Preclinical evaluation of [11 C]L-235 as a radioligand for Positron Emission Tomography cathepsin K imaging in bone.

The cathepsin K (CatK) enzyme is abundantly expressed in osteoclasts, and CatK inhibitors have been developed for the treatment of osteoporosis. In our effort to support discovery and clinical evaluations of a CatK inhibitor, we sought to discover a radioligand to determine target engagement of the enzyme by therapeutic candidates using positron emission tomography (PET). L-235, a potent and selective CatK inhibitor, was labeled with carbon-11. PET imaging studies recording baseline distribution of [11 C]L-235, and chase and blocking studies using the selective CatK inhibitor MK-0674 were performed in juvenile and adult nonhuman primates (NHP) and ovariectomized rabbits. Retention of the PET tracer in regions expected to be osteoclast-rich compared with osteoclast-poor regions was examined. Increased retention of the radioligand was observed in osteoclast-rich regions of juvenile rabbits and NHP but not in the adult monkey or adult ovariectomized rabbit. Target engagement of CatK was observed in blocking studies with MK-0674, and the radioligand retention was shown to be sensitive to the level of MK-0674 exposure. [11 C]L-235 can assess target engagement of CatK in bone only in juvenile animals. [11 C]L-235 may be a useful tool for guiding the discovery of CatK inhibitors.

Soccer injuries in children requiring trauma center admission.

BACKGROUND: Soccer continues to gain popularity among youth athletes, and increased numbers of children playing soccer can be expected to result in increased injuries. OBJECTIVE: We reviewed children with soccer injuries severe enough to require trauma activation at our Level I trauma center to determine injury patterns and outcome. Our goal is to raise awareness of the potential for injury in youth soccer. METHODS: A retrospective review was performed using the trauma registry and electronic medical records at a Level I trauma center to identify children (< 18 years old) treated for soccer injury from 1999-2009. Data reviewed include age, gender, mechanism, injury, procedures, and outcome. RESULTS: Eighty-one children treated for soccer injury were identified; 38 (47%) were male. Of these, 20 had injury severe enough to require trauma team activation and 61 had minor injury. Mean age was 14 years old (range 5-17 years, SD 2.3). Lower extremity was the most common site of injury (57%), followed by upper extremity (17%), head (16%), and torso (10%). Mechanisms were: kicked or kneed in 27 patients (33%), collision with another player in 25 (31%), fall in 18 (22%), struck by ball in 10 (12%), and unknown in 1 (1%). Procedures included reduction of fractures, splenectomy, abdominal abscess drainage, and surgical feeding access. Long hospitalizations were recorded in some cases. There were no deaths. CONCLUSION: Although less common, injury requiring prolonged hospital admission and invasive operative procedures exist in the expanding world of youth soccer. With increasing participation in the sport, we anticipate greater numbers of these child athletes presenting with serious injury.

The Correlation of Thyroid Hormone Levels and Anti-Thyroidal Drugs on Thyroid Size, Weight, and Ease of Surgical Dissection for Thyroidectomy for Graves' Disease.

BACKGROUND: Patients with Graves' Disease often have a larger thyroid size than patients without thyroid disease. These patients also have elevated T3 and T4 with decreased TSH. PURPOSE: We evaluate whether these thyroid labs, the use of antithyroid agents, or the size of a thyroid on ultrasound, correlate with the pathological size of a thyroid in patients who undergo total thyroidectomy for Graves' Disease. We further determine whether these parameters affect perioperative complications. RESEARCH DESIGN: A retrospective review of patients undergoing total thyroidectomy for Graves' Disease was performed from January 2004 to December 2016 in a single institution. STUDY SAMPLE: 392 patients were included in the study. DATA COLLECTION AND/OR ANALYSIS: Univariate analyses were performed to compare thyroid size on US and pathology as well as weight to preoperative thyroid hormone values and medical comorbidities. Spearman rank correlation and ANOVA were used to identify factors associated with thyroid weight, total pathology size, and differences in size. Multivariate analysis was also performed to evaluate for correlation between thyroid function and perioperative complications. RESULTS: We found that elevated pre-operative T3 levels were associated with larger pathologic size (P = .027) and a greater difference in pathology vs. US thyroid volumes (P = .005), but not increased thyroid weight (P = .286). No significant differences were found for thyroid weight, pathology size, or difference in size for TSH, T4, or any specific preoperative ATD given. Only postoperative calcium levels were found to be statistically significant for TSH < 0.27 (P = .024) for peri-operative complications. CONCLUSIONS: These findings may allow for more accurate preoperative planning and intraoperative expectations in patients with Graves' Disease.

Screening for Breast Cancer Risk: An Analysis of Under-recognized Risk Factors and Comparison of Interventions.

Recognition of patients at high risk (HR) for breast cancer allows earlier screening and opportunities for risk reduction. We compare patients referred to our breast clinic as HR vs referrals for other reason (ROR) and found to be HR. We evaluate under-recognized factors and treatment differences. A retrospective chart review of patients found to be HR but referred for any reason to our breast clinic from July 2012 to December 2022 was performed. Referral reason, demographics, hormonal history, family history, and other risk factors were evaluated and compared (HR vs ROR). While other risk models were used for screening, Gail and Tyrer-Cuzick version 7 (TCv7) were used for comparison. Breast imaging received, hormonal therapy, and genetics referral evaluations were compared. 195 patients were referred to our breast team, 113 (58%) were referred as HR while 82 (42%) were ROR. Average age was 47 years old. 175 (91%) were Caucasian. 74 (65.5%) were referred for genetic testing, and 32 (26%) tested positive for a genetic mutation (n = 10, 12% ROR). 67 (35%) were recommended chemoprevention (n = 32, 16.4% took chemoprevention). 6 (3.1%) underwent prophylactic mastectomies and 163 (85%) had supplemental breast imaging. Comparison of HR vs ROR did not show significant differences in hormonal factors or treatments received; however, TCv7 was higher in the group referred as HR (P < .001). Our study showed that HR patients are more commonly referred secondary to family history but undergo similar treatments as those ROR. Accessibility to screening tools and education of risk factors, especially in minorities and those not otherwise being screened, may help better recognize HR.

The Cedar Project: exploring the role of colonial harms and childhood maltreatment on HIV and hepatitis C infection in a cohort study involving young Indigenous people who use drugs in two Canadian cities.

OBJECTIVES: This study examined associations between childhood maltreatment, colonial harms and sex/drug-related risks for HIV and hepatitis C virus (HCV) infection among young Indigenous people who use drugs. DESIGN: The Cedar Project is a cohort involving young Indigenous people who use drugs in British Columbia (BC), Canada. Indigenous collaborators, collectively known as the Cedar Project Partnership, govern the entire research process. SETTING: Vancouver is a large city on the traditional territory of the Coast Salish peoples. Prince George is a mid-sized city, on the traditional territory of Lheidli T'enneh First Nation. PARTICIPANTS: 420 participants completed the Childhood Trauma Questionnaire and returned for follow-up from 2003 to 2016. PRIMARY/SECONDARY OUTCOME MEASURES: Primary outcomes were HIV and HCV infection over the study period. Secondary outcomes included sex and substance use-related risks. RESULTS: Prevalence of childhood maltreatment was 92.6% experienced any maltreatment; 73.4% experienced emotional abuse; 62.6% experienced physical abuse; 60.3% experienced sexual abuse; 69.5% experienced emotional neglect and 79.1% experienced physical neglect. We observed significant associations between childhood maltreatment and apprehensions into residential schools and foster care. All maltreatment types were associated with higher odds of sex/substance use-related risks; sexual abuse was associated with higher odds of HCV infection (adjusted OR: 1.67; 95% CI 1.05 to 2.66; p=0.031). CONCLUSIONS: Findings reflect high prevalence of childhood maltreatment and their associations with HIV/HCV risk and HCV infection. Public health prevention and treatment initiatives must be trauma informed and culturally safe to support healing, health, and well-being.

Smoking-related health risks among persons with HIV in the Strategies for Management of Antiretroviral Therapy clinical trial.

OBJECTIVES: We sought to determine smoking-related hazard ratios (HRs) and population-attributable risk percentage (PAR%) for serious clinical events and death among HIV-positive persons, whose smoking prevalence is higher than in the general population. METHODS: For 5472 HIV-infected persons enrolled from 33 countries in the Strategies for Management of Antiretroviral Therapy clinical trial, we evaluated the relationship between baseline smoking status and development of AIDS-related or serious non-AIDS events and overall mortality. RESULTS: Among all participants, 40.5% were current smokers and 24.8% were former smokers. Adjusted HRs were higher for current than for never smokers for overall mortality (2.4; P < .001), major cardiovascular disease (2.0; P = .002), non-AIDS cancer (1.8; P = .008), and bacterial pneumonia (2.3; P < .001). Adjusted HRs also were significantly higher for these outcomes among current than among former smokers. The PAR% for current versus former and never smokers combined was 24.3% for overall mortality, 25.3% for major cardiovascular disease, 30.6% for non-AIDS cancer, and 25.4% for bacterial pneumonia. CONCLUSIONS: Smoking contributes to substantial morbidity and mortality in this HIV-infected population. Providers should routinely integrate smoking cessation programs into HIV health care.

Exploring spirituality among youth in foster care: findings from the Casey Field Office Mental Health Study.

This study examined spiritual coping mechanisms, beliefs about spirituality and participation in spiritual activities and in other positive activities among adolescents in foster care. A multidimensional measure of spirituality was developed for face-to-face interviews with 188 youth (ages 14-17) from diverse racial/ethnic backgrounds in the United States. Findings revealed 95% of youth believe in God, over 70% believe God is 'creator' and God is 'love', and 79% considered prayer a spiritual practice. Most youth said love and forgiveness help them heal. Two-thirds (67%) reported responding to 'bad or tragic things happening' by spending time alone, and over half responded by praying (59%) or sharing the problem with someone else (56%). Youth's top three spiritual goals were to follow God's plan for them, become a better person, and know their purpose in life. Based on the value youth ascribed to spiritual coping mechanisms, recommendations for policy and practice focus on the integration of spirituality into practice and caregiving for youth in foster care.

Thyroidectomy Remains a Safe Option for Graves' Disease.

Total thyroidectomy (TT) or near-TT (NTT) is often recommended over medical management for the treatment of Graves' disease (GD). We assess the safety within surgical subspecialties at our institution for TT/NTT in GD patients. A retrospective review of patients undergoing TT/NTT for GD was performed from 2004 to 2016. Patient factors, thyroid size, surgeon subspecialty, and intraoperative/postoperative outcomes were all reviewed. Multivariate analyses were used to determine risk factors for complications. A total of 383 patients underwent TT/NTT. Two hundred thirty-three patients underwent TT/NTT by otolaryngology (n = 233, 60.8%), surgical oncology (n = 140, 36.6%), general surgery (n = 8, 2.1%), and unknown (n = 2, 0.5%). On multivariate analysis, surgical duration was longer for males (P = 0.001) and increased thyroid weights (P = 0.001). No association with hypocalcemia or recurrent laryngeal nerve paralysis was found with factors considered. No factors were found to be associated with the ability to identify the recurrent laryngeal nerve. Estimated blood loss (EBL) was increased in younger patients (0.010), males (P = 0.001), increased BMI (P = 0.012), and increased thyroid weight (P < 0.001). EBL was also associated with the physician performing the operation, where EBL was greatest for TT/NTT performed by general surgeons, followed by surgical oncologists and then by otolaryngology (P = 0.006). TT/NTT is safe and a reasonable option for the treatment of GD.

Adrenocortical carcinoma arising from an adrenal adenoma in a young adult female.

Adrenocortical carcinoma (ACC) is a rare malignancy that often carries a poor prognosis whereas adrenal incidentalomas are relatively common findings on imaging. Although most adrenal lesions are benign, 15% of patients with ACC are diagnosed based on workup for an adrenal incidentaloma. Continued surveillance or surgical resection may be recommended depending on size. The risk of a benign, non-functional adrenal lesion becoming malignant is low. Therefore, adrenal lesions typically undergo surveillance for no more than 2 years in patients with stable findings and no history of malignancy. This case describes a young adult female with a benign left adrenal adenoma who was found to have high grade ACC 7 years later. Based on interval size increase with indeterminate density, patient underwent surgical resection with adjuvant radiation and medical therapy.

Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons.

PURPOSE: To compare long-term virologic, immunologic, and clinical outcomes in antiretroviral-naïve persons starting efavirenz (EFV)- versus nevirapine (NVP)-based regimens. METHOD: The FIRST study randomized patients into three strategy arms: PI+NRTI, NNRTI+NRTI, and PI+NNRTI+NRTI. NNRTI was determined by optional randomization (NVP or EFV) or by choice. For this randomized substudy, the primary endpoint was HIV RNA >50 copies/mL after 8 months or death. Genotypic resistance testing was done at virologic failure (VF; HIV RNA >1,000 copies/mL at or after 4 months). RESULTS: 228 persons (111 randomized to EFV, 117 to NVP) were followed for median 5 years. Rates per 100 person years for the primary endpoint were 41.2 (EFV) and 42.8 (NVP; p = .59). The percent of persons with HIV RNA <50 copies/mL was similar throughout follow-up (p = .24), as were average increases in CD4+ cells (p = .30). 423 persons declining the substudy chose EFV; 264 chose NVP. There were 915 persons in the combined cohort (randomized and choice). In the combined cohort, the risk of VF and VF with any NNRTI or NRTI resistance or resistance of any class was significantly less for EFV compared to NVP. CONCLUSIONS: EFV-based regimens as initial therapy resulted in a lower risk of VF and VF with resistance than did NVP-based regimens, although immunologic and clinical outcomes were similar.

A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial.

BACKGROUND: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. METHODS: Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922. FINDINGS: 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001). INTERPRETATION: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.

The Incidence of HIV drug resistance and its impact on progression of HIV disease among antiretroviral-naïve participants started on three different antiretroviral therapy strategies.

BACKGROUND: Treatment-naïve participants were randomized to three antiretroviral strategies (all with nucleoside reverse transcriptase inhibitor [NRTI] background): protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or PI+NNRTI. The strategies were compared for drug resistance at first virologic failure (VF; HIV RNA >1000 copies/mL). The impact of resistance on AIDS or death was determined. METHOD: Drug resistance was determined by genotype. Cox models were used to compare the strategies for VF with resistance and to determine the impact of resistance on AIDS or death. RESULTS: Of 1,360 participants, 866 experienced VF; 226 experienced AIDS or death (median follow-up 5 years). Rates (per 100 personyears) for VF with resistance were 14.9 (PI), 10.8 (NNRTI), and 11.5 (PI+NNRTI); hazard ratio (HR) was 0.78 (95% CI 0.61-0.99) for NNRTI versus PI. Compared to those with no VF, there was a significantly increased risk of AIDS or death for participants with solitary NNRTI resistance (HR 2.31, 95% CI 1.46-3.66) and for those failing with no known resistance (HR 1.78, 95% CI 1.18-2.68). Participants failing with solitary NNRTI resistance and with no resistance had the lowest percent of time on antiretroviral treatment (ART) and the lowest cumulative mean adherence scores. CONCLUSION: For treatment-naïve participants, the risk of AIDS or death is increased for those who failed virologically with solitary NNRTI resistance and those who failed with no known drug resistance compared to those with no virologic failure. Both the lack of ART exposure in nonadherent participants and the development of NNRTI resistance among those who take and fail their ART regimen predict poor clinical outcomes.

Acupuncture and Cutaneous Medicine: Is It Effective?

Background: In China, acupuncture has been used as a form of medical therapy for more than 2500 years. It is a part of traditional medical practice and is used to treat the entire spectrum of human and veterinary disease. Although dermatologic disease has received much less attention in worldwide acupuncture research than pain and musculoskeletal conditions, there is a growing body of evidence suggesting acupuncture's usefulness in this area. Objective: The aim of this article was to review the evidence in the literature regarding the usefulness of acupuncture in managing dermatologic illness. Results: Trials and case reports of patients using acupuncture have been published in the areas of atopic dermatitis and urticaria, herpes zoster, psoriasis, acne, melasma, and hyperhidrosis, as well as in promoting wound healing. Itch modulation by acupuncture has been the focus of recent research as itch is a predominant symptom in allergic skin diseases and leads to serious impairment of quality of life. Conclusions: Although more research is needed, acupuncture's use in cutaneous medicine is promising in the area of itch modulation, in treating atopic dermatitis and herpes zoster pain, and in promoting wound healing.

Reducing False-Positive HIV Diagnosis in Niger: A Women's Issue.

The entry into both HIV care and secondary prevention is first through the knowledge of one's own HIV status. Testing for HIV remains challenging in countries where clinicians rely on rapid testing algorithms because the routine use of confirmatory Western blot technology is unavailable. In this case report, we describe the case of a pregnant woman in Niger, who was falsely labeled as HIV positive during prenatal visits. We also describe our clinical algorithm that was developed to facilitate retesting in patients who initially tested HIV positive or indeterminant with rapid diagnostic tests. Vigilance is necessary to ensure that appropriate identification and treatment of HIV is provided to reduce mother-to-child transmission of HIV, to appropriately allocate resources, and to avoid falsely labeling patients with HIV.

Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy.

BACKGROUND: The prevalence of drug resistance among persons with newly acquired human immunodeficiency virus (HIV) infection is well documented. However, it is unclear to what extent these mutations persist in chronically infected, treatment-naive patients. METHODS: Prevalence of and factors associated with genotypic drug resistance were analyzed retrospectively in a subset of 491 chronically HIV-infected, antiretroviral-naive patients enrolled at 25 cities in the Terry Beirn Community Programs for Clinical Research on Acquired Immune Deficiency Syndrome (AIDS) Flexible Initial Retrovirus Suppressive Therapies trial during 1999-2001. Resistance was defined on the basis of the International AIDS Society 2003 definition, as well as the presence of additional mutations at codons 215 (C/D/E/S) and 69 (A/N/S) in the pol gene. Prevalence of mutations was estimated by use of techniques for stratified random samples. Logistic regression models were used to determine factors associated with resistance. RESULTS: Among the 491 chronically HIV-infected patients (mean CD4 cell count, 269 cells/mm(3); 31% of patients had a prior AIDS diagnosis), 57 (11.6%) had >or=1 resistance mutation, resulting in an estimated prevalence for the cohort of 10.8% (95% confidence interval [CI], 9.5%-12.1%). The prevalence was 8.8% if the 118I mutation was excluded. By drug class, the estimated prevalence of mutations conferring resistance to nucleoside reverse-transcriptase inhibitors was 7.8%, and the prevalence was 3.0% for nonnucleoside reverse-transcriptase inhibitors and 0.7% for protease inhibitors. In a multiple logistic regression analysis, non-Hispanic white subjects were twice as likely than African American subjects to have resistance (odds ratio [OR], 2.1; 95% CI, 1.1-4.1; P=.03), and there was a 40% increase per year in prevalence of mutations by later year of enrollment (OR, 1.4; 95% CI, 1.0-2.1; P=.05). CONCLUSIONS: These results demonstrate the persistence of drug resistance mutations in chronically HIV-infected patients and an increasing prevalence of resistance over time, and they support genotyping of virus at baseline for chronically HIV-infected patients.

Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study.

PURPOSE: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. PATIENTS AND METHODS: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. RESULTS: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (< or = 1 microg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses > or = 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. CONCLUSION: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.