United States

Background: 
Testosterone therapy amongst men is on the rise, resulting in an increase in testosterone-related side effects, most notably gynecomastia. Testosterone therapy occurs in one of two forms: Testosterone Replacement Therapy (TRT) and Anabolic Androgenic Steroids (AAS). Both have been associated with gynecomastia, yet it remains unclear whether one impacts gynecomastia more than the other. The objective of this study was to systematically review the evidence on TRT and AAS-induced gynecomastia to determine which was more associated with gynecomastia.

Methods: A systematic review protocol was registered with PROSPERO (CRD42023454216) and adhered to PRISMA-P guidelines. A literature search in PubMed, Embase, and Cochrane Library yielded 212 eligible articles. Inclusion criteria targeted gynecomastia, TRT, and AAS use and treatment regimens for gynecomastia. We utilized the MINORS criteria to assess the risk of bias.

Results: Of 212 studies, 10 met inclusion criteria. Incidence of TRT-induced gynecomastia ranged from 2.3 to 6.6%, while AAS-induced gynecomastia was reported at 19 to 35%. TRT cessation often led to spontaneous gynecomastia regression. With respect to surgical intervention, AAS-related treatment was associated with higher rates of surgical revision compared to non-AAS treatment (3.8% vs. 1.2%, respectively; p = 0.02).

Conclusion: This systematic review demonstrates distinct differences in gynecomastia incidence between TRT and AAS testosterone therapy. Notably, AAS exhibits higher rates of induced gynecomastia compared to TRT. Additionally, discontinuing TRT more commonly led to spontaneous gynecomastia regression compared to AAS. This may support delayed plastic surgery intervention for these patients. AAS-related gynecomastia regresses less commonly, yet when treated has a higher revision rate.


AMA Research Challenge 2023

Gynecomastia related to Testosterone Therapy: A Systematic Review

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AMA Research Challenge 2022

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Introduction:
Thermal injury to the anterior chest wall not only causes physical and emotional trauma, but also leaves survivors grappling with disfigurement, lack of physiologic function, such as breastfeeding, and impaired quality of life. This review evaluates possible breast reconstruction options for patients following thermal injury by comparing the aesthetic outcomes, complications, and functionality through breastfeeding ability.

Methods:
PubMed, EMBASE, and Scopus were used in an unrestricted search for postburn breast reconstruction cases. 6,162 articles were screened through an independent and blinded dual review to ensure they included patients with at least one breast affected by burns, provided details about breast reconstruction surgery, and reported postoperative outcomes. Articles were further analyzed for patient and burn characteristics, reconstruction specifications, and the effectiveness of breast reconstruction procedures in retaining breastfeeding ability. Registered on PROSPERO: CRD42023437347.

Results: 
There were 50 articles with a low risk of bias, analyzing 505 female patients with a history of chest burns. 32 of these studies utilized either local, regional, or distant autologous flaps from various donor sites, including Z-plasties, TDAPs, and TRAMs, with 16 reported satisfactory cosmetic results. 24 of the 50 articles described reconstruction using full- or split-thickness skin grafts, with 12 reporting patient satisfaction. 21 studies described implant-based breast reconstruction, with 13 studies reporting high patient satisfaction and 1 study reporting low patient satisfaction. 3 studies included the ability to breastfeed or breastfeed comfortably as an outcome and 2 patients with minimal damage to the nipple who received skin grafts retained breastfeeding ability. 

Conclusion: 
This review highlights how breast reconstruction following thermal injury requires careful consideration of affected anatomic structures. The level of destruction or alteration of important anatomic structures such as the nipple were key in determining future breastfeeding ability. The majority of included articles reported outcomes on satisfaction and aesthetics. Future articles may consider reporting breastfeeding outcomes such as the ability to lactate or breastfeed without discomfort. In particular, studies can consider the breastfeeding ability of patients who were actively breastfeeding at the time of thermal injury or postpartum mothers after reconstruction surgery. This review provides physicians with a collective evaluation of the breast reconstruction options after chest burns and their differences in outcomes and potential effectiveness of retaining breast contour, nipple sensitivity, and ability to breastfeed.

Can I still Breastfeed? Breast Reconstruction Options Post Chest Burns: A Systematic Review

Abnormal calcium deposition is among the sequelae that may follow major burn injury. This may manifest as heterotopic ossification or dystrophic calcification (DC) of scarred skin. While the two processes are distinct, the term heterotopic ossification (HO) is often used by clinicians in reference to both processes. While HO is well-documented, there appears to be less attention devoted to DC, the most common subtype of calcinosis cutis. HO is the abnormal formation of mature lamellar extraskeletal bone in muscle and soft tissues. Risk factors include traumatic injuries and surgeries such as spinal cord injury, hip arthroplasty, and burns with >30% TBSA. It commonly occurs in upper extremities, especially the elbows, and on average takes weeks to months to develop. In contrast, DC is the pathologic calcification of scar itself, and can present in cases of burn survivors as the calcification of burn and skin graft scar, often decades after the original burn injury. It manifests as the build-up of insoluble calcium salts in damaged subcutaneous tissues in the absence of abnormal serum calcium and phosphate levels. Applicability of this research is to increase awareness of burn sequelae; this research was not externally funded. 
We present a case of DC to highlight the distinct differences between DC and HO in hopes of promoting use of the semantically correct terms. A 67 year old female presented to the clinic 65 years after a >40% TBSA burn treated with excision and skin grafting at the time of injury. She had a months-long history of a draining sinus with a~5mm diameter white hard plaque at the base, and a broader contiguous area of hard plaque palpable beneath the surrounding area of skin graft scar. She had been experiencing recurrent bouts of infection and sought definitive treatment. The area was widely excised and ultimately resurfaced with a new split thickness skin graft. Clinical and histopathologic photographs will be presented. The histopathologic findings were consistent with the dystrophic calcification variant of calcinosis cutis. The presentation was consistent with ~10-12 other cases seen by the senior author over a 20 year career, and consistent with other cases reported in the literature. The term "heterotopic ossification" is sometimes used too broadly to describe any pathologic calcium deposition in burn survivors. We highlight the difference between heterotopic ossification and dystrophic calcification out of a belief that as subject matter experts in burns and their sequelae, burn care providers should want to use the most accurate terminology wherever possible.

Revisiting the Taxonomy of Abnormal Calcium Deposits in Burn Survivors: Heterotopic Ossification versus Calcinosis Cutis

Background: Since the FDA has mandated a boxed warning on all psychostimulants due to risks for misuse and death, coupled with nationwide shortages, clinicians have utilized non-stimulants, such as alpha-2-agonists for hyperactivity/impulsivity and the norepinephrine reuptake inhibitor atomoxetine for inattention, as safer alternatives. However, these agents lack comparable efficacy with delayed onset compared to psychostimulants. Insurers require generic atomoxetine prior to covering Viloxazine ER (VER), a novel 5-HT2B antagonist, 5-HT2C partial agonist, and 5-HT7 antagonist. We wanted to know whether patients taking atomoxetine would experience improvement in ADHD symptoms after switching to VER.
Methods: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to FDA guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine; 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; same protocol after treatment with VER. We conducted a retrospective chart review of these 50 patients. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05.
Results: From baseline total ADHD-RS-5 mean score (40.3+10.3), improvements were greater on VER (13.9+10.2) than atomoxetine (33.1+12.1) (t = -10.12, p < 0.00001), in Inattention (t = -8.57, p < 0.00001) and in Hyperactivity/Impulsivity (t = -9.87, p < 0.00001). From baseline total AISRS mean score (37.3+11.8), improvements were greater on VER (11.9+9.4) than atomoxetine (28.8+14.9) (t = -4.18, p = 0.0009), in Inattention (t = -3.50, p < 0.004) and in Hyperactivity/Impulsivity (t = -3.90, p < 0.002). 86% of patients on VER reported positive response by 2 weeks versus 14% on atomoxetine. 36% discontinued atomoxetine for side effects, including GI upset (6 patients), irritability (6), fatigue (5), insomnia (1) versus 4% who discontinued VER due to fatigue. 96% preferred VER over atomoxetine with 85% (22/26) able to taper psychostimulants following stabilization on VER. 
Conclusion: Pediatric and adult ADHD patients, who have experienced less than optimal response to atomoxetine, demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on viloxazine extended-release, which deserves consideration as a new first-line ADHD treatment option

Viloxazine Extended-Release As A Paradigm Shift In The Treatment Of ADHD

Background 

Deposition of amyloid plaques in brain is considered as an index event in the pathophysiology of Alzheimer’s disease (AD) which leads to series of events resulting in cognitive impairment. AD commonly involves non-cognitive symptoms like depression, anxiety, etc. We attempted to explore whether amyloid burden is directly related to depressive symptoms, or this relationship is mediated by cognitive symptoms.

Methods 

We examined the relationship between quantitative amyloid PET data (Standardized Uptake Value Ratios), cognition measured with cognitive function instrument (CFI), and depression measured with geriatric depression scale among 4486 cognitively unimpaired older adults who were screened for a multisite secondary prevention trial (A4 study; Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). The relationships among the variables were assessed through path analysis using structural equation modeling (SEM).

Results 

Our path analysis showed that amyloid burden is not directly related to depression and this association is mediated by cognitive performance, objectively measured as well as subjectively reported. All variables were controlled for age and education. Our model showed good fit (Model 1; CFI= 0.0931, RMSEA= 0.058 & Model 2; CFI = 0.9205, RMSEA = 0.086). Greater amyloid burden correlated with greater subjective cognitive impairment (p < 0.001) and greater objective cognitive impairment (p < 0.001). In both models, increased cognitive impairment was associated with increased depression scores (p < 0.001) and (p = 0.03), respectively. 


Conclusion 

Our findings indicate that amyloid burden is not directly correlated with depression, but rather its relationship with depression is mediated through cognitive impairment. This mediation may also be secondary to intermediate steps between amyloid deposition and cognitive alteration. Identifying this relationship will have implications for targeted interventions to mitigate depressive symptoms and improve the quality of life for individuals in the preclinical stages of Alzheimer’s disease.

Associations Between Amyloid Burden, Cognitive Impairment, and Depression in Preclinical Alzheimer's

Background: Anxiety disorders have complex etiologies. However, several key risk factors have been identified, such sex, stress exposure and more recently neuroinflammation. In response to stress, the Hypothalamus-Pituitary-Adrenal (HPA) axis and the Locus coeruleus (LC)-Norepinephrine (NE) system are triggered. While beneficial in the short-term, chronic, and persistent stress exposure results in HPA axis and LC-NE system dysregulation and neuroinflammatory changes, often leading to anxiety-like phenotypes in animal models. Despite the current findings, the role of sex and the link between chronic stress exposure, neuroinflammation, and LC dysregulation in the development of anxiety disorders has not been elucidated.

Methods: This study demonstrates the sex-dependent neuroinflammatory and neuronal changes in the rodent LC using elevated plus maze (EPM), ex-vivo electrophysiology, and immunohistochemistry (IHC). To model chronic stress, male and female adolescent (8-week-old) Sprague Dawley rats were restrained and exposed to predator odorant for two hours per day for ten days over two consecutive weeks.

Results: Two-way ANOVA analysis of EPM reveals a main effect of stress in open arm time (F1,12=5.127, p=0.0429), suggesting increased anxiety-like behaviors in response to chronic stress. Likewise, a main effect of stress was also noted in LC spontaneous firing frequency (F1,73=6.394, p=0.0136) along with other measures of LC neuronal physiology such as Action potential (AP) threshold, afterhyperpolarization, and activation gap. IHC staining for IBA-1, a microglial marker, and Major histocompatibility II (MHC-II), an activation marker within the LC, reveals a reveal a significant increase in microglia (p=0.0001) and activated microglia (p=0.0351) in stressed males relative to control males. In contrast, an opposite trend was noted in females. Furthermore, correlation analysis between percent weight change, a measure of stress induction, and IBA-1 cell counts within the LC demonstrates a significant negative correlation in males (p=0.0113) and no correlations in females suggesting increased male LC neuroinflammation in response to chronic stress.

Conclusion: Our results indicate that chronic stress exposure induces sex-dependent LC neuroinflammation, which may lead to alterations in LC neuronal physiology and influence rodent anxiety-like behaviors. 


Chronic stress induces sex-dependent neuroinflammation and neuronal physiology alterations in the rodent Locus coeruleus

Background: Every year, over 3 million new concussions are diagnosed in the United States. The recovery from these concussions is not yet standardized as the post concussive symptoms (PCS) patients face are influenced by a myriad of medical, social, and psychological problems. Although recent studies have noted a correlation between premorbid psychological conditions and worsened PCS, there is not enough literature that studies a possible relationship between adverse childhood experiences (ACEs) and PCS. ACEs, traumatic events that occur to individuals during their childhood, have been shown to be associated with numerous negative health outcomes. This study aims to identify if higher ACE scores are correlated with worse PCS, or if patients with high ACEs develop a resiliency that is protective against PCS. 



Methods: This is a cross-sectional study of patients recruited from a concussion clinic at Saint Louis University Hospital. The inclusion criteria for this study: (1) patients between ages of 18-80, (2) diagnosed with a concussion or mild traumatic brain injury by their physician, (3) presenting as a new patient or a follow up for concussion care, (4) possess ability to speak and read English. Eligible participants, after completing appropriate consent and HIIPA authorization forms, complete assessments evaluating their ACEs and current PCS. Surveys for this study include: the Adverse Childhood Experiences questionnaire (ACEs), Adult Resilience Measure (ARM), Neuropsychiatric Symptom Inventory (NSI), Patient Healthcare Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7). The data from these assessments is compiled into a HIIPA-compliant spreadsheet. From there, statistical analyses are done to identify possible correlations between ACEs, PCS, ARM scores, depression, and anxiety. 



Results: Values from 66 patients were collected and Pearson Correlation values were subsequently calculated. The analyses yielded the following correlations: NSI and ACEs had a mild positive correlation of 0.19, NSI and ARM had a moderate negative correlation of -0.46, and ACE & ARM had a mild negative correlation of -0.13. Scatterplots with trendlines of these correlations were also created. 



Conclusion: Our results so far indicate a mild positive correlation between PCS and ACE and a moderate negative correlation between PCS and resiliency. There is not a strong correlation between ACE and resiliency.

Influence of Adverse Childhood Experiences on Postconcussive Symptoms

While studies have been performed to analyze the relationship between individuals who have committed sexual offenses and their levels of neuroticism, psychopathy, and narcissism, these three traits have not been analyzed in their relationship to paraphilia diagnoses. The Personality Assessment Inventory (PAI), Hare Psychopathy Checklist Revised (PCL-R), and calculated neuroticism and narcissism scores from the Alternative DSM-5 Model for Personality Disorders (AMPD) of 83 adult males charged with or convicted of sexual offending were reviewed and analyzed for a relationship between the three traits of interest and the presence of a paraphilic diagnosis. Each subject’s forensic evaluation report was reviewed for diagnoses of paraphilic disorders (pedophilic, sadism, exhibitionism, coercive paraphilic disorder/biastophilia), antisocial personality disorder, borderline personality disorder, narcissistic personality disorder, or other personality disorders given at the time of evaluation. The presence of neuroticism and narcissism could not be directly measured from an available inventory; thus, the AMPD was utilized to help approximate these traits. PAI T-score results were used to calculate the approximate equivalent AMPD B-Criterion scores for antisocial personality disorder, borderline personality disorder, and narcissistic personality disorder. While no significant relationship was found for paraphilic diagnoses in general, individuals diagnosed with pedophilic disorder displayed lower mean psychopathy scores. Individuals diagnosed with exhibitionism showed mixed results with higher scores in some facets of psychopathy and lower scores in others. Individuals diagnosed with narcissistic personality disorder displayed increased scores in measures of psychopathy and narcissism, but decreased scores in neuroticism measurements. Individuals diagnosed with paraphilic coercive disorder displayed higher scores in parts of psychopathy measurements. Individuals diagnosed with borderline personality disorder displayed higher levels of neuroticism, which is to be expected. Unsurprisingly, individuals diagnosed with antisocial personality disorder scored higher in measures of antisocial and psychopathic behavior. Individuals diagnosed with a personality disorder showed increased psychopathy and narcissistic scores. 


Neuroticism, Narcissism, and Psychopathy: An Analysis of Personality Traits in Convicted Sex Offenders

Background
Access to mental health services remains limited globally, and with increasing global needs remaining unmet, the need for rapid innovation in mental health care delivery continues to remain clear. Digital mental health apps and artificial intelligence, such as chatbots, have previously been proposed as a solution toward increased access to quality mental health care. Chatbots are digital tools capable of engaging in natural language conversations and mimicking human responses and behaviors, in addition to engaging in task-oriented dialogue with users. The widespread use of digital voice assistants coupled with low-cost availability of smartphone apps may uniquely position conversational agents as digital tools able to increase access to mental health care.
Methods
A systematic literature search was conducted in May 2023, using the PubMed, EmBase, PsychINFO, and Cochrane databases as well as ArXiv and IEEE Xplore. Included were studies that assessed the efficacy of a conversational agent on the treatment of serious mental illnesses (SMI), including mood disorders, anxiety disorders, psychotic disorders, and substance use disorders.
Results
Of the 677 papers reviewed, 21 were included and 656 were excluded. When compared to reviews of the chatbot landscape from 2018 and 2020, there continues to be a lack of standard measures to ensure ease of comparison between studies in this space. Some populations continued to lack representation, while others are now gaining representation. Overall, there were generally positive experiences with chatbots when measured across domains of usability, acceptability, and engagement. The continued degree of heterogeneity between studies in this space, however, makes direct comparison challenging.
Conclusion
Chatbots remain an important technology in consideration of increasing access to mental health services, gaining tremendous interest and popularity since the release of ChatGPT in November 2022. This literature review revealed areas of improvement in this space as well as increased need for standardization of scales used across studies, and the need to include clinician perspectives.

Chatbots in Mental Health Care: An Updated Systematic Review and Meta Analysis

Background:
Neuropsychiatric symptoms (NPS) emerging after the age of 50 may be a risk factor or an early clinical expression of AD dementia. Mild Behavioral Impairment (MBI) is a syndrome of new-onset and persistent NPS in older adults either with or without cognitive impairment. NPS in the context of race and ethnicity have not been studied and the influence of biology or culture on the expression of NPS is unknown.

Method:
Participants over the age of 60 ranging from cognitively normal to mild AD (N = 17,491) from the National Alzheimer’s Coordinating Center were categorized for MBI status (yes/no) using Neuropsychiatric Inventory-Questionnaire (NPI) scores and a published algorithm. MBI prevalence across White non-Hispanics, White Hispanics, African Americans, and Asians was compared using multivariable logistic regression with adjustment for a priori specified confounding factors including diagnostic group, age, sex, and other relevant factors. Among MBI negative participants at baseline, a Cox proportional hazards model was also fit to estimate the relative risk of progression to MBI across race/ethnicity groups.

Result:
After adjustment, White Hispanics were estimated to have a 2-fold higher odds of MBI when compared to White non-Hispanics (OR, 2.03; 95% CI, 1.65-2.50; p<0.001). In contrast, African Americans were less likely than White non-Hispanics to have MBI (OR, 0.79; 95% CI, 0.68-0.92; p<0.003). The odds of MBI were significantly higher among men when compared to women (OR, 1.28; 95% CI, 1.16-1.41; p<0.001). In the prospective analysis, African Americans were estimated to have 26% lower risk of progressing to MBI when compared to White non-Hispanics (RR, 0.74; 95% CI, 0.65-0.84; p<0.001). 

Conclusion:
These findings suggest there are racial/ethnic differences in the prevalence of MBI and the progression to MBI in older adults at risk for or with mild AD dementia. African Americans had a lower likelihood of having MBI and progression to MBI, while White Hispanics had a higher likelihood compared to White non-Hispanics. Future research is warranted to investigate potential biological features or cultural factors such as the differential expression or perception of NPS in older adults that explain these differences.

Neuropsychiatric Symptoms and Alzheimer’s Disease Risk Differences across Racial and Ethnic Groups

Background/Objective: Suicide is a public health crisis for children
and adolescents. Suicidal ideation and suicidal behavior are
important predictors of suicide risk. Peripheral biological correlates of
suicidal ideation and behavior can guide precision care of suicidality.
To assess the current literature landscape of the field, we conducted
a systematic review of peripheral biological correlates for suicidal
ideation and suicidal behavior of children and adolescents.

Method: We searched through 4 databases (PubMed, the Cochrane
Library, Embase, and PsychInfo) from the earliest date to April 2023.
We used MeSH terms with keyword synonyms related to children
and adolescents, suicidality, and peripheral biological correlates. We
excluded reviews, editorials, protocol papers, abstracts, conference
proceedings, abstracts, and non-English studies. We employed two
independent reviewers for the title/abstract screening and full-text
screening. We followed PRISMA guidelines for reporting systematic
review and used JBI risk of bias tool for the screened studies.

Results: A total of 27980 articles were screened by reviewers, and
133 full texts were extracted. The peripheral biological markers are
grouped into physiologic stress response, serotonin system,
neuromodulators, immune system/inflammation, lipid/metabolism,
HP Axis, genetics, and other.

Conclusion: This systematic review provides a valuable synthesis of
the current literature on peripheral biological correlates for suicidality
in children and adolescents. The review identifies potential
peripheral correlates that can serve as valued biomarkers for
suicidality, and areas of needed studies. The review also notes the
feasibility of meta-analysis of specific peripheral biological markers
on this topic. 


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