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Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488–97. ©2016 AACR.

Figure S1. Mouse characteristics prior to tumor injection and at time of sacrifice. Figure S2.Mouse physiology following EE Figure S3. Overexpressing BDNF in the hypothalamus mimics EE's effects on T cells. Figure S4. Knockdown BDNF in the hypothalamus blocks EE's effects.

Background Complex facial wounds can be difficult to stabilize due to proximity of vital structures. We present a case in which a patient-specific wound splint was manufactured using computer assisted design and three-dimensional printing at the point-of-care to allow for wound stabilization in the setting of hemifacial necrotizing fasciitis. We also describe the process and implementation of the United States Food and Drug Administration Expanded Access for Medical Devices Emergency Use mechanism. Case presentation A 58-year-old female presented with necrotizing fasciitis of the neck and hemiface. After multiple debridements, she remained critically ill with poor vascularity of tissue in the wound bed and no evidence of healthy granulation tissue and concern for additional breakdown towards the right orbit, mediastinum, and pretracheal soft tissues, precluding tracheostomy placement despite prolonged intubation. A negative pressure wound vacuum was considered for improved healing, but proximity to the eye raised concern for vision loss due to traction injury. As a solution, under the Food and Drug Administration’s Expanded Access for Medical Devices Emergency Use mechanism, we designed a three-dimensional printed, patient-specific silicone wound splint from a CT scan, allowing the wound vacuum to be secured to the splint rather than the eyelid. After 5 days of splint-assisted vacuum therapy, the wound bed stabilized with no residual purulence and developed healthy granulation tissue, without injury to the eye or lower lid. With continued vacuum therapy, the wound contracted to allow for safe tracheostomy placement, ventilator liberation, oral intake, and hemifacial reconstruction with a myofascial pectoralis muscle flap and a paramedian forehead flap 1 month later. She was eventually decannulated and at six-month follow-up has excellent wound healing and periorbital function. Conclusions Patient-specific, three-dimensional printing is an innovative solution that can facilitate safe placement of negative pressure wound therapy adjacent to delicate structures. This report also demonstrates feasibility of point-of-care manufacturing of customized devices for optimizing complex wound management in the head and neck, and describes successful use of the United States Food and Drug Administration’s Expanded Access for Medical Devices Emergency Use mechanism.

Previous studies examining changes in central sleep apnea (CSA) following adenotonsillectomy (TA) performed for obstructive sleep apnea (OSA) in children have been limited by sample size and analysis of only certain populations. The aim of this study was to determine whether CSA improves following TA and what factors mediate this change.This was a retrospective case series from 1994 to 2020 of children undergoing primary TA for OSA (obstructive apnea-hypopnea index ≥1) with CSA (central apnea index [CAI] ≥1) and preoperative and postoperative polysomnograms within 12 months of TA. Polysomnograms were analyzed for improvement in CSA, defined as: 1) if preoperative CAI5, a postoperative CAI5; or 2) if preoperative CAI5, a postoperative CAI1.One hundred twenty-three patients were included. Median age was 5.5 years (interquartile range, 2.9-8.4). Most patients were overweight/obese (58.5%). Nineteen (15.4%) had a syndromic condition. Preoperative CAI was ≥5 in 21 (17.1%) patients. CAI significantly decreased following TA (preoperative 2.1, postoperative 0.4; P .001). Thirty-two (26.0%) patients had CSA postoperatively. Improvement in the microarousal index and older age were significantly associated with improvement in CSA.TA led to resolution of CSA in most children with OSA. Improvement in the microarousal index was associated with improvement in CAI, suggesting that preoperative central apneas may be postarousal and thus resolve following TA.4 Laryngoscope, 132:478-484, 2022.

Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic β-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.

The association between patients’ confidence in their ability to attend appointments and future retention in care has not previously been studied in a general HIV clinic. A survey of potential and known risk factors for poor retention was developed using validated screening tools and administered to 105 patients at an HIV clinic. Retention in care was assessed prospectively using two definitions: (1) two appointments at least three months apart within one year (“HRSA/HAB retention”) and (2) no missed appointments within one year (“missed visits retention”). Most patients were African American (86%) and male (59%). Although most patients were confident they could keep their HIV appointments (89%), fewer were retained (HRSA/HAB: 73%; missed visits: 56%). Patients’ confidence in their ability to keep future appointments was not associated with retention. Employment was associated with lower odds of HRSA/HAB retention (aOR 0.26 [95% CI 0.09–0.77]), and childcare was a common barrier that was associated with lower odds of missed visits retention (aOR 0.06 [95% CI 0.006–0.62]). Other known risk factors for poor retention were inconsistently associated with retention in care.

Objective: Surgery on the ossicular chain may impact its underlying mechanical properties. This study aims to investigate comparative differences in frequency-specific hearing outcomes for ossiculoplasty versus stapedotomy. Methods: A retrospective chart review was conducted on subjects who underwent ossiculoplasty with partial ossicular replacement prosthesis (PORP) or laser stapedotomy with self-crimping nitinol/fluoroplastic piston, and achieved closure of postoperative pure tone average air-bone gap (PTA-ABG) ≤ 15 dB. 45 PORP and 38 stapedotomy cases were included, with mean length of follow-up of 7.6 months. Results: The mean change in PTA-ABG was similar for the 2 procedures (−17.9 dB vs −18.1 dB, P = .98). Postoperative ABG closure for stapedotomy was superior at 1000 Hz (8.9 dB vs 13.9 dB, P = .0003) and 4000 Hz (11.8 dB vs 18.0 dB, P = .0073). Both procedures also had improved postoperative bone conduction (BC) thresholds at nearly all frequencies, but there was no statistical difference in the change in BC at any particular frequency between the 2 procedures. Conclusion: Both procedures achieved a similar mean change in PTA-ABG. Stapedotomy was superior to PORP at ABG closure at 1000 Hz and at 4000 Hz, with 1000 Hz the most discrepant. The exact mechanism responsible for these changes is unclear, but the specific frequencies affected suggest that differences in each procedure’s respective impact on the native resonant frequency and mass load of the system could be implicated.

OBJECTIVE To assess the usefulness of numeric grading scales of middle ear risk in predicting ossiculoplasty hearing outcomes. STUDY DESIGN Retrospective review. SETTING Tertiary care, academic medical center. PATIENTS Adults and children undergoing ossiculoplasty between May 2013 and May 2019 including: synthetic ossicular replacement prosthesis, autograft interposition, bone cement repair, and mobilization of lateral chain fixation. INTERVENTION Cases were scored via middle ear risk index (MERI), surgical prosthetic infection tissue eustachian tube (SPITE) method, and ossiculoplasty outcome scoring parameter (OOPS) scale. Preoperative and postoperative hearing outcomes were recorded. MAIN OUTCOME MEASURE Statistical correlation between risk score and postoperative pure-tone average air-bone gap (PTA-ABG). RESULTS The 179 included cases had average pre and postoperative PTA-ABGs of 30.3dB (standard deviation [SD] 12.7) and 20.3dB (SD 11.1), respectively. Mean MERI, SPITE, and OOPS scores were 4.5 (SD 2.3), 2.8 (SD 1.7), and 3.1 (SD 1.8), respectively. Statistically significant correlations with hearing outcome were noted for all three methods (MERI r = 0.22, p = 0.003; OOPS r = 0.19, p = 0.012; SPITE r = 0.27, p 30dB) outcomes; only low SPITE scores predicted excellent (PTA-ABG < 10dB) outcomes (odds ratio [OR] 0.74 [Confidence Interval: 0.57 - 0.97], p = 0.032). CONCLUSIONS Significant weak correlations between each middle ear risk score and hearing outcomes were encountered. Although only the SPITE method predicted postoperative PTA-ABG, it was not overwhelmingly superior. Current grading scale selection may be justified by familiarity or ease of use.

PURPOSE: We aimed to assess the association between complication rate and time to feeding in a cohort of patients undergoing radiologically guided placement of gastrostomy tubes. METHODS: A retrospective study was conducted of all patients receiving pull-type and push-type gastrostomy tubes placed by interventional radiologists between January 1(st), 2017 and December 31(st), 2018 at a single institution. Primary outcomes included procedural and tube-related complications per medical chart review with a follow-up interval of 30 days. Exclusion criteria were enteral nutrition delayed more than 48 hours, no feeding information, and tubes placed for venting (n=20). Overall, 303 gastrostomy tubes (pull-type, n=184; push-type, n=119) were included. The most common indications for placement included head and neck carcinoma for push-type tubes (n=76, 63.9%) and cerebral vascular accident for pull-type tubes (n=78, 42.4%). RESULTS: In a multiple regression analysis, there was no statistically significant association between complications and time to feeding (p = 0.096), age (p = 0.758), gender (p = 0.127), indication for tube placement (p = 0.206), or type of tube placed (p = 0.437). Average time to initiation of enteral nutrition was 12.3 hours for the pull-type and 21.7 hours for the push-type cohort (p < 0.001). Additional multiple regression analyses of pull-type tubes and push-type tubes separately also did not find any significant association between complications and the above factors (p > 0.05). CONCLUSION: There was no statistically significant correlation between time to feed and complications, suggesting that there is no clinical difference between early and late feeding following gastrostomy tube placement.

Creating visual art to teach and learn histologic concepts is uncommon. A pilot visual art program was developed for use in first-year medical student courses that include histology with the hypothesis that creating visual art would subjectively improve the learning process and lead to learner-based personal incorporation of art into in future learning. Prior to the term, volunteers (n=25) were recruited from 89 first-year medical students. The volunteer group was given art supplies and encouraged to draw histologic images in a free-form setting without restrictions. The control group (n=64) consisted of non-volunteers. Pre- and post-term surveys were distributed to all students, of which 72% and 45% completed the surveys, respectively. Regardless of participation, a majority of students viewed art as a valuable tool to learn medicine prior to and following the term (73% and 82.5%, respectively), however less than half admitted to using art to learn medical concepts (42% and 40%, respectively). In the post-term survey, a higher percentage of students in the experimental group stated they will use art to learn medical concepts in the future (75% vs 40.6%). Most students considered art to be a valuable resource to learn concepts in medicine, including all the students who participated in the art program. Based on the number of students who reported intent to change behavior, the initial hypothesis is supported. Many students favor incorporation of visual art into medical education, we believe that creating visual art may be a worthwhile adjunct tool for histology education.

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488–97. ©2016 AACR.

Environmental and social factors have profound impacts on immune homeostasis. Our work on environmental enrichment (EE) has revealed a novel anti-obesity and anticancer phenotype associated with enhanced activity of CD8+ cytotoxic T lymphocytes in secondary lymphoid tissues. Here we investigated how an EE modulated thymus and thymocyte development. EE decreased thymus mass and cellularity, decreased the double positive thymocyte population, increased the proportion of CD8+ T cells, reduced the CD4:CD8 ratio, and downregulated CD69 expression in T cells. In a model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE), EE alleviated symptoms, inhibited spinal cord inflammation through regulation of type 1 T-helper cells mediated by glucocorticoid receptor signaling, and prevented EAE-induced thymic disturbance. Our mechanistic studies demonstrated that hypothalamic BDNF activated a hypothalamic-pituitary-adrenal axis mediating the EE’s thymic effects. Our results indicate that a lifestyle intervention links the nervous, endocrine, and adaptive immune system, allowing the body to adapt to internal and external environments.

Obesity leads to a switch in subsets of CD4+ T cell in adipose tissue, characterized by an increase in IFNγ producing Th1 cells and a decrease in anti-inflammatory regulatory T (Treg) cells, which impairs systemic insulin sensitivity. What signals these changes is unknown. Herein we demonstrate that genetic deficiency of adipocyte MHCII decreases adipose IFNγ expression and increases adipose Treg abundance in obese mice, leading to reduced obesity-induced adipose inflammation and reduced insulin resistance without affecting weight gain. The preserved insulin sensitivity of high fat diet (HFD)-fed adipocyte-specific MHCII knockout (aMHCII−/−) mice was substantially attenuated by adipose-specific Treg ablation. Adipocytes of aMHCII−/− mice exhibit decreased capacity to stimulate IFNγ production in Th1 cells, whereas HFD-fed IFNγR1−/− mice were more insulin sensitive and had similarly high levels of Tregs in adipose tissue as aMHCII−/− mice. We further show that IFNγ strongly inhibits IL-33 effects to promote adipose Treg proliferation. Our results identify MHCII in adipocyte as a critical determinant of the obesity-induced adipose T cell subset switch and insulin resistance., Obesity is associated with inflammation in adipose tissue, characterized by a shift in local T cell subsets. Here the authors show that loss of MHCII expression on adipocytes increases levels of immunosuppressive regulatory T cells in adipose tissue, which enhances insulin sensitivity.