Publications by authors named "Jenny Lam"

97 Publications

Optimization of PEGylated KL4 Peptide for siRNA Delivery with Improved Pulmonary Tolerance.

Mol Pharm 2021 Jun 20;18(6):2218-2232. Epub 2021 May 20.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR.

Pulmonary delivery of small interfering RNA (siRNA) is a promising therapeutic strategy for treating various respiratory diseases but an effective carrier for the delivery of siRNA into the cells of the lungs and a robust gene-silencing effect is still lacking. Previously, we reported that the KL4 peptide, a synthetic cationic peptide with a repeating KLLLL sequence, can mediate effective siRNA transfection in lung epithelial cells but its high hydrophobic leucine content, and hence poor water solubility, limits its application as a delivery vector. Here, we show that the covalent attachment of monodisperse poly(ethylene glycol) (PEG) improves the solubility of KL4 and the uptake of its complex with siRNA into lung epithelial cells, such that very robust silencing is produced. All PEGylated KL4 peptides, with PEG length varying between 6 and 24 monomers, could bind and form nanosized complexes with siRNA, but the interaction between siRNA and peptides became weaker as the PEG chain length increased. All PEGylated KL4 peptides exhibited satisfactory siRNA transfection efficiency on three human lung epithelial cell lines, including A549 cells, Calu-3 cells, and BEAS-2B cells. The PEGKL4 peptide, which contains 12 monomers of PEG, was optimal for siRNA delivery and also demonstrated a low risk of inflammatory response and toxicity following pulmonary administration.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01242DOI Listing
June 2021

Memory care approaches to better leverage capacity of dementia specialists: a narrative synthesis.

Neurodegener Dis Manag 2021 Jun 10;11(3):239-250. Epub 2021 May 10.

Center for Economic & Social Research, University of Southern California, Los Angeles, CA 90089-3333, USA.

Prior research suggests that a scarcity of dementia specialists could hamper access to disease-modifying Alzheimer's treatments. We describe alternative approaches on how to leverage specialist time for memory care in this narrative synthesis based on 17 semi-structured interviews and a targeted literature review on memory care approaches that leverage specialist time. We identified four types of approaches: community primary care practices empowered with better tools and training; primary care memory clinics; specialty memory clinics and; specialty memory centers. Several approaches to use specialist time efficiently have been implemented and some but not all evaluated. The optimal approach may depend on the local context.
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http://dx.doi.org/10.2217/nmt-2020-0038DOI Listing
June 2021

Impact of diabetes and chronic dialysis on post-transplant survival in combined heart-kidney transplant recipients.

Clin Transplant 2021 May 4:e14338. Epub 2021 May 4.

Division of Transplantation, Department of Surgery, University of California San Diego, La Jolla, CA, USA.

Growing research supports an increased survival benefit of combined heart and kidney transplantation in patients with both heart and renal failure. As a result, the frequency of these combined transplants continues to increase. Despite this trend, little has been done to quantify the impact of chronic illness in this population. We identified adult recipients of combined heart-kidney transplant from the Scientific Registry of Transplant Recipients (SRTR) database between 2005 and 2018. We focused on renal disease secondary to diabetes and duration of dialysis as markers of chronic illness. The primary outcome was post-transplant mortality. Our final multivariable Cox proportional hazard model found that diabetes-associated renal disease (HR 1.57, 95% CI 1.14-2.15, p = .01) and dialysis duration (HR 1.08, 95% CI 1.01-1.15, p = .02) were significant predictors of post-transplant mortality. Given the significant impact of dialysis duration and renal disease secondary to diabetes mellitus, these chronically ill patients should be closely examined for conditions such as peripheral vascular disease and frailty, which have been shown to affect mortality in heart transplant recipients and are prevalent in the chronic dialysis population.
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http://dx.doi.org/10.1111/ctr.14338DOI Listing
May 2021

Inhalable Protein Powder Prepared by Spray-Freeze-Drying Using Hydroxypropyl-β-Cyclodextrin as Excipient.

Pharmaceutics 2021 Apr 24;13(5). Epub 2021 Apr 24.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China.

The prospect of inhaled biologics has garnered particular interest given the benefits of the pulmonary route of administration. Pertinent considerations in producing inhalable dry powders containing biological medicines relate to aerosol performance and protein stability. Spray-freeze-drying (SFD) has emerged as an established method to generate microparticles that can potentially be deposited in the lungs. Here, the SFD conditions and formulation composition were evaluated using bovine serum albumin (BSA) as a model protein and 2-hydroxypropyl-beta-cyclodextrin (HPβCD) as the protein stabilizer. A factorial design analysis was performed to investigate the effects of BSA content, solute concentration of feed solution, and atomization gas flow rate on dispersibility (as an emitted fraction), respirability (as fine particle fraction), particle size, and level of protein aggregation. The atomization gas flow rate was identified as a significant factor in influencing the aerosol performance of the powder formulations and protein aggregation. Nonetheless, high atomization gas flow rate induced aggregation, highlighting the need to further optimize the formulation. Of note, all the formulations exhibited excellent dispersibility, while no fragmentation of BSA occurred, indicating the feasibility of SFD and the promise of HPβCD as an excipient.
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http://dx.doi.org/10.3390/pharmaceutics13050615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145196PMC
April 2021

Real-world outcomes of immunotherapy-based regimens in first-line advanced non-small cell lung cancer.

Lung Cancer 2021 Jun 14;156:41-49. Epub 2021 Apr 14.

University of Minnesota, Minneapolis, MN, USA.

Background: First-line (1L) immunotherapy (I-O) has improved outcomes in patients with advanced non-small cell lung cancer (NSCLC) in clinical trials and is now routinely used alone or combined with chemotherapy. Although efficacy and safety of I-O therapies have been established in clinical trials, little is known about their performance and long-term efficacy in the real-world setting. We aimed to characterize real-world outcomes for patients with advanced NSCLC treated with 1L I-O therapy in the United States.

Methods: Patients aged ≥18 years with confirmed advanced (stage III-IV) NSCLC who received either 1L I-O monotherapy or single-agent I-O combined with chemotherapy on or after January 1, 2016 were identified from the Flatiron Health database. Primary objectives were to examine overall survival (OS) and real-world progression-free survival. Index date was defined as date of 1L treatment initiation; data cut-off date was June 30, 2020.

Results: Among 4271 patients receiving I-O plus chemotherapy, median OS was 10.6 (95 % confidence interval [CI], 9.3-11.8) months in patients with squamous NSCLC (n=814) and 12.0 (95 % CI, 11.3-12.8) months in those with non-squamous disease (n=3457). Regardless of histology, patients with high (≥50 %) tumor programmed death ligand 1 (PD-L1) expression demonstrated longer median OS vs those with low expression. Among 3041 patients receiving I-O monotherapy, median OS was 11.3 (95 % CI, 9.8-12.8) months in patients with squamous NSCLC (n=875) and 14.1 (95 % CI, 12.4-15.8) months in those with non-squamous disease (n=2166). OS benefit appeared to be greatest in the ≥50 % tumor PD-L1 expression group of the non-squamous cohort.

Conclusion: Survival estimates were generally lower than those reported in pivotal clinical trials. These findings indicate that there remains room for improvement of real-world survival outcomes in patients with advanced NSCLC who receive 1L I-O-based regimens and for identification of subgroups of patients not benefitting from treatment with current I-O regimens.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.007DOI Listing
June 2021

Treatment patterns in patients with metastatic non-small-cell lung cancer in the era of immunotherapy.

Future Oncol 2021 Apr 14. Epub 2021 Apr 14.

OHC Cincinnati, Cincinnati, OH 45211, USA.

Chemotherapy (CT) alone was previously standard first-line (1L) therapy for metastatic non-small-cell lung cancer (NSCLC) but alternative treatments, including immunotherapy (I-O), are now available. In this retrospective study, adults with stage IV NSCLC who initiated 1L treatment between 1 August 2018 and 31 December 2019 and had ≥2 visits were identified in the Flatiron database. Patients were followed up until 30 June 2020. Baseline characteristics and treatment patterns were described by treatment group: CT, I-O + CT, I-O monotherapy and other. Approximately 20% of patients received 1L CT in the 2018-2019 timeframe studied; these patients tended to have squamous histology and low (≤49%) programmed death ligand-1 expression. A proportion of patients with metastatic NSCLC still receive 1L CT despite the availability and widespread use of I-O therapies.
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http://dx.doi.org/10.2217/fon-2021-0230DOI Listing
April 2021

Projection of budgetary savings to US state Medicaid programs from reduced nursing home use due to an Alzheimer's disease treatment.

Alzheimers Dement (Amst) 2021 17;13(1):e12159. Epub 2021 Mar 17.

University of Southern California Los Angeles California USA.

Introduction: The approval of a disease-modifying Alzheimer's disease (AD) treatment could provide relief to US state budgets that were hit hard by the COVID-19 pandemic, as mostly Medicare would cover treatment cost, whereas Medicaid would see savings from reduced nursing home use.

Methods: We project savings from 2021 to 2040 with a simulation model from the perspective of state Medicaid programs.

Results: Assuming a 40% and 22% relative reduction of disease progression rates with treatment, Medicaid would avoid payments of $186.2 and $93.5 billion for around 1.11 and 0.57 million nursing home patient-years, respectively. The savings correspond to a 5.06% and 2.49%, respectively, relative reduction of Medicaid spending on nursing home care. Higher per capita savings were projected for older states, those with higher Medicaid payment rates, those with more nursing home residents covered by Medicaid, and those with a lower federal contribution.

Discussion: States stand to realize substantial savings from a potential AD treatment. A state's health system preparedness to handle the large number of patients will influence the actual magnitude of the savings and how fast they will accrue.
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http://dx.doi.org/10.1002/dad2.12159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968122PMC
March 2021

Psychometric properties and use of the DEMQOL suite of instruments in research: a systematic review protocol.

BMJ Open 2021 02 5;11(2):e041318. Epub 2021 Feb 5.

Faculty of Nursing, University of Alberta, Edmonton, Alberta, Canada.

Introduction: Dementia is a public health issue and a major risk factor for poor quality of life among older adults. In the absence of a cure, enhancing health-related quality of life (HRQoL) of people with dementia is the primary goal of care. Robust measurement of HRQoL is a prerequisite to effective improvement. The DEMQOL suite of instruments is considered among the best available to measure HRQoL in people with dementia; however, no review has systematically and comprehensively examined the use of the DEMQOL in research and summarised evidence to determine its feasibility, acceptability and appropriateness for use in research and practice.

Methods And Analysis: We will systematically search 12 electronic databases and reference lists of all included studies. We will include systematically conducted reviews, as well as, quantitative and qualitative research studies that report on the development, validation or use in research studies of any of the DEMQOL instruments. Two reviewers will independently screen all studies for eligibility, and assess the quality of each included study using one of four validated checklists appropriate for different study designs. Discrepancies at all stages of the review will be resolved by consensus. We will use descriptive statistics (frequencies, proportions, ranges), content analysis of narrative data and vote counting (for the measures of association) to summarise the data elements. Using narrative synthesis, we will summarise what is known about the development, validation, feasibility, acceptability, appropriateness and use of the DEMQOL. Our review methods will follow the reporting and conduct guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

Ethics And Dissemination: Ethical approval is not required as this project does not involve primary data collection. We will disseminate our findings through peer-reviewed publications and conference presentations.

Prospero Registration Number: CRD42020157851.
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http://dx.doi.org/10.1136/bmjopen-2020-041318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925918PMC
February 2021

Inhaled Antifungal Agents for the Treatment and Prophylaxis of Pulmonary Mycoses.

Curr Pharm Des 2021 ;27(12):1453-1468

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, Hong Kong.

Pulmonary mycoses are associated with high morbidity and mortality. The current standard treatment by systemic administration is limited by inadequate local bioavailability and systemic toxic effects. Aerosolisation of antifungals is an attractive approach to overcome these problems, but no inhaled antifungal formulation is currently available for the treatment of pulmonary mycoses. Hence, the development of respirable antifungals formulations is of interest and in high demand. In this review, the recent advances in the development of antifungal formulations for pulmonary delivery are discussed, including both nebulised and dry powder formulations. Although the clinical practices of nebulised parenteral amphotericin B and voriconazole formulations (off-label use) are reported to show promising therapeutic effects with few adverse effects, there is no consensus about the dosage regimen (e.g. the dose, frequency, and whether they are used as single or combination therapy). To maximise the benefits of nebulised antifungal therapy, it is important to establish standardised protocol that clearly defines the dose and specifies the device and the administration conditions. Dry powder formulations of antifungal agents such as itraconazole and voriconazole with favourable physicochemical and aerosol properties are developed using various powder engineering technologies, but it is important to consider their suitability for use in patients with compromised lung functions. In addition, more biological studies on the therapeutic efficacy and pharmacokinetic profile are needed to demonstrate their clinical potential.
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http://dx.doi.org/10.2174/1381612826666210101153547DOI Listing
January 2021

A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.

Commun Biol 2020 11 27;3(1):697. Epub 2020 Nov 27.

Institute of Pharmaceutical Science, School of Cancer & Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.

Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.
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http://dx.doi.org/10.1038/s42003-020-01420-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699649PMC
November 2020

Transmucosal drug administration as an alternative route in palliative and end-of-life care during the COVID-19 pandemic.

Adv Drug Deliv Rev 2020 1;160:234-243. Epub 2020 Nov 1.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region; Centre for Medicines Optimisation Research and Education (CMORE), Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom.

The Coronavirus disease 2019 (COVID-19) pandemic has led to a surge in need for alternative routes of administration of drugs for end of life and palliative care, particularly in community settings. Transmucosal routes include intranasal, buccal, sublingual and rectal. They are non-invasive routes for systemic drug delivery with the possibility of self-administration, or administration by family caregivers. In addition, their ability to offer rapid onset of action with reduced first-pass metabolism make them suitable for use in palliative and end-of-life care to provide fast relief of symptoms. This is particularly important in COVID-19, as patients can deteriorate rapidly. Despite the advantages, these routes of administration face challenges including a relatively small surface area for effective drug absorption, small volume of fluid for drug dissolution and the presence of a mucus barrier, thereby limiting the number of drugs that are suitable to be delivered through the transmucosal route. In this review, the merits, challenges and limitations of each of these transmucosal routes are discussed. The goals are to provide insights into using transmucosal drug delivery to bring about the best possible symptom management for patients at the end of life, and to inspire scientists to develop new delivery systems to provide effective symptom management for this group of patients.
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http://dx.doi.org/10.1016/j.addr.2020.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603972PMC
December 2020

Gastrointestinal-resident, shape-changing microdevices extend drug release in vivo.

Sci Adv 2020 Oct 28;6(44). Epub 2020 Oct 28.

Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

Extended-release gastrointestinal (GI) luminal delivery substantially increases the ease of administration of drugs and consequently the adherence to therapeutic regimens. However, because of clearance by intrinsic GI motility, device gastroretention and extended drug release over a prolonged duration are very challenging. Here, we report that GI parasite-inspired active mechanochemical therapeutic grippers, or theragrippers, can reside within the GI tract of live animals for 24 hours by autonomously latching onto the mucosal tissue. We also observe a notable sixfold increase in the elimination half-life using theragripper-mediated delivery of a model analgesic ketorolac tromethamine. These results provide first-in-class evidence that shape-changing and self-latching microdevices enhance the efficacy of extended drug delivery.
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http://dx.doi.org/10.1126/sciadv.abb4133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608789PMC
October 2020

Pulmonary Delivery of Biological Drugs.

Pharmaceutics 2020 Oct 26;12(11). Epub 2020 Oct 26.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China.

In the last decade, biological drugs have rapidly proliferated and have now become an important therapeutic modality. This is because of their high potency, high specificity and desirable safety profile. The majority of biological drugs are peptide- and protein-based therapeutics with poor oral bioavailability. They are normally administered by parenteral injection (with a very few exceptions). Pulmonary delivery is an attractive non-invasive alternative route of administration for local and systemic delivery of biologics with immense potential to treat various diseases, including diabetes, cystic fibrosis, respiratory viral infection and asthma, etc. The massive surface area and extensive vascularisation in the lungs enable rapid absorption and fast onset of action. Despite the benefits of pulmonary delivery, development of inhalable biological drug is a challenging task. There are various anatomical, physiological and immunological barriers that affect the therapeutic efficacy of inhaled formulations. This review assesses the characteristics of biological drugs and the barriers to pulmonary drug delivery. The main challenges in the formulation and inhalation devices are discussed, together with the possible strategies that can be applied to address these challenges. Current clinical developments in inhaled biological drugs for both local and systemic applications are also discussed to provide an insight for further research.
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http://dx.doi.org/10.3390/pharmaceutics12111025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693150PMC
October 2020

Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability.

Eur J Med Chem 2020 Dec 9;208:112674. Epub 2020 Aug 9.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, United States. Electronic address:

Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions as to what mechanism(s) of action should be targeted for developing pharmacotherapies. Atypical dopamine transporter (DAT) inhibitors, based on (±)modafinil, have shown therapeutic potential in preclinical models of psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1-3 have impeded further development. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT affinities and metabolic stability in rat liver microsomes. Aminopiperidines 7 (DAT K = 50.6 nM), 21b (DAT K = 77.2 nM) and 33 (DAT K = 30.0 nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.
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http://dx.doi.org/10.1016/j.ejmech.2020.112674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680422PMC
December 2020

It's not always too late: a case for minimally invasive salvage esophagectomy.

Surg Endosc 2020 Sep 17. Epub 2020 Sep 17.

Department of Surgery, Division of Minimally Invasive Surgery, UC San Diego School of Medicine, MET Building, Lower Level, 9500 Gilman Drive MC 0740, La Jolla, CA, 92093-0740, USA.

Introduction: Standard of care for locally advanced esophageal carcinoma is neoadjuvant chemoradiation (nCRT) and surgical resection 4-8 weeks after completion of nCRT. It is recommended that the CRT to surgery interval not exceed 90 days. Many patients do not undergo surgery within this timeframe due to patient/physician preference, complete clinical response, or poor performance status. Select patients are offered salvage esophagectomy (SE), defined in two ways: resection for recurrent/persistent disease after complete response to definitive CRT (dCRT) or esophagectomy performed > 90 days after completion of nCRT. Salvage esophagectomy reportedly has higher postoperative morbidity and poor survival outcomes. In this study, we assessed outcomes, overall, and disease-free survival of patients undergoing salvage esophagectomy by both definitions (recurrent/persistent disease after dCRT and/or > 90 days), compared to planned (resection after nCRT/within 90 days) esophagectomy (PE).

Materials And Methods: Retrospective review of a prospectively maintained database identified patients who underwent minimally invasive esophagectomy at a single institution from 2009 to 2019. Esophagectomy for benign disease and patients who did not receive nCRT were excluded. Outcomes included postoperative complications, length of stay (LOS), disease-free survival, and overall survival.

Results: 97 patients underwent minimally invasive esophageal resection for esophageal carcinoma. 89.7% of patients were male. Mean age was 64.9 years (range 36-85 years). 94.8% of patients had adenocarcinoma, with 16 transthoracic and 81 transhiatal approaches. On comparing planned esophagectomy (n = 87) to esophagectomy after dCRT failure (n = 10), no significant differences were identified in overall survival (p = 0.73), disease-free survival (p = 0.32), 30-day or major complication rate, anastomotic leak, or LOS. Similarly, when comparing esophagectomy < 90 days after CRT (n = 62) to > 90 days after CRT completion (n = 35), no significant differences were identified in overall survival (p = 0.39), disease-free survival (p = 0.71), 30-day or major complication rate, LOS, or anastomotic leak rate between groups. In this comparison, local recurrence was noted to be elevated with SE as compared to PE (64.3% vs. 25.0%, p = 0.04).

Conclusion: Overall survival and disease-free survival were equivalent between SE and PE. Local recurrence was noted to be increased with SE, though this did not appear to affect survival. Although planned esophagectomy remains the standard of care, salvage esophagectomy has comparable outcomes and is appropriate for selected patients.
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http://dx.doi.org/10.1007/s00464-020-07937-2DOI Listing
September 2020

Inhaled RNA Therapy: From Promise to Reality.

Trends Pharmacol Sci 2020 10 4;41(10):715-729. Epub 2020 Sep 4.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR. Electronic address:

RNA-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. The largest obstacle in its clinical translation remains identifying a safe and effective delivery system. Studies investigating RNA therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of RNA therapeutics to the target site of action while minimizing systemic exposure. In this review, we highlight recent developments in pulmonary RNA delivery systems with the use of nonviral vectors. We also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside.
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http://dx.doi.org/10.1016/j.tips.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471058PMC
October 2020

Intratracheal Administration of Dry Powder Formulation in Mice.

J Vis Exp 2020 07 25(161). Epub 2020 Jul 25.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong;

In the development of inhalable dry powder formulations, it is essential to evaluate their biological activities in preclinical animal models. This paper introduces a noninvasive method of intratracheal delivery of dry powder formulation in mice. A dry powder loading device that consists of a 200 µL gel loading pipette tip connected to an 1 mL syringe via a three-way stopcock is presented. A small amount of dry powder (1-2 mg) is loaded into the pipette tip and dispersed by 0.6 mL of air in the syringe. Because pipette tips are disposable and inexpensive, different dry powder formulations can be loaded into different tips in advance. Various formulations can be evaluated in the same animal experiment without device cleaning and dose refilling, thereby saving time and eliminating the risk of cross-contamination from residual powder. The extent of powder dispersion can be inspected by the amount of powder remaining in the pipette tip. A protocol of intubation in mouse with a custom-made light source and a guiding cannula is included. Proper intubation is one of the key factors that influences the intratracheal delivery of dry powder formulation to the deep lung region of the mouse.
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http://dx.doi.org/10.3791/61469DOI Listing
July 2020

Using a Location-Sensing Time-Keeping App to Help Track Resident Work Hours.

J Grad Med Educ 2020 Jun;12(3):349-351

Professor of Surgery, General Surgery Program Director, Department of Surgery, University of California San Diego.

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http://dx.doi.org/10.4300/JGME-D-19-00546.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301951PMC
June 2020

Effect of formulation and inhaler parameters on the dispersion of spray freeze dried voriconazole particles.

Int J Pharm 2020 Jun 21;584:119444. Epub 2020 May 21.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region. Electronic address:

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (-10 °C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119444DOI Listing
June 2020

Modification of KL4 Peptide Revealed the Importance of Alpha-Helical Structure for Efficient siRNA Delivery.

Nucleic Acid Ther 2021 Jun 29;31(3):220-228. Epub 2020 Apr 29.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.

A safe and effective delivery system is considered a key to the success of nucleic acid therapeutics. It has been reported that pulmonary surfactants or their components could facilitate the uptake of small interfering RNA (siRNA) into the lung epithelial cells. Previously, our group investigated the use of KL4 peptide, a synthetic cationic peptide that simulates the structural properties of surfactant protein B (SP-B), as siRNA delivery vector. Although KL4 peptide exhibits good siRNA transfection efficiency on lung epithelial cells, its therapeutic potential is limited by its poor aqueous solubility due to the presence of a high proportion of hydrophobic leucine residues. In this study, we aim to address the solubility issue, designing five different modified peptides by replacing the hydrophobic leucine with alanine or valine, and assess their potential as siRNA delivery vectors. While the modified peptides retain the overall cationic property, their siRNA binding is also affected and their transfection efficiency is inferior to the parent KL4 peptide. A closer examination of the conformation of these peptides by circular dichroism shows that substitution of leucine residues leads to the change of the secondary structure from α-helical content to either β-sheet or more disordered, β-turn conformations. Relatively conservative amino acid substitutions, in terms of hydrophobicity bulk, lead to substantial conformational alteration, heavily impacting siRNA binding and release, cellular uptake, and transfection efficiency. Although the peptide modification strategy employed in this study was unsuccessful in developing an improved version of KL4 peptide for siRNA delivery, it highlights the importance of the α-helical conformation for efficient siRNA transfection, providing useful insights for future development of peptide-based RNA delivery system.
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http://dx.doi.org/10.1089/nat.2020.0855DOI Listing
June 2021

Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer's Disease.

J Med Chem 2020 06 27;63(11):6028-6056. Epub 2020 May 27.

Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.

Neutral sphingomyelinase 2 (nSMase2) catalyzes the cleavage of sphingomyelin to phosphorylcholine and ceramide, an essential step in the formation and release of exosomes from cells that is critical for intracellular communication. Chronic increase of brain nSMase2 activity and related exosome release have been implicated in various pathological processes, including the progression of Alzheimer's disease (AD), making nSMase2 a viable therapeutic target. Recently, we identified phenyl ()-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-]pyridazin-8-yl)pyrrolidin-3-yl)carbamate , the first nSMase2 inhibitor that possesses both favorable pharmacodynamics and pharmacokinetic (PK) parameters, including substantial oral bioavailability, brain penetration, and significant inhibition of exosome release from the brain in vivo. Herein we demonstrate the efficacy of in a mouse model of AD and detail extensive structure-activity relationship (SAR) studies with 70 analogues, unveiling several that exert similar or higher activity against nSMase2 with favorable pharmacokinetic properties.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025741PMC
June 2020

Clinical risk model to predict 28-day unplanned readmission via the accident and emergency department after discharge from acute psychiatric units for patients with psychotic spectrum disorders.

BJPsych Open 2020 Jan 28;6(1):e13. Epub 2020 Jan 28.

Department of General Adult Psychiatry, Castle Peak Hospital, Hong Kong, China.

Background: Unplanned readmissions rates are an important indicator of the quality of care provided in a psychiatric unit. However, there is no validated risk model to predict this outcome in patients with psychotic spectrum disorders.

Aims: This paper aims to establish a clinical risk prediction model to predict 28-day unplanned readmission via the accident and emergency department after discharge from acute psychiatric units for patients with psychotic spectrum disorders.

Method: Adult patients with psychotic spectrum disorders discharged within a 5-year period from all psychiatric units in Hong Kong were included in this study. Information on the socioeconomic background, past medical and psychiatric history, current discharge episode and Health of the Nation Outcome Scales (HoNOS) scores were used in a logistic regression to derive the risk model and the predictive variables. The sample was randomly split into two to derive (n = 10 219) and validate (n = 10 643) the model.

Results: The rate of unplanned readmission was 7.09%. The risk factors for unplanned readmission include higher number of previous admissions, comorbid substance misuse, history of violence and a score of one or more in the discharge HoNOS overactivity or aggression item. Protective factors include older age, prescribing clozapine, living with family and relatives after discharge and imposition of conditional discharge. The model had moderate discriminative power with a c-statistic of 0.705 and 0.684 on the derivation and validation data-set.

Conclusions: The risk of readmission for each patient can be identified and adjustments in the treatment for those with a high risk may be implemented to prevent this undesirable outcome.
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http://dx.doi.org/10.1192/bjo.2019.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001467PMC
January 2020

The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey.

J Am Board Fam Med 2019 Nov-Dec;32(6):931-940

From the Leonard D. Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles, CA (JM); Price School of Public Policy, University of Southern California, Los Angeles, CA (JH); Center for Economic and Social Research, University of Southern California, Los Angeles, CA (SM).

Despite recent setbacks, disease-modifying treatments (DMTs) for Alzheimer disease (AD) might become available within a few years. These DMTs are likely to be used in the early stages of AD to avoid the progression to manifest dementia, which implies that a large reservoir of prevalent cases would need to be evaluated when DMTs first become available. Primary care providers (PCPs) would play a vital role in managing the patient flow to specialty care. We review the literature on diagnostic tests that could be used by PCPs and estimate the impact of different testing approaches on demand for specialty care.While many tests have been evaluated, only the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) perform acceptably for detection of early-stage cognitive decline with sensitivities and specificities of 55% to 82% and 72% to 84%, respectively, for the MMSE; and 77% to 96% and 73% to 95%, respectively, for the MoCA. However, neither test is sufficiently specific for the AD pathology and would result in 4 to 5 false positives for each true positive. Blood-based tests for AD biomarkers may soon become available for clinical use. A plasma amyloid-β (Aβ) test has been shown to have a sensitivity of up to 97% and specificity of up to 81%. Adding this test to the MMSE or MoCA could reduce false positives by approximately 80%.These findings suggest a combination of brief cognitive tests and blood-based biomarker tests will allow PCPs to identify patients with potential early stage AD efficiently and triage them for further evaluation.
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http://dx.doi.org/10.3122/jabfm.2019.06.180328DOI Listing
September 2020

High siRNA loading powder for inhalation prepared by co-spray drying with human serum albumin.

Int J Pharm 2019 Dec 31;572:118818. Epub 2019 Oct 31.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong. Electronic address:

The development of small interfering RNA (siRNA) formulation for pulmonary delivery is a key to the clinical translation of siRNA therapeutics for the treatment of respiratory diseases. Most inhalable siRNA powder formulations published to date were limited by the siRNA content which was often too low to be clinically relevant. This study aimed to prepare inhalable siRNA powder formulations that contained high siRNA loading of over 6% w/w by spray drying, with human serum albumin (HSA) investigated as a dispersion enhancer to improve the aerosol performance. The effect of siRNA, HSA and solute concentrations in the formulations were evaluated systemically using factorial analyses. All the spray dried siRNA powders exhibited excellent aerosol performance with fine particle fraction (FPF) consistently over 50% in all the formulations. An enrichment of HSA on the particle surface was observed. Surface corrugation was more prominent as HSA composition increased. Importantly, the bioactivity of siRNA was successfully preserved upon spray drying as demonstrated in the in vitro transfection study, and up to 78% of intact siRNA retained in the spray dried powder. Overall, HSA is an effective dispersion enhancer and spray drying is an appropriate technique to produce inhalable dry powder with high siRNA loading for further investigation.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118818DOI Listing
December 2019

A cluster-randomized controlled trial of the effectiveness of the JUMP Math program of math instruction for improving elementary math achievement.

PLoS One 2019 30;14(10):e0223049. Epub 2019 Oct 30.

Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.

Students in many western countries struggle to achieve acceptable standards in numeracy despite its recognition as an important 21st century skill. As commercial math programs remain a staple of classroom instruction, investigations of their effectiveness are essential to inform decision-making regarding how to invest limited resources while maximizing student gains. We conducted a cluster randomized-controlled trial of the effectiveness of JUMP Math, a distinctive math program whose central tenets are empirically supported, for improving elementary math achievement (clinical trial.gov no. NCT02456181). The study involved 554 grade 2 (primary) and 592 grade 5 (junior) students and 193 teachers in 41 schools, in an urban-rural Canadian school board. Schools were randomly assigned to use either JUMP Math or their business-as-usual, problem-based approach to math instruction. We tracked student progress in math achievement on standardized and curriculum-based measures of computation and problem solving, for 2 consecutive school years. Junior students taught with JUMP Math made significantly greater progress in computation than their non-JUMP peers but the groups did not differ significantly in problem solving. Effects took hold relatively quickly, replicating the results from an earlier pilot study. Primary students in the non-JUMP group made significantly greater gains in problem solving and computation in year 1. But those taught with JUMP Math made significantly greater gains in problem solving and the groups did not differ in computation, in year 2. The positive effects of JUMP Math are noteworthy given that the JUMP Math teachers were likely still adjusting to the new program. That these positive findings were obtained in an effectiveness study (i.e. in real-world conditions), suggests that JUMP Math may be a valuable evidence-based addition to the teacher's toolbox. Given the importance of numeracy for 21st century functioning, identifying and implementing effective math instruction programs could have far-reaching, positive implications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223049PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821143PMC
March 2020

Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability.

J Med Chem 2020 03 14;63(5):2343-2357. Epub 2019 Nov 14.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol () was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ receptors. Within the series, showed improved DAT affinity ( = 23 nM) over ( = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of as a potential treatment for psychostimulant use disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01188DOI Listing
March 2020

Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide.

J Control Release 2019 11 16;314:102-115. Epub 2019 Oct 16.

Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region; The University of Hong Kong Shenzhen Institute of Research and Innovation, 5/F, Key Laboratory Platform Building, Shenzhen 518057, China. Electronic address:

Pulmonary delivery of messenger RNA (mRNA) has considerable potential as therapy or vaccine for a range of lung diseases. Inhaled dry powder formulation of mRNA is particularly attractive as it has superior stability and dry powder inhaler is relatively easy to use. A safe and effective mRNA delivery vector as well as a suitable particle engineering method are required to produce a dry powder formulation that is respirable and mediates robust transfection in the lung. Here, we introduce a novel RNA delivery vector, PEGKL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEGKL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEGKL4/mRNA complexes were successfully formulated into dry powder by spray drying (SD) and spray freeze drying (SFD) techniques. Both SD and SFD powder exhibited satisfactory aerosol properties for inhalation. More importantly, the biological activity of the PEGKL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEGKL4 /mRNA complexes at a dose of 5μg mRNA resulted in luciferase expression in the deep lung region of mice 24h post-transfection. The transfection efficiency was superior to naked mRNA or lipoplexes (Lipofectamine 2000), in which luciferase expression was weaker and restricted to the tracheal region only. There was no sign of inflammatory response or toxicity of the PEGKL4 /mRNA complexes after single intratracheal administration. Overall, PEGKL4 is an excellent mRNA transfection agent for pulmonary delivery. This is also the first study that successfully demonstrates the preparation of inhalable dry powder mRNA formulations with in vivo transfection efficiency, showing the great promise of PEGKL4 peptide as a mRNA delivery vector candidate for clinical applications.
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http://dx.doi.org/10.1016/j.jconrel.2019.10.026DOI Listing
November 2019

Intelligibility of Children With Speech Sound Disorders Evaluated by Listeners With Swedish as a Second Language.

J Speech Lang Hear Res 2019 10 17;62(10):3714-3727. Epub 2019 Oct 17.

Division of Speech and Language Pathology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.

Purpose This study aimed to investigate the intelligibility of children's atypical speech in relation to listeners' language background. Method Forty-eight participants listened to and transcribed isolated words repeated by children with speech sound disorders. Participants were divided into, on the one hand, a multilingual group ( = 29) that was further divided into subgroups based on age of acquisition (early, 0-3 years; intermediate, 4-12 years; and late, > 12 years) and, on the other hand, a monolingual comparison group ( = 19). Results The monolingual listeners obtained higher intelligibility scores than the multilingual listeners; this difference was statistically significant. Participants who acquired Swedish at an older age (> 4 years) were found to have lower scores than other listeners. The later the age of acquisition, the less of the atypical speech was decoded correctly. A further analysis of the transcriptions also revealed a higher level of nonwords among the incorrect transcriptions of the multilinguals than that of the monolinguals who used more real words, whereas both groups were equally prone to using blanks when they did not perceive a word. Conclusions This indicates a higher risk of communicative problems between late acquirers of Swedish and children with speech sound disorders. Clinical implications, such as involving communication partners in the intervention process, are discussed as well as possible linguistic explanations to the findings. This study could be seen as a starting point in the field of research regarding the relations between the language background of the listener and the ability to perceive atypical speech.
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http://dx.doi.org/10.1044/2019_JSLHR-S-18-0492DOI Listing
October 2019

The Novel Glutamine Antagonist Prodrug JHU395 Has Antitumor Activity in Malignant Peripheral Nerve Sheath Tumor.

Mol Cancer Ther 2020 02 8;19(2):397-408. Epub 2019 Oct 8.

Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.

The carbon and nitrogen components of glutamine are used for multiple biosynthetic processes by tumors. Glutamine metabolism and the therapeutic potential of glutamine antagonists (GA), however, are incompletely understood in malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma observed in patients with neurofibromatosis type I. We investigated glutamine dependence of MPNST using JHU395, a novel orally bioavailable GA prodrug designed to circulate inert in plasma, but permeate and release active GA within target tissues. Human MPNST cells, compared with Schwann cells derived from healthy peripheral nerve, were selectively susceptible to both glutamine deprivation and GA dose-dependent growth inhibition. , orally administered JHU395 delivered active GA to tumors with over 2-fold higher tumor-to-plasma exposure, and significantly inhibited tumor growth in a murine flank MPNST model without observed toxicity. Global metabolomics studies and stable isotope-labeled flux analyses in tumors identified multiple glutamine-dependent metabolites affected, including prominent effects on purine synthesis. These data demonstrate that glutamine antagonism is a potential antitumor strategy for MPNST.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007868PMC
February 2020

Making the Jump: A Qualitative Analysis on the Transition From Bedside Assistant to Console Surgeon in Robotic Surgery Training.

J Surg Educ 2020 Mar - Apr;77(2):461-471. Epub 2019 Sep 23.

Department of Surgery, University of California San Diego, La Jolla, California; Department of Surgery, VA San Diego Healthcare System, La Jolla, California.

Objective: To determine barriers associated with the transition from bedside assistant to console surgeon for general surgery residents in the era of robotic surgery in general surgery training.

Design: Qualitative thematic analysis using one-on-one interviews of general surgery residents and attendings conducted between June 2018 and February 2019.

Setting: An urban, academic, multihospital general surgery residency program with a robust robotic surgery program.

Participants: Convenient and purposeful sampling was performed to ensure a variety of resident graduate-years and attending subspecialties were represented. Sample size was determined by data saturation, which occurred after 20 resident and 7 attending interviews.

Results: Residents identified the low volume of general surgery robotic cases, the infrequency of exposure to robotic surgery, and attending comfort with robotic surgery (and with teaching on the robot) as potential barriers in the transition from bedside assistant to console surgeon. Residents had to find a replacement bedside assistant in order to be the console surgeon, which was challenging. In addition, residents felt that the current culture surrounding robotic surgery is very hierarchal, limiting their exposure. Attendings' trust in the residents' console skills was a major determining factor in allowing residents on the console.

Conclusions: Most robotic surgery education curricula are sequential, requiring the resident to progress from bedside assistant to console surgeon. Unfortunately, there are many potential barriers for residents in the transition from bedside assistant to console surgeon. Some barriers apply to general surgery training overall, but are amplified in robotic surgery, while others are unique to robotic surgery education. Recognition of, and rectifying, these barriers may increase resident participation as the console surgeon.
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http://dx.doi.org/10.1016/j.jsurg.2019.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036000PMC
June 2021