OBJECTIVE: Fenestrated endovascular aortic aneurysm repair (FEVAR) has been widely applied for the treatment of pararenal (PAA) and thoracoabdominal aortic aneurysms (TAAA). If custom-made devices or off-the-shelf devices are not available, physician-modified endografts (PMEG) are an alternative device option. Several different endograft platforms have been used for PMEG; however, minimal data exists on utilizing the Terumo TREO Abdominal stent-graft system in this setting. The purpose of this study was to evaluate our single-center experience treating PAA and TAAA with a physician-modified FEVAR using the TREO platform. METHODS: A prospective database of consecutive patients with PAA and TAAA treated at a single-center with a FEVAR utilizing a PMEG device between March 2021 and September 2023 was queried for those having a Terumo TREO device implanted. Demographics, operative details, and postoperative complications were analyzed. Rates of technical success, type I or III endoleak, branch vessel status, reintervention, and 2-year survival were also assessed. RESULTS: Of the 153 patients who underwent FEVAR with a PMEG device during the study period, 100 had repair using a Terumo TREO stent-graft. The mean age of the cohort was 73.7±7.0years with the majority suffering from hypertension (n=94, 94%), coronary artery disease (n=51, 51%), and COPD (n=40, 40%). Thirty-four patients (34%) had a prior failed EVAR device in place. Mean aneurysm size was 66.0±13.7mm, with 58 (50%) patients classified as PAA and 30 (30%) patients as an extent IV TAAA. Six (6%) patients presented with symptomatic/ruptured aneurysms. The average number of target arteries incorporated per patient was 3.8±0.6. Overall technical success was 99%, procedure time was 218±116 minutes, contrast volume was 82±21mL, and cumulative air kerma was 3,054±1,560mGy. Postoperative complications were present in 20 patients (20%) and 2 patients (2%) died within 30-days. Rates of type I or III endoleak, branch vessel stenosis/occlusion, and reintervention were 2%, 1%, and 7%, respectively. Two-year overall survival was 87%. CONCLUSIONS: Treatment of pararenal and extent IV TAAA using a physician-modified fenestrated Terumo TREO endograft is safe and effective. This large, early experience using the Terumo TREO platform supports preferential use of this device in this setting due to the device design and low likelihood of type I or III endoleak.
BACKGROUND: Medications for opioid use disorders (MOUDs) are effective, but most people with opioid use disorder (OUD) do not receive treatment. Prior research has explored patients' structural barriers to access and perceptions of MOUD. Little research has considered treatment knowledge and perceptions outside of the patient population. Members of the public without OUD themselves (eg, family, friends) can significantly influence treatment decisions of persons with OUD. Considering these gaps, we conducted an original survey with a diverse sample of US adults to explore knowledge and preferences toward OUD treatments. METHODS: We conducted an online survey with 1505 White, Black, and Latino/a Americans including a small percentage (8.5%) with self-reported lifetime OUD. The survey used vignettes to describe hypothetical patients with OUD, provide basic treatment information (ie, methadone, buprenorphine, naltrexone, nonmedication treatment), and then assessed treatment preferences. Using multivariable logistic regression, we examined associations between covariates of interest (eg, perceived access, knowledge, demographics) and preference for MOUD versus nonmedication treatment. RESULTS: There were 523 White, 502 Black, and 480 Latino/a respondents. Across racial/ethnic subsamples, respondents had the greatest knowledge of nonmedication treatments, with Black (72.7%) and Latino/a (70.2%) respondents having significantly greater knowledge compared to White respondents (61.8%). However, after viewing the vignette, a greater proportion of respondents chose methadone (35.8%) or buprenorphine (34.8%) as their first-choice treatment for hypothetical patients. Multivariable logistic regression suggested that among Black respondents, those with knowledge of nonmedication treatment were more likely to choose MOUD than those without knowledge (odds ratio = 2.41, 95% confidence interval = 1.34-4.34). Perceived treatment access did not affect treatment choice. CONCLUSIONS: Across racial groups, knowledge and perceived access to nonmedication treatment was greater than for MOUD, but many still selected MOUD as a first-choice treatment. Significant findings emphasized the importance of treatment knowledge around decision-making, highlighting opportunities for tailored education efforts to improve uptake of evidence-based treatment.
OBJECTIVES: Our aim was to explore postpartum individuals' experiences and perceptions of breastfeeding and International Board Certified Lactation Consultants' (IBCLC) knowledge and perceptions of maternity care practices and perceived barriers to breastfeeding among their patient populations in Appalachia. METHODS: Semistructured interviews were conducted with seven IBCLCs and seven postpartum individuals. Interviews were recorded and transcribed. Thematic analysis was conducted to determine emergent themes and subthemes related to knowledge/perceptions, experiences, and barriers to breastfeeding among postpartum individuals, as well as emergent themes associated with the knowledge and perceptions of maternity care practices, easy-/difficult-to-implement Baby-Friendly Hospital Initiative maternity care practices, and perceived barriers to breastfeeding among IBCLCs. RESULTS: Postpartum individuals recruited from an Appalachian obstetrics/gynecology clinic were aware of the benefits of breastfeeding, but their infant feeding journeys were more stressful than they expected, and they had limited access to lactation support and breastfeeding education/information. IBCLCs identified the benefits of the Baby-Friendly maternity care practices but mentioned some risks, especially when there is a lack of communication and coordination among providers. Environmental and informational barriers were identified by both postpartum individuals and IBCLCs as breastfeeding challenges potentially amenable to change. CONCLUSIONS: To support postpartum mothers in the Appalachian region, environmental barriers (eg, lack of lactation support) and informational barriers (eg, lack of prenatal education) need to be addressed.
Breast Feeding , Humans , Breast Feeding/psychology , Breast Feeding/statistics & numerical data , Appalachian Region , Female , Adult , Health Knowledge, Attitudes, Practice , Maternal Health Services/standards , Infant, Newborn , Qualitative Research , Pregnancy , Interviews as Topic , Consultants/psychology
Anterior cruciate ligament (ACL) injuries are a common clinical entity among people involved in contact sports activities. With the number of primary ACL reconstructions increasing, there has been a proportional increase in the revision of failed ACL reconstruction surgeries. As our understanding of knee kinematics improves over time, there has been evidence that alignment of the lower limb weight-bearing axis also plays an important part in ACL functioning. Medial opening wedge high tibial osteotomy (MOWHTO) is one such procedure that has been used extensively worldwide to correct the varus lower limb alignment. This procedure is usually reserved for young active patients with varus lower limb weight-bearing alignment. The technical dilemma for the surgeon arises when there is a need to revise a failed ACL reconstruction while at the same time correcting the axis malalignment. The general dictum says that alignment correction is done first followed by ligament reconstruction in a dual-stage procedure. However, single-stage surgery is possible in certain indications. In this case report, we present the case of a 31-year-old male involved in recreational sports who sustained a repeat ACL tear five years post the index surgery. He also had a significant varus alignment of the lower limb weight-bearing axis which was considered to be one of the causes of index surgery failure. In this report, we would like to highlight the problems we encountered in a single-stage procedure and certain surgical facets of a single-stage alignment surgery with arthroscopic revision ACL reconstruction.
Amniotic band syndrome (ABS) constriction rings in the lower limb are common. Despite this, there is insufficient literature on anatomical abnormalities in the knee joints of children with ABS. There is an increasing incidence of paediatric anterior cruciate ligament (ACL) injuries recently. ACL reconstruction in this population has an extra dilemma of sparing the physis to prevent growth disturbances. Treating both these conditions simultaneously is a challenge that is rarely encountered. In our literature review, we found no case such as this. As such a case is being described for the first time, we also found certain meniscal anatomical variations on diagnostic arthroscopy. A 12-year-old adolescent Indian girl presented with an ACL tear in her left leg after a school sports injury. She had a known case of ABS constriction bands in both her lower limbs. Her distal femoral and proximal femoral physis was fused on radiographs, so we went ahead with a transphyseal ACL soft-tissue graft reconstruction. On the diagnostic round, we found an anatomical variation of the menisci, which was previously not described since arthroscopy of the knee in an adolescent kid with ABS has not been published in the literature as of yet. These kinds of clinical presentations can become common in the future as more and more kids with ABS take part in recreational sports. In such a scenario, having knowledge about common anatomical variations in the knee of such syndromic patients is essential. While performing ACL reconstructions in this population, we have to be aware of the risk of growth deformities along with vascular and neurological complications, which are added risks with constriction bands around the lower limb.
BACKGROUND: Despite advancements in treatments of multiple sclerosis (MS), there is a lack of awareness of early MS symptoms, especially in students and the public, contributing to delays in diagnosis and treatment. This review aims to identify gaps in tools to increase awareness and to provide a bilingual framework to facilitate recognition of early MS symptoms. METHODS: We performed a literature review to determine the use of English and Spanish mnemonics in MS education for medical students and patients. RESULTS: There is no educational tool to help remember the early signs of MS at present. Here we present a framework for early awareness encompassed in the bilingual mnemonics VISIBLY (English) and VISIBLE (Spanish). VISIBLY stands for (1) Vision changes: Painful vision loss, loss of color vision or double vision; (2) Belly or Back numbness and Balance issues; (3) Limb weakness or Numbness; (4), Young people. Spanish version is included in the manuscript. CONCLUSION: We posit that VISIBL-MS provides a framework for MS awareness that addresses the interconnection between language, culture, health literacy, and health outcomes and can be a useful educational tool to tackle the effects of health literacy on diverse communities.
Hypesthesia , Multiple Sclerosis , Humans , Educational Status , Multiple Sclerosis/diagnosis , Multiple Sclerosis/therapy
Tendon biomechanical properties and fibril organization are altered in patients with diabetes compared to healthy individuals, yet few biomarkers have been associated with in vivo tendon properties. We investigated the relationships between in vivo imaging-based tendon properties, serum variables, and patient characteristics across healthy controls (n = 14, age: 45 ± 5 years, body mass index [BMI]: 24 ± 1, hemoglobin A1c [HbA1c]: 5.3 ± 0.1%), prediabetes (n = 14, age: 54 ± 5 years, BMI: 29 ± 2; HbA1c: 5.7 ± 0.1), and type 2 diabetes (n = 13, age: 55 ± 3 years, BMI: 33 ± 2, HbA1c: 6.7 ± 0.3). We used ultrasound speckle-tracking and measurements from magnetic resonance imaging (MRI) to estimate the patellar tendon in vivo tangent modulus. Analysis of plasma c-peptide, interleukin-1ß (IL-1ß), IL-6, IL-8, tumor necrosis factor-α (TNF-α), adiponectin, leptin, insulin-like growth factor 1 (IGF-1), and C-reactive protein (CRP) was completed. We built regression models incorporating statistically significant covariates and indicators for the clinically defined groups. We found that tendon cross-sectional area normalized to body weight (BWN CSA) and modulus were lower in patients with type 2 diabetes than in healthy controls (p < 0.05). Our regression analysis revealed that a model that included BMI, leptin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), age, and group explained ~70% of the variability in BWN CSA (R2 = 0.70, p < 0.001). For modulus, including the main effects LDL, groups, HbA1c, age, BMI, cholesterol, IGF-1, c-peptide, leptin, and IL-6, accounted for ~54% of the variability in modulus (R2 = 0.54, p < 0.05). While BWN CSA and modulus were lower in those with diabetes, group was a poor predicter of tendon properties when considering the selected covariates. These data highlight the multifactorial nature of tendon changes with diabetes and suggest that blood variables could be reliable predictors of tendon properties.
Introduction There is constant debate regarding the best surgical technique for the fixation of shaft humerus fractures. Intramedullary nailing and dynamic compression plating are the most popular surgical options. Materials and methods In our study, we retrospectively analyze the results of 27 patients with shaft humerus fractures managed with intramedullary nailing (10) and dynamic compression plating (17) at our institute from September 2021 to October 2022. Preoperative clinical assessment sheets, postoperative follow-up sheets, operative notes, anesthesia sheets, and preoperative and follow-up radiographs were analyzed. Reamed antegrade nailing was done in all cases, while dynamic compression plating was done through a posterior approach. Results The operative time of the nailing group was 82.1 ± 7.61 mins, which was significantly lesser (P value <0.05) than that of the plating group, which was 119.59 ± 10.16 mins. The intraoperative blood loss of the patients who were managed with nailing was 71 ± 7.38 mL, which was significantly lesser (P value <0.05) than that of the plating group, which was 130.59 ± 11.44 mL. The patients in both groups had a statistically nonsignificant difference in terms of functional results, which were assessed using Rodriguez-Merchan criteria. Complications were similar in both groups with infection (17.65%), and postoperative radial nerve palsy (11.76%) was more common among the patients undergoing plating, and shoulder impingement(20%) was common among those undergoing nailing. Conclusion This study concluded that both surgical options are similar in the case of functional results. The selection of the surgical method should be as per the surgeon's surgical familiarity and personalized to individual patients.
BACKGROUND: Increasing an individual's ability to focus on concrete, specific detail, thus reducing the tendency toward overly broad, decontextualised generalisations about the self and world, is a target within cognitive behavioural therapy (CBT). However, empirical investigation of the impact of within-treatment specificity on treatment outcomes is scarce. We evaluated whether the specificity of patient dialogue predicted a) end-of-treatment symptoms and b) session completion for CBT for common mental health issues. METHODS: This preregistered (https://osf.io/agr4t) study trained a deep learning model to score the specificity of patient dialogue in transcripts from 353,614 internet-enabled CBT sessions for common mental health disorders, delivered on behalf of UK NHS services. Data were from obtained from 65,030 participants (n = 47,308 female, n = 241 unstated) aged 18-94 years (M = 34.69, SD = 12.35). Depressive disorders were the most common (39.1 %) primary diagnosis. Primary outcome was end-of-treatment score on the Patient Health Questionnaire-9 (PHQ-9). Secondary outcome was number of sessions attended. RESULTS: Linear mixed-effects models demonstrated that increased patient specificity significantly predicted lower post-treatment symptoms on the PHQ-9, although the size and direction of the effect varied depending on the type of therapeutic activity being completed. Effect sizes were consistently small. Higher patient specificity was associated with completing a greater number of sessions. LIMITATIONS: We are unable to infer causation from our data. CONCLUSIONS: Although effect sizes were small, an effect of specificity was observed across common mental health disorders. Further studies are needed to explore whether encouraging patient specificity during CBT may provide an enhancement of treatment attendance and treatment effects.
Cognitive Behavioral Therapy , Deep Learning , Mental Disorders , Humans , Female , Mental Health , Mental Disorders/diagnosis , Mental Disorders/therapy , Treatment Outcome
Most school-based prevention curricula for young children fail to address multiple types of abuse and limit instruction to a single day, despite evidence that polyvictimization is common and children learn better when allowed to practice material repeatedly. This study utilized a cluster randomized control trial design to evaluate a multi-abuse prevention program, the Monique Burr Foundation for Children (MBF) Child Safety Matters®, based on varying lesson structure. Participants included nine Florida schools consisting of 843 children in grades K-2. Schools were randomized within cluster to implement in two lessons, four lessons, or after study data collection (i.e., control group). Lessons averaged 34 minutes (SD = 8.8 minutes) in length for 2-lesson group and 23.6 minutes (SD = 6.9 minutes) for the 4-lesson condition. Knowledge was assessed before implementation and on average 11 weeks after implementation. There were no statistical differences between clusters. Controlling for pre-test scores, schools in the four-lesson group scored highest on a measure of knowledge of potentially risky and unsafe situations (M = 69.68, SE = .80) on post-test, followed by schools in the two-lesson group (M = 67.31, SE = .77), followed by schools in the control group (M = 62.92, SE = .76). Results support use of more frequent, shorter lessons for prevention programs and the promise of addressing multiple forms of child victimization.
Child Abuse , Child , Humans , Child, Preschool , Child Abuse/prevention & control , Curriculum , Schools , School Health Services , Program Evaluation
BACKGROUND: Differences in treatment outcomes between community or academic centers are incompletely understood. METHODS: Retrospective review of head and neck cancer patients between 2010 and 2020 in a rural health region. Kaplan-Meier curves and log-rank tests were used to evaluate survival outcomes, along with bivariate and multivariable Cox proportional hazards models. Linear regression was used for functional outcomes of tracheotomy and gastrostomy tube dependence. RESULTS: Two hundred and forty-eight patients treated at an academic center were compared with 94 patients treated in community centers. In multivariable analysis, the risk of death (HR = 0.60, p = 0.019), and risk of recurrence were lower (HR = 0.29, p < 0.001) for patients treated in academic centers. Patients treated in community centers had longer gastrostomy tube dependence (p = 0.002). CONCLUSION: Our findings suggest that treatment at an academic center was associated with a lower risk of recurrence and shorter gastrostomy tube dependence compared to treatment in the community.
Chemoradiotherapy , Head and Neck Neoplasms , Humans , Chemoradiotherapy/adverse effects , Head and Neck Neoplasms/therapy , Head and Neck Neoplasms/etiology , Retrospective Studies , Gastrostomy , Treatment Outcome
PURPOSE: We report a novel method of intraoperative localization of a retained anterior intraocular foreign body (IOFB), using a combination of ultrasound biomicrosopy and an insulated needle. METHODS: A retrospective case report of a 56-year-old man who presented with a right eye IOFB. RESULTS: On presentation, vision was decreased in the right eye to count fingers with a small subconjunctival hemorrhage, but no other signs of a penetrating laceration. Orbital CT revealed an IOFB, and the initial vitrectomy failed to retrieve the IOFB. Then, during the subsequent vitrectomy, using an ultrasound compatible needle and an ultrasound biomicrosopy, we were able to precisely locate and remove the small anterior IOFB. CONCLUSION: Retained IOFBs can lead to severe irreversible vision loss if not promptly removed. Ancillary imaging modalities and localization techniques can help locate occult IOFBs in difficult cases.
Eye Foreign Bodies , Eye Injuries, Penetrating , Male , Humans , Middle Aged , Retrospective Studies , Microscopy, Acoustic , Eye Injuries, Penetrating/diagnostic imaging , Eye Injuries, Penetrating/surgery , Eye Foreign Bodies/diagnostic imaging , Eye Foreign Bodies/surgery , Vitrectomy/methods
BACKGROUND: Existing clinical trials of cognitive behavioural therapies with a trauma focus (CBTs-TF) are underpowered to examine key variables that might moderate treatment effects. We aimed to determine the efficacy of CBTs-TF for young people, relative to passive and active control conditions, and elucidate putative individual-level and treatment-level moderators. METHODS: This was an individual participant data meta-analysis of published and unpublished randomised studies in young people aged 6-18 years exposed to trauma. We included studies identified by the latest UK National Institute of Health and Care Excellence guidelines (completed on Jan 29, 2018) and updated their search. The search strategy included database searches restricted to publications between Jan 1, 2018, and Nov 12, 2019; grey literature search of trial registries ClinicalTrials.gov and ISRCTN; preprint archives PsyArXiv and bioRxiv; and use of social media and emails to key authors to identify any unpublished datasets. The primary outcome was post-traumatic stress symptoms after treatment (<1 month after the final session). Predominantly, one-stage random-effects models were fitted. This study is registered with PROSPERO, CRD42019151954. FINDINGS: We identified 38 studies; 25 studies provided individual participant data, comprising 1686 young people (mean age 13·65 years [SD 3·01]), with 802 receiving CBTs-TF and 884 a control condition. The risk-of-bias assessment indicated five studies as low risk and 20 studies with some concerns. Participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress symptoms before treatment (b=-13·17, 95% CI -17·84 to -8·50, p<0·001, τ2=103·72). Moderation analysis indicated that this effect of CBTs-TF on post-traumatic stress symptoms post-treatment increased by 0·15 units (b=-0·15, 95% CI -0·29 to -0·01, p=0·041, τ2=0·03) for each unit increase in pre-treatment post-traumatic stress symptoms. INTERPRETATION: This is the first individual participant data meta-analysis of young people exposed to trauma. Our findings support CBTs-TF as the first-line treatment, irrespective of age, gender, trauma characteristics, or carer involvement in treatment, with particular benefits for those with higher initial distress. FUNDING: Swiss National Science Foundation.
Cognitive Behavioral Therapy , Stress Disorders, Post-Traumatic , Child , Humans , Adolescent , Stress Disorders, Post-Traumatic/therapy , Stress Disorders, Post-Traumatic/psychology , Randomized Controlled Trials as Topic
Intravenous immunoglobulin (IVIG) is used to treat multiple conditions, one of which is Guillain-Barré syndrome. Despite its multiple benefits, IVIG can cause a wide variety of side effects, most of which resolve with supportive care. We present a case in which a patient with new-onset Guillain-Barré syndrome was treated with IVIG and subsequently developed an acute elevation in liver enzymes with positive hepatitis B serology.
Pneumatosis intestinalis (PI) is a relatively rare gastrointestinal finding that has a wide variety of causes - ranging from benign to life-threatening. It is described as the pathological presence of gas within the bowel wall with multiple hypotheses emerging as to the likely mechanism. An important indicator of a life-threatening source of PI is the presence of gas within the hepatic portal vein, referred to as hepatic portal venous gas (HPVG). While non-specific for isolated PI, HPVG has been reported in PI patients to be associated with bowel ischemia and is thereby considered an indication for emergent management. Herein we report a case involving an atypical presentation of altered mental status in which the patient was found to have PI with contemporaneous HPVG. These findings have been reported to have a high mortality rate. Our patient rapidly deteriorated during their hospital course, expiring shortly after being deemed a poor surgical candidate due to their severe co-morbidity burden. Through this case, we review evidence supporting the management of patients with PI and concurrent HPVG from an extensive review of available literature. While PI is a non-specific finding and commonly a source of diagnostic confusion, a better understanding of its natural course and potentially unorthodox sequela may afford more directed and crucial care for critically ill patients, in which time is often a precious commodity.
A 2-year-old boy with recently treated head lice presented with worsening right eyelid pruritus, irritation, and bleeding that was presumed to be a reinfection of head lice. Clinical examination revealed ectoparasites along the superior eyelid margin that were later identified as Phthirus pubis, or pubic lice. Treatment and management strategies are discussed. [J Pediatr Ophthalmol Strabismus. 2023;60(5):e55-e58.].
Eyelashes , Eyelid Diseases , Lice Infestations , Phthirus , Animals , Male , Humans , Child, Preschool , Eyelashes/parasitology , Lice Infestations/diagnosis , Lice Infestations/drug therapy , Lice Infestations/parasitology , Physical Examination , Eyelid Diseases/diagnosis
BACKGROUND: Medicinal plants play an essential role in everyday life; plants highly contain therapeutic phytoconstituents commonly used to treat various diseases. This paper discusses the Chemical composition, In vitro antiproliferative activity and In silico study of essential oil extracted from Ocimum tenuiflorum (family Lamiaceae), and Coriandrum sativum (family Apiaceae). OBJECTIVE: In present study GC-MS was used to identify the chemical constituents from O. tenuiflorum and C. sativum. In vitro antiproliferative activity was performed on A549 cancer cell lines. In silico study was performed by Schrodinger's maestro software to identify chemical constituents in both plants as potential EGFR inhibitors for the treatment of lung cancer. METHODS: The essential oil was extracted by hydro distillation from aerial parts of O. tenuiflorum and C. sativum. The volatile oil sample was analyzed by (GC-MS) Gas Chromatography-Mass Spectrometry. Different chemical constituents were identified based on the retention index and compared with the NIST library. The oil samples from O. tenuiflorum and C. sativum was also evaluated for antiproliferative activity against human lung cancer A549 cell lines. In silico study was performed by Schrodinger maestro software against EGFR (PDB ID 5HG8). RESULT: O. tenuiflorum essential oil contains Eugenol (42.90%), 2-ß-Elemene (25.98%), ß-Caryophyllene (19.12%) are the major constituents. On the other side, C. sativum contains n-nonadecanol-1 (16.37%), decanal (12.37%), dodecanal (12.27%), 2-Dodecanal (9.67%), Phytol (8.81%) as the major constituents. Both the oils have shown in vitro antiproliferative activity against human lung cancer cell lines A549 having IC50 values of 38.281µg/ml (O. tenuiflorum) and 74.536 µg/ml (C. sativum). Molecular interactions of constituents hydro distilled from two oils was analysed by schrodinger maestro software against EGFR (PDB ID 5HG8). CONCLUSION: The oil sample extracted from O. tenuiflorum showed more antiproliferative activity than C. sativum. In silico study showed that two chemical constituents, namely di-isobutyl phthalate (-7.542kcal/mol) and dibutyl phthalate (-7.181kcal/mol) from O. tenuiflorum and one diethyl phthalate (-7.224 kcal/mol) from C. sativum having more docking score than standard Osimertinib which indicates the effectiveness of oils for lung cancer.
The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with protein inhibition. Recent advancements in the biotech and pharmaceutical sectors have led to the development of compounds that are currently in human trials, with some showing promising clinical results. However, the use of computational tools in TPD is still limited, as it has distinct characteristics compared with traditional computational drug design methods. TPD involves creating a ternary structure (protein-degrader-ligase) responsible for the biological function, such as ubiquitination and subsequent proteasomal degradation, which depends on the spatial orientation of the protein of interest (POI) relative to E2-loaded ubiquitin. Modeling this structure necessitates a unique blend of tools initially developed for small molecules (e.g., docking) and biologics (e.g., protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, are generally larger than conventional small molecule drugs, leading to challenges in determining drug-like properties like solubility and permeability. Furthermore, the catalytic nature of TPD makes occupancy-based modeling insufficient. TPD consists of multiple interconnected yet distinct steps, such as POI binding, E3 ligase binding, ternary structure interactions, ubiquitination, and degradation, along with traditional small molecule properties. A comprehensive set of tools is needed to address the dynamic nature of the induced proximity ternary complex and its implications for ubiquitination. In this Perspective, we discuss the current state of computational tools for TPD. We start by describing the series of steps involved in the degradation process and the experimental methods used to characterize them. Then, we delve into a detailed analysis of the computational tools employed in TPD. We also present an integrative approach that has proven successful for degrader design and its impact on project decisions. Finally, we examine the future prospects of computational methods in TPD and the areas with the greatest potential for impact.
Biological Products , Humans , Proteolysis , Catalysis , Drug Design , Permeability
We describe a rare case of a Streptococcus pneumoniae (S. pneumoniae) infection causing mitral valve endocarditis and bacterial meningitis in a previously healthy young adult male in his 20s who presented with altered mentation. Though our patient did not endorse any respiratory issues, we suspected the paranasal sinuses to have been the cryptic primary source of disseminated infection into the respiratory system and meninges due to incidental mucosal thickening being found on imaging. Blood and cerebrospinal fluid analyses and cultures revealed the proliferation of S. pneumoniae serotype 23B, despite our patient having previously received appropriate pneumococcal vaccinations in his childhood without delinquency. Ultimately, surgical replacement of the mitral valve, as well as a course of ceftriaxone, was indicated for this patient, in which full resolution of symptoms was achieved upon discharge.
