Incidence of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents.

This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality.

Fatty aldehyde bisulfite adducts as a purification handle in ionizable lipid synthesis.

Rapid access to ALC-0315, a crucial component of the formulated Pfizer Covid vaccine, was obtained by employing solid adduct formation and filtration after an oxidation step in place of the standard chromatographic separation, allowing for a more scalable synthesis. Impurities were removed by formation of this fatty aldehyde bisulfite adduct at the penultimate step and by performing the final reductive amination directly with the fatty aldehyde bisulfite adduct. This eliminates chromatographic separations for all prepared aldehyde containing intermediates. Along with ALC-0315, FTT5 and SM-102 ionizable lipids were prepared utilizing this strategy. This work paves the way for more sustainable access to these critical ionizable lipids that would de-risk the world supply of important vaccines and medicines in the future.

Core outcomes in nerve surgery: development of a core outcome set for common peroneal (fibular) neuropathy.

OBJECTIVE: Common peroneal (fibular) neuropathy is the most common mononeuropathy of the lower extremity. Despite this, there are surprisingly few studies on the topic, and a knowledge gap remains in the literature. As one attempts to address this knowledge gap, a core outcome set (COS) is needed to guide the planning phases of future studies to allow synthesis and comparability of these studies. The objective of this study was to develop the COS-common peroneal neuropathy (CoPe) using a modified Delphi approach. METHODS: A 5-stage approach was used to develop the COS-CoPe: 1) stage 1, consortium development; 2) stage 2, a literature review to identify potential outcome measures; 3) stage 3, a Delphi survey to develop consensus on outcomes for inclusion; 4) stage 4, a Delphi survey to develop definitions; and 5) stage 5, a consensus meeting to finalize COS and definitions. The study followed the COS-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. The final COS-CoPe consisted of 31 data points/outcomes covering domains of demographics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 12 months. The consensus optimal time points for assessment were preoperatively and 3, 6, 12, and 24 months postoperatively. CONCLUSIONS: The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-CoPe should serve as a minimum set of data that should be collected in all future neurosurgical studies on common peroneal neuropathy. Incorporation of this COS should help improve consistency in reporting, data synthesis, and comparability, and should minimize outcome reporting bias.

Palmoplantar Pustulosis: Therapy Update

Palmoplantar pustulosis is a variant of psoriasis and a chronic skin disorder in which pruritic pustular eruptions appear on the palms and soles. It is thought to arise from a variety of genetic and environmental factors, is limited in prevalence, and has proven quite difficult to treat. The symptoms it inflicts on those affected are quite debilitating and the treatment landscape is constantly evolving, thus emphasizing the need for updates of the literature as time passes. Current treatments include topical agents, oral therapies, and phototherapy, amongst other treatments. In this systemic review, we explore newer literature from 2015 to 2022 on various treatment regimens for palmoplantar pustulosis. J Drugs Dermatol. 2024;23(8):626-631.     doi:10.36849/JDD.doi:10.36849/7612R1.

Predictors of Patient-Reported Outcomes After Hyaluronic Acid Injections: Effect of Expectations and Psychological Stress.

INTRODUCTION: Hyaluronic acid (HA) injections are a common nonsurgical treatment of knee osteoarthritis (OA). Patient expectations and psychological stress are believed to affect outcomes after orthopaedic procedures. METHODS: This was a prospective cohort study seeking to identify factors predictive of greater patient-reported outcomes after HA injections, particularly expectations and psychological stress. 250 patients receiving a series of HA injections for knee OA were enrolled, with 196 being included for analysis. Demographics, surgical history, and preoperative Kellgren-Lawrence severity scores were collected, and patients completed the Knee Osteoarthritis Outcome Score (KOOS) questionnaire, a modified KOOS questionnaire assessing their 6-month postinjection expectations, and the Perceived Stress Scale before the first injection. Outcomes were assessed at 3 weeks and 3 and 6 months after the final injection. RESULTS: KOOS scores improved from preinjection to 6-month follow-up but did not meet patients' expectations or minimal clinically important difference. Expectations correlated with 6-month KOOS pain, activities of daily living, sport, and quality of life subscales (ρ = 0.19 to 0.34), but not the symptom subscale (P = 0.10). Expectations (ρ = 0.31 to 0.37), younger age (ρ = -0.17 to -0.18), and greater perceived stress (ρ = 0.23) correlated with greater improvement from baseline KOOSs. Lower body mass index (ρ = -0.19 to -0.22), male sex (ρ = -0.17), and greater preinjection function (ρ = 0.37 to 0.46) correlated with greater 6-month outcomes. Stress measured on the Perceived Stress Scale did not correlate with 6-month KOOSs (P ≥ 0.27). Lower Kellgren-Lawrence severity score was weakly associated with greater 6-month KOOS activities of daily living and sport scores (ρ = -0.15 to -0.16) and greater improvement in the KOOS symptom score (ρ = -0.15). DISCUSSION: This study identified that higher expectations, lower body mass index, younger age, male sex, lower radiographic severity, greater preinjection function, and greater perceived stress are associated with greater patient outcomes after HA injection. Physicians should consider these factors when counseling patients with knee OA about viscosupplementation. STUDY TYPE: Prospective Cohort Study (Level of Evidence II).

3D modeling of anterior 2/3rds glossectomy reconstruction: A volume based donor site evaluation.

OBJECTIVE: Anterior 2/3rds glossectomy results in significant patient morbidity due to speech and swallowing impairment. Microvascular free flap reconstruction compensates for large volume defects. Flap volume is based on the adipose content of the donor site and varies by patient body mass index (BMI) and donor site location. We sought to correlate flap thickness at different donor sites with patient BMI to determine optimal donor site selection. METHODS: Patients with CT scans of the oral cavity, thorax and lower extremity were identified and included. The volumes of the anterior 2/3rds of the tongue were measured and recorded using computed tomography-generated modeling. Pre-muscular tissue thicknesses at anterolateral thigh (ALT), deep inferior epigastric artery (DIEP), latissimus dorsi, and parascapular donor sites were measured. The donor site adequency was defined as reconstructing the tongue volume within 10% of the ideal volume required and stratified based on patient BMI. RESULTS: In 144 patients, the average anterior 2/3rds glossectomy defect was 100.3 cm3. Glossectomy defect size was highly correlated with BMI (p < 0.001). The DIEP flap had the largest volume (155.4 cm3), followed by latissimus (105.6 cm3), parascapula (97.8 cm3), and ALT (60.5 cm3). For patients with BMI ≤ 30, the DIEP flap best reconstructed native tongue volume (up to 113 % of native tongue volume). In patients with BMI > 30.1, native tongue volumes were approximated by the latissimus flap (89-92 % of native tongue) and parascapular flap (85-95 % of native tongue volume). In BMI > 30.1 the DIEP flap provided excess tissue bulk (129-135 % of native tongue volume). CONCLUSION: The DIEP flap more closely approximates the volume needed to reconstruct anterior two-thirds tongue defects for BMIs ≤ 30. The subscapular system flaps provided the best volume match for BMIs > 30 and the DIEP flap provided excess tissue bulk which could be adjusted in the reconstruction process.

The Impact of SIV-Induced Immunodeficiency on SARS-CoV-2 Disease, Viral Dynamics, and Antiviral Immune Response in a Nonhuman Primate Model of Coinfection.

The effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. In this pilot study, we exposed two pigtail macaques (PTMs) chronically infected with SIVmac239, exhibiting from very low to no CD4 T cells across all compartments, to SARS-CoV-2. We monitored the disease progression, viral replication, and evolution, and compared these outcomes with SIV-naïve PTMs infected with SARS-CoV-2. No overt signs of COVID-19 disease were observed in either animal, and the SARS-CoV-2 viral kinetics and evolution in the SIVmac239 PTMs were indistinguishable from those in the SIV-naïve PTMs in all sampled mucosal sites. However, the single-cell RNA sequencing of bronchoalveolar lavage cells revealed an infiltration of functionally inert monocytes after SARS-CoV-2 infection. Critically, neither of the SIV-infected PTMs mounted detectable anti-SARS-CoV-2 T-cell responses nor anti-SARS-CoV-2 binding or neutralizing antibodies. Thus, HIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants but may remove the ability of infected individuals to mount adaptive immune responses against SARS-CoV-2.

BATF2 is a regulator of interferon-γ signaling in astrocytes during neuroinflammation.

Astrocytic interferon (IFN)γ signaling is associated with a reduction in neuroinflammation. We have previously shown that the benefits of astrocytic IFNγ arise from a variety of mechanisms; however, downstream effectors responsible for regulating this protection are unknown. We address this by identifying a specific transcription factor that may play a key role in modulating the consequences of IFNγ signaling. RNA-sequencing of primary human astrocytes treated with IFNγ revealed basic leucine zipper ATF-like transcription factor ( BATF )2 as a highly expressed interferon-specific gene. Primarily studied in the periphery, BATF2 has been shown to exert both inflammatory and protective functions; however, its function in the central nervous system (CNS) is unknown. Here, we demonstrate that human spinal cord astrocytes upregulate BATF2 transcript and protein in an IFNγ-specific manner. Additionally, we found that BATF2 prevents overexpression of interferon regulatory factor (IRF)1 and IRF1 targets such as Caspase-1, which are known downstream pro-inflammatory mediators. We also show that Batf2 -/- mice exhibit exacerbated clinical disease severity in a murine model of CNS autoimmunity, characterized by an increase in both CNS immune cell infiltration and demyelination. Batf2 -/- mice also exhibit increased astrocyte-specific expression of IRF1 and Caspase-1, suggesting an amplified interferon response in vivo . Further, we demonstrate that BATF2 is expressed primarily in astrocytes in MS lesions and that this expression is co-localized with IRF1. Collectively, our results further support a protective role for IFNγ and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation.

Patient proximity to follow-up care after bariatric surgery: Does it matter?

One factor that may play a significant role in the follow-up care compliance and long-term weight loss of post-bariatric surgery patients is the geographical distance from the surgery center to the patient's home address. This is a retrospective review which aims to evaluate whether the distance from a patient's home address to two Gundersen Health System (GHS) facilities (La Crosse and Onalaska, Wisconsin) is predictive of follow-up appointment compliance and subsequent long-term weight loss. 1336 patients undergoing bariatric surgery at GHS between October 15, 2013 and Dec 31, 2022 were included. Patients were grouped according to the distance between their home addresses and GHS with 60 â€‹% of patients living less than 30 miles from GHS, 33 â€‹% living 30 to 60 miles from GHS, and the remaining 7.3 â€‹% living >60 miles away. No significant difference was observed in the distribution of patients falling short, meeting, or exceeding the recommended number of post-operative appointments with a surgery provider based on proximity (p â€‹= â€‹0.10). As distance increased, the number of nutrition and behavioral health appointments completed per year decreased [nutrition/dietary appointments (p â€‹= â€‹0.046); behavioral health appointments (p â€‹= â€‹0.040)]. The pattern of percent excess weight loss (%EWL) over time was significantly different based on distance from home (p â€‹< â€‹0.001). Specifically, we found a similar %EWL among all groups in the first year post-operatively but an 18.8 â€‹% higher %EWL in the >60-mile group compared to the <60-mile group at 5 years (SE â€‹= â€‹5.4, P â€‹= â€‹0.0014). The lower number of post-op nutrition and behavioral health visits among patients living farther from the surgery center was an expected result, given potentially greater inconvenience of follow-up appointments for these patients. However, there was a paradoxical finding of significantly increased %EWL among patients living >60 miles from the surgery center. Greater distance from the bariatric surgical center was therefore not found to represent a barrier to favorable weight loss outcomes.

Trajectories of Housing Insecurity From Infancy to Adolescence and Adolescent Health Outcomes.

BACKGROUND AND OBJECTIVES: Housing insecurity is associated with adverse effects on child growth and development cross-sectionally; less is known about its cumulative, long-term effects. This study describes longitudinal experiences of housing insecurity during childhood from infancy (age 1 year) to adolescence (age 15 years) and examines their associations with adolescent health outcomes. METHODS: Using data from the Future of Families and Child Wellbeing Study, we created a composite measure of housing insecurity using 5 indicators (eg, skipping a rent or mortgage payment, eviction) for participants at ages 1, 3, 5, 9, and 15 years. We used group-based trajectory modeling to identify distinct patterns of housing insecurity, sociodemographic predictors of these patterns, and how these patterns relate to adolescent health outcomes. RESULTS: We identified 3 trajectories of housing insecurity from infancy to adolescence: secure, moderately insecure, and highly insecure. Adolescents who experienced moderately and highly insecure housing had decreased odds of excellent health (adjusted odds ratio, 0.81; 95% confidence interval [CI], 0.69-0.95; adjusted odds ratio, 0.67; 95% CI, 0.50-0.92, respectively) and more depressive symptoms (adjusted incidence rate ratio, 1.05; 95% CI, 1.02-1.08; 1.13; 95% CI, 1.08-1.19, respectively) than adolescents with secure housing. Adolescents who experienced highly insecure housing reported significantly higher anxiety symptoms (adjusted incidence rate ratio, 1.05; 95% CI, 1.003-1.113). CONCLUSIONS: Housing insecurity starting in infancy was associated with poorer adolescent health outcomes. These longitudinal patterns emphasize the need for novel screening mechanisms to identify housing insecurity when it emerges, as well as policies to prevent housing insecurity and its associated health outcomes.

Impact of Bariatric Surgery on Asthma Severity and Medication Use.

INTRODUCTION: Bariatric surgery improves many obesity-related comorbidities, yet the literature remains inconclusive on the impact of bariatric surgery on asthma. Our primary objective was to identify the long-term impact of bariatric surgery on asthma severity and medication use. METHODS: A retrospective review was completed of all patients with a diagnosis of asthma who underwent bariatric surgery over 10 years at a single institution. Primary outcomes were the number of asthma medications prescribed at five time points (preoperative, postoperative < 18 months, 19-36 months, 37-60 months, 60 + months) after bariatric surgery. Secondary outcomes were spirometry results and BMI. RESULTS: There were 260 patients with 84.6% female predominance. There were 168 sleeve gastrectomy patients and 92 Roux-en-Y gastric bypass patients. Mean age was 47.6 ± 10.7 years, mean BMI was 46.0 ± 6.8 kg/m2, and 54.2% were previous tobacco users. The total number of patients on two or more asthma medications decreased from 46% preoperatively to 41% at 18 months, to 36% at 36 months, and to 32% at 60 months after surgery. The total number of patients free from asthma medication increased from 25% preoperatively to 33% at 60 months postoperatively. Asthma medication use decreased in both surgery groups, and neither operation demonstrated superiority. No significant improvement nor differences were found between groups at any time point regarding FEV1/FVC ratio spirometry measures. CONCLUSION: Bariatric surgery reduces the use of medications taken for management of asthma. The amount of asthma medication usage decreases with time and is sustained at 60 months after bariatric surgery.

Reduction in ACE2 expression in peripheral blood mononuclear cells during COVID-19 - implications for post COVID-19 conditions.

BACKGROUND: Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC). METHODS: The IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10. RESULTS: Forty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals. CONCLUSIONS: This work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.

Long-term outcomes in virtual surgical planning for mandibular reconstruction: A cost-effectiveness analysis.

OBJECTIVE: This study is an economic evaluation comparing virtual surgical planning (VSP) utilization to free hand mandibular reconstruction (FHR) for advanced oral cavity cancer, for which the cost effectiveness remains poorly understood. The proposed clinical benefits of VSP must be weighed against the additional upfront costs. METHODS: A Markov decision analysis model was created for VSP and FHR based on literature review and institutional data over a 35-year time horizon. Model parameters were derived and averaged from systematic review and institutional experience. VSP cost and surgical time saving was incorporated. We accounted for long-term risks including cancer recurrence and hardware failure/exposure. We calculated cost in US dollars and effectiveness in quality-adjusted-life-years (QALYs). A health care perspective was adopted, discounting costs and effectiveness at 3%/year. Deterministic and probabilistic sensitivity analyses tested model robustness. RESULTS: In the base case scenario, total VSP strategy cost was $49,498 with 8.37 QALYs gained while FHR cost was $42,478 with 8.27 QALY gained. An incremental cost-effectiveness ratio (ICER), or the difference in cost/difference in effectiveness, for VSP was calculated at $68,382/QALY gained. VSP strategy favorability was sensitive to variations of patient age at diagnosis and institutional VSP cost with one-way sensitivity analysis. VSP was less economically favorable for patients >75.5 years of age or for institutional VSP costs >$10,745. In a probabilistic sensitivity analysis, 55% of iterations demonstrated an ICER value below a $100,000/QALY threshold. CONCLUSIONS/RELEVANCE: VSP is economically favorable compared to FHR in patients requiring mandibular reconstruction for advanced oral cancer, but these results are sensitive to the patient's age at diagnosis and the institutional VSP cost. Our results do not suggest if one "should or should not" use VSP, rather, emphasizes the need for patient selection regarding which patients would most benefit from VSP when evaluating quality of life and long-term complications. Further studies are necessary to demonstrate improved long-term risk for hardware failure/exposure in VSP compared to FHR.

Initiatives to improve lung and sleep health in children: Delphi consensus from the pediatrics, pulmonary, and sleep conference.

BACKGROUND AND OBJECTIVES: The lung and sleep health of adults is heavily influenced by early factors, both genetic and environmental; therefore, optimizing respiratory health begins in childhood. Multiple barriers impede improvements in lung and sleep health for children. First, the traditional siloing between general pediatric care in the community, pediatric pulmonary and sleep subspecialty care, and the research community limits the translation of knowledge into practice. Additionally, identifying and addressing health disparities remains a challenge. The 2021 NHLBI-sponsored workshop "Defining and Promoting Pediatric Pulmonary Health (DAP3H)" was a first step in defining critical gaps in our current healthcare system in identifying and optimizing lung and sleep health in children. The workshop identified key opportunities including measuring pulmonary function in young children, sleep-focused outcomes, developing biomarkers, and longitudinal research cohorts. To expand on the work of DAP3H and continue initiatives to improve childhood lung and sleep health, the Pediatrics & Pulmonary Network: Improving Health Together conference was held in 2023. STUDY DESIGN: A modified Delphi process was applied to form consensus surrounding gaps, barriers, and action items, with the goal of identifying the most urgent opportnities for improving childhood lung and sleep health. RESULTS: Cross-cutting foundational principles were identified as: (1) Authentic Stakeholder Collaboration & Engagement, (2) Reach & Implementation in Real World Settings, (3) Understanding Current Landscape & Resources and (4) Purposeful Diversity, Equity, & Inclusion Initiatives. CONCLUSIONS: To improve lung and sleep health in children, these principles should be the foundation for research design, development, and implementation.

When virtual reality becomes psychoneuroendocrine reality: A stress(or) review.

This review article was awarded the Dirk Hellhammer award from ISPNE in 2023. It explores the dynamic relationship between stressors and stress from a historical view as well as a vision towards the future of stress research via virtual reality (VR). We introduce the concept of a "syncytium," a permeable boundary that blurs the distinction between stress and stressor, in order to understand why the field of stress biology continues to inadequately measure stress alone as a proxy for the force of external stressors. Using Virtual Reality (VR) as an illustrative example to explicate the black box of stressors, we examine the distinction between 'immersion' and 'presence' as analogous terms for stressor and stress, respectively. We argue that the conventional psychological approaches to stress measurement and appraisal theory unfortunately fall short in quantifying the force of the stressor, leading to reverse causality fallacies. Further, the concept of affordances is introduced as an ecological or holistic tool to measure and design a stressor's force, bridging the gap between the external environment and an individual's physiological response to stress. Affordances also serve to ameliorate shortcomings in stress appraisal by integrating ecological interdependencies. By combining VR and psychobiological measures, this paper aims to unravel the complexity of the stressor-stress syncytium, highlighting the necessity of assessing both the internal and external facets to gain a holistic understanding of stress physiology and shift away from reverse causality reasoning. We find that the utility of VR extends beyond presence to include affordance-based measures of immersion, which can effectively model stressor force. Future research should prioritize the development of tools that can measure both immersion and presence, thereby providing a more comprehensive understanding of how external stressors interact with individual psychological states.

Social support for young people with eating disorders-An integrative review.

Eating disorder treatment should be underpinned by a recovery-oriented approach, be therapeutic, personalised and trauma informed. Within such models of care, social support is an important factor to explore in terms of its influence in supporting hope for recovery, reducing stigma, and mitigating life stressors. Limited research has been conducted to understand the types of social support that are available to young people formally diagnosed with an eating disorder, their feasibility and acceptability and the positive outcomes. This integrative review sought to explore the positive outcomes of social support or social support programs for young people with eating disorders. An integrative review was conducted based on a search of five electronic databases from inception to 31 March 2023. Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Tools and findings have been narratively synthesised and presented in accordance with the review's aims and questions. Seven studies (total 429 individuals, range 3-160) published between 2001 and 2023 were included in the final synthesis. Overall social support interventions showed promising preliminary evidence as a feasible and acceptable adjunct to treatment for young people with an eating disorder motivated to change, with some clinical improvements in psychopathology. Social support augmented existing relationships, providing a human element of open dialogue, friendship and a sense of hope for recovery. Despite the small number and heterogeneity of the studies, this review has highlighted some promising preliminary benefits. Future treatment for eating disorders should embrace adjunct modalities that enhance psychosocial recovery for young people with eating disorders.

Giant electron-mediated phononic nonlinearity in semiconductor-piezoelectric heterostructures.

Efficient and deterministic nonlinear phononic interactions could revolutionize classical and quantum information processing at radio frequencies in much the same way that nonlinear photonic interactions have at optical frequencies. Here we show that in the important class of phononic materials that are piezoelectric, deterministic nonlinear phononic interactions can be enhanced by orders of magnitude via the heterogeneous integration of high-mobility semiconductor materials. To this end, a lithium niobate and indium gallium arsenide heterostructure is utilized to produce the most efficient three- and four-wave phononic mixing to date, to the best of our knowledge. We then show that the conversion efficiency can be further enhanced by applying semiconductor bias fields that amplify the phonons. We present a theoretical model that accurately predicts the three-wave mixing efficiencies in this work and extrapolate that these nonlinearities can be enhanced far beyond what is demonstrated here by confining phonons to smaller dimensions in waveguides and optimizing the semiconductor material properties.