood pressure control.

Peroxide Activation Regulated by Hydrogen Bonds within Artificial Cu Proteins.

Copper-hydroperoxido species (CuII-OOH) have been proposed to be key intermediates in biological and synthetic oxidations. Using biotin-streptavidin (Sav) technology, artificial copper proteins have been developed to stabilize a CuII-OOH complex in solution and in crystallo. Stability is achieved because the Sav host provides a local environment around the Cu-OOH that includes a network of hydrogen bonds to the hydroperoxido ligand. Systematic deletions of individual hydrogen bonds to the Cu-OOH complex were accomplished using different Sav variants and demonstrated that stability is achieved with a single hydrogen bond to the proximal O-atom of the hydroperoxido ligand: changing this interaction to only include the distal O-atom produced a reactive variant that oxidized an external substrate.

Modular Artificial Cupredoxins.

Cupredoxins are electron-transfer proteins that have active sites containing a mononuclear Cu center with an unusual trigonal monopyramidal structure (Type 1 Cu). A single Cu-Scys bond is present within the trigonal plane that is responsible for its unique physical properties. We demonstrate that a cysteine-containing variant of streptavidin (Sav) can serve as a protein host to model the structure and properties of Type 1 Cu sites. A series of artificial Cu proteins are described that rely on Sav and a series of biotinylated synthetic Cu complexes. Optical and EPR measurements highlight the presence of a Cu-Scys bond, and XRD analysis provides structural evidence. We further provide evidence that changes in the linker between the biotin and Cu complex within the synthetic constructs allows for small changes in the placement of Cu centers within Sav that have dramatic effects on the structural and physical properties of the resulting artificial metalloproteins. These findings highlight the utility of the biotin-Sav technology as an approach for simulating active sites of metalloproteins.

Loop Diuretics in the Treatment of Hypertension.

Loop diuretics are not recommended in current hypertension guidelines largely due to the lack of outcome data. Nevertheless, they have been shown to lower blood pressure and to offer potential advantages over thiazide-type diuretics. Torsemide offers advantages of longer duration of action and once daily dosing (vs. furosemide and bumetanide) and more reliable bioavailability (vs. furosemide). Studies show that the previously employed high doses of thiazide-type diuretics lower BP more than furosemide. Loop diuretics appear to have a preferable side effect profile (less hyponatremia, hypokalemia, and possibly less glucose intolerance). Studies comparing efficacy and side effect profiles of loop diuretics with the lower, currently widely prescribed, thiazide doses are needed. Research is needed to fill gaps in knowledge and common misconceptions about loop diuretic use in hypertension and to determine their rightful place in the antihypertensive arsenal.

Personalizing the diuretic treatment of hypertension: the need for more clinical and research attention.

Neither randomized controlled trials nor efforts to identify genetic markers have been helpful with regard to the goal of individualizing diuretic therapy in the treatment of hypertension, a goal that receives little clinical or research attention. This review will examine, and bring attention to, the considerable yet overlooked information relevant to individualizing diuretic therapy. It will bring attention to clinical, biochemical, and pharmacological clues that can be helpful in identifying who is likely to respond to a diuretic, who needs a stronger diuretic regimen, which diuretic to prescribe, and how to minimize adverse effects. New directions for clinical research aimed at individualizing use in hypertension will be explored. Research and clinical attention to the goal of individualizing diuretic treatment in hypertension need to be renewed, to help us achieve greater hypertension control with fewer adverse effects and lower costs.

Labile and Paroxysmal Hypertension: Common Clinical Dilemmas in Need of Treatment Studies.

Although "labile hypertension" is regularly encountered by clinicians, there is a paucity of information available to guide therapeutic decisions. This review discusses its clinical relevance, the limitations of current knowledge, and possible directions for future research and clinical management. Results of studies that assessed measures of blood pressure variability or reactivity are reviewed. The limited information about effects of antihypertensive drugs on blood pressure variability is discussed. Two different clinical presentations are differentiated: labile hypertension and paroxysmal hypertension. Labile hypertension remains a clinical impression without defined criteria or treatment guidance. Paroxysmal hypertension, also called pseudopheochromocytoma, presents as dramatic episodes of abrupt and severe blood pressure elevation. The disorder can be disabling. Although it regularly raises suspicion of a pheochromocytoma, such a tumor is found in <2 % of patients. The cause, which involves both emotional factors and the sympathetic nervous system, and treatment approaches, are presented.

Sexual orientation based health disparities in Chile.

Numerous studies from Europe and North America have documented sexual orientation-based health disparities, but due to data limitations, very little is known about the health of sexual minorities (i.e., lesbians, gay men, bisexual individuals, and other non-heterosexual populations) in developing countries. This research note uses newly available nationally representative data from the Chilean Socio-Economic Characterization Survey (CASEN) to explore sexual orientation-based disparities in self-rated health, health insurance coverage, and healthcare utilization in Chile. Our findings indicate that sexual minority respondents report worse self-rated health and greater health care utilization, and that sexual minority men are more likely to have private health insurance relative to heterosexual men. These findings are important in facilitating continued efforts to reduce health disparities in Latin America.

Mental Health of Transgender Youth Following Gender Identity Milestones by Level of Family Support.

Importance: Transgender youth are at an elevated risk for adverse mental health outcomes compared with their cisgender peers. Identifying opportunities for intervention is a priority. Objective: To estimate differences in the association between gender identity milestones and mental health outcomes among transgender youth, stratified by level of family support. Design, Settings, and Participants: This retrospective cohort study compares changes in mental health outcomes among transgender youth who initiate gender identity milestones compared with those who initiate the same milestones 1 year later, stratified by level of family support, using the 2015 US Transgender Survey. The analytic samples included 18 303 transgender adults aged 18 and older who had initiated at least 1 gender identity milestone between ages 4 and 18 years. Exposure: Four gender identity milestones: feeling one's gender was different, thinking of oneself as transgender, telling another that one is transgender, and living full-time in one's gender identity, stratified by 3 levels of family support: supportive, neutral, and adverse. Main Outcomes: Age at first suicide attempt and at running away. Results: Study participants included 18 303 transgender adults (10 288 [56.2%] assigned female at birth; 14 777 [80.7%] White). Initiating a gender identity milestone was associated with a higher risk of suicide attempt and running away from home among transgender youth. This finding was driven by children who live in unsupportive families. For example, thinking of oneself as transgender was associated with a meaningful increase in the overall probability of attempting suicide among those in either adverse families (estimate = 1.75 percentage points; 95% CI, 0.47-3.03) or neutral families (estimate = 1.39 percentage points; 95% CI, 0.72-2.05). Among youth living with supportive families, there were no statistically significant associations between gender identity milestones and adverse mental health outcomes and 95% CIs generally ruled out any meaningful associations. Conclusion: These results demonstrate that without a supportive family environment, gender identity development increases the risk of transgender youth attempting suicide or running away from home. Social services and community resources to establish supportive relationships between transgender children and their parents are essential.

De novo design of drug-binding proteins with predictable binding energy and specificity.

The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free energy calculations performed directly on the designed models were in excellent agreement with the experimentally measured affinities. We conclude that de novo design of high-affinity small molecule-binding proteins with tuned interaction energies is feasible entirely from computation.

Sexual Orientation, High-Deductible Health Plans, And Financial Barriers To Care.

Among US adults in 2013-18, we found high-deductible health plan enrollment to be the lowest among heterosexual and gay/lesbian adults in families with incomes below 200 percent of the federal poverty level and the highest among bisexual adults in families with incomes at or above 400 percent of poverty. Gay/lesbian and bisexual adults in these plans experienced greater financial barriers to health care than heterosexual adults.

Effects of the affordable care Act's Medicaid expansion on health insurance coverage for individuals in same-sex couples.

OBJECTIVE: To examine whether the Affordable Care Act's (ACA's) Medicaid expansions affected health insurance coverage for individuals in same-sex couples. DATA SOURCES AND STUDY SETTING: We used data on adults aged 18-64 years in same-sex couples (n = 33,512) from the 2008-2018 American Community Survey (ACS). STUDY DESIGN: To estimate the effect of the impact of the state Medicaid expansions under the ACA on health insurance coverage for sexual minorities, we utilize a standard difference-in-differences approach to leverage the variation across geography and time in expanding Medicaid. DATA COLLECTION: Secondary and publicly available ACS data were obtained from IPUMS at the University of Minnesota. PRINCIPAL FINDINGS: We find that Medicaid expansion significantly increased health insurance coverage among low-income men and women in same-sex couples by 4.9 (standard error [SE] = 1.75) and 6.5 (SE = 1.96) percentage points, respectively. We find increases in the likelihood of having Medicaid and reductions in private health insurance from an employer or privately purchased insurance. Effects on Medicaid take-up are consistently larger for low-income women in same-sex couples as compared to low-income men in same-sex couples. CONCLUSIONS: We provide the first evidence on the relationship between state Medicaid expansions under the ACA and health insurance coverage among sexual minority adults, a group that has been understudied in past research. Our results confirm that sexual minority adults benefitted from the ACA's Medicaid expansions with respect to increased health insurance coverage.

De novo design of drug-binding proteins with predictable binding energy and specificity.

The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low µM, in a predictable manner. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free-energy calculations performed directly on the designed models are in excellent agreement with the experimentally measured affinities, suggesting that the de novo design of small-molecule-binding proteins with tuned interaction energies is now feasible entirely from computation. We expect these methods to open many opportunities in biomedicine, including rapid sensor development, antidote design, and drug delivery vehicles.

Copper assisted sequence-specific chemical protein conjugation at a single backbone amide.

Direct, site-specific methods of protein functionalization are highly desirable for biotechnology. However, such methods are challenging due to the difficulty of chemically differentiating a single site within a large protein. Herein, we propose "metal binding targeting" strategy and develop a Copper Assisted Sequence-specific conjugation Tag (CAST) method to achieve rapid (second order rate 8.1 M-1 s-1), site-specific protein backbone chemical modification with pinpoint accuracy. We demonstrate the versatility of CAST conjugation by preparing various on-demand modified recombinant proteins, including a homogeneous antibody-drug conjugate with high plasma stability and potent efficacy in vitro and in vivo. Thus, CAST provides an efficient and quantitative method to site-specifically attach payloads on large, native proteins.

High Dietary Sodium, Measured Using Spot Urine Samples, is Associated with Higher Blood Pressure among Young Adults in Haiti.

Background: Hypertension (HTN) is the leading cardiovascular disease (CVD) risk factor in Haiti and is likely driven by poverty-related social and dietary factors. Salt consumption in Haiti is hypothesized to be high but has never been rigorously quantified. Methods: We used spot urine samples from a subset of participants in the population-based Haiti Cardiovascular Disease Cohort to estimate population mean daily sodium intake. We compared three previously validated formulas for estimating dietary sodium intake using urine sodium, urine creatinine, age, sex, height, and weight. We explored the association between dietary sodium intake and blood pressure, stratified by age group. Results: A total of 1,240 participants had spot urine samples. Median age was 38 years (range 18-93), and 48% were female. The mean dietary sodium intake was 3.5-5.0 g/day across the three estimation methods, with 94.2%-97.9% of participants consuming above the World Health Organization (WHO) recommended maximum of 2 g/day of sodium. Among young adults aged 18-29, increasing salt intake from the lowest quartile of consumption (<3.73 g/day) to the highest quartile (>5.88 g/day) was associated with a mean 8.71 mmHg higher systolic blood pressure (SBP) (95% confidence interval: 3.35, 14.07; p = 0.001). An association was not seen in older age groups. Among participants under age 40, those with SBP ≥120 mmHg consumed 0.5 g/day more sodium than those with SBP <120 mmHg (95% confidence interval: 0.08, 0.69; p = 0.012). Conclusions: Nine out of 10 Haitian adults in our study population consumed more than the WHO recommended maximum for daily sodium intake. In young adults, higher sodium consumption was associated with higher SBP. This represents an inflection point for increased HTN risk early in the life course and points to dietary salt intake as a potential modifiable risk factor for primordial and primary CVD prevention in young adults.

Inaccuracy of self-reported low sodium diet.

OBJECTIVES: This study evaluates how often the self-report of a low sodium (Na) intake is reflected by a low 24-h urinary sodium excretion and examines the influence of incomplete urinary collections on this comparison. METHODS: In a study in which 24-h urine collections were obtained for measurement of Na and creatinine excretion, 120 participants were asked whether their Na intake was low, medium, or high. A 24-h urine collection was considered complete if creatinine excretion was ≥20 mg/kg in men or ≥15 mg/kg in women, and incomplete if below those amounts. The kappa statistic was computed to assess the level of agreement between 24-h Na excretion, dichotomized at 100 meq and self-report responses. RESULTS: Agreement between self-reported and actual Na excretion was poor. The kappa statistic was 0.18 for the total sample, 0.04 for complete collectors, and 0.51 for incomplete collectors, respectively. Overall, 24-h Na excretion exceeded 100 meq among 75% of those reporting an average or high Na intake, but it also exceeded 100 meq among 57% of those reporting a low sodium intake. Further, among those reporting a low sodium intake, Na excretion exceeded 100 meq in 80% of those who submitted a complete collection, but in only 29% of those who submitted an incomplete collection. CONCLUSIONS: These findings suggest that many individuals who report a low salt diet actually excrete ≥100 meq/day. Na intake is also frequently underestimated because many 24-h urine collections are incomplete.