A Comparative Analysis of Prophylactic Antibiotic Administration in Emergency Surgery Versus Elective Surgery: A Comprehensive Review.

Surgical site infections (SSIs) contribute to increased patient morbidity, prolonged hospital stays, and substantial healthcare costs. Prophylactic antibiotics play a pivotal role in mitigating the risk of SSIs, with their administration being a standard practice before both emergency and elective surgeries. This paper provides a comprehensive review and comparative analysis of the benefits of prophylactic antibiotic administration in emergency surgery versus elective surgery. Through a systematic literature review and analysis of relevant studies identified through PubMed searches, this paper highlights the specific benefits of prophylactic antibiotics between emergency and elective surgeries. The findings underscore the importance of tailored antibiotic regimens and administration protocols to optimize patient care and promote successful surgical outcomes in diverse clinical settings. Further research is warranted to refine guidelines and enhance understanding of the relationship between prophylactic antibiotics and surgical outcomes across different surgical contexts.

Impact of N-Glycosylation on Protein Structure and Dynamics Linked to Enzymatic C-H Activation in the M. oryzae Lipoxygenase.

Lipoxygenases (LOXs) from pathogenic fungi are potential therapeutic targets for defense against plant and select human diseases. In contrast to the canonical LOXs in plants and animals, fungal LOXs are unique in having appended N-linked glycans. Such important post-translational modifications (PTMs) endow proteins with altered structure, stability, and/or function. In this study, we present the structural and functional outcomes of removing or altering these surface carbohydrates on the LOX from the devastating rice blast fungus, M. oryzae, MoLOX. Alteration of the PTMs did notinfluence the active site enzyme-substrate ground state structures as visualized by electron-nuclear double resonance (ENDOR) spectroscopy. However, removal of the eight N-linked glycans by asparagine-to-glutamine mutagenesis nonetheless led to a change in substrate selectivity and an elevated activation energy for the reaction with substrate linoleic acid, as determined by kinetic measurements. Comparative hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis of wild-type and Asn-to-Gln MoLOX variants revealed a regionally defined impact on the dynamics of the arched helix that covers the active site. Guided by these HDX results, a single glycan sequon knockout was generated at position 72, and its comparative substrate selectivity from kinetics nearly matched that of the Asn-to-Gln variant. The cumulative data from model glyco-enzyme MoLOX showcase how the presence, alteration, or removal of even a single N-linked glycan can influence the structural integrity and dynamics of the protein that are linked to an enzyme's catalytic proficiency, while indicating that extensive glycosylation protects the enzyme during pathogenesis by protecting it from protease degradation.

Complete biosynthesis of QS-21 in engineered yeast.

QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans1,2. However, owing to the complex structure of QS-21, its availability is limited. Today, the supply depends on laborious extraction from the Chilean soapbark tree or on low-yielding total chemical synthesis3,4. Here we demonstrate the complete biosynthesis of QS-21 and its precursors, as well as structural derivatives, in engineered yeast strains. The successful biosynthesis in yeast requires fine-tuning of the host's native pathway fluxes, as well as the functional and balanced expression of 38 heterologous enzymes. The required biosynthetic pathway spans seven enzyme families-a terpene synthase, P450s, nucleotide sugar synthases, glycosyltransferases, a coenzyme A ligase, acyl transferases and polyketide synthases-from six organisms, and mimics in yeast the subcellular compartmentalization of plants from the endoplasmic reticulum membrane to the cytosol. Finally, by taking advantage of the promiscuity of certain pathway enzymes, we produced structural analogues of QS-21 using this biosynthetic platform. This microbial production scheme will allow for the future establishment of a structure-activity relationship, and will thus enable the rational design of potent vaccine adjuvants.

Vertebral Artery Dissection in a Young Adult: A Case Report.

Vertebral artery dissections (VAD) pose a significant risk for strokes, particularly in young adults. This case report details the presentation and management of a 48-year-old patient who was diagnosed with an extracranial VAD following cervical spine manipulation (CSM). The patient's symptoms included acute right-sided ataxia, giddiness, vertigo, nausea, vomiting, and persistent pain behind the right ear, prompting immediate evaluation. After ruling out acute intracerebral hemorrhages, a computed tomography angiogram (CTA) of the head and neck identified a severe narrowing of the right distal vertebral artery with a string sign at the level of the right C1 loop (V3 segment), indicating an extracranial VAD. This finding was further supported when ultrasound (US) imaging revealed a high resistance flow pattern in the right distal vertebral artery. Furthermore, T2 and diffusion-weighted magnetic resonance imaging (MRI) confirmed a 1.8 cm VAD/hematoma and a 1.4 cm acute/subacute infarct in the right posterior inferior cerebellar artery (PICA) territory. This research accentuates the importance of recognizing and addressing that neck pain can be a symptom of musculoskeletal dysfunction or could have neurovascular origins. In this case, the patient's neck pain may have been musculoskeletal or could have been due to a previous dissection. Thus, differentiation should be considered before cervical spine manipulation.

The Impact of Electrocautery Smoke on Surgical Staff and the Efficacy of Normal Surgical Masks Versus N95 Masks.

Electrocautery is a commonly used technique in surgical procedures, generating smoke that poses health risks to surgical staff. This study investigates the comparative efficacy of normal surgical masks versus N95 masks in mitigating the harmful effects of electrocautery smoke. Through a systematic review of literature spanning two decades, we explore the causes and effects of electrocautery smoke exposure, including potential long-term inhalation effects. Our findings highlight significant disparities in the protection offered by different masks and underscore the importance of adequate respiratory protection in surgical settings. In addition, we examine the factors influencing the generation and composition of electrocautery smoke, such as the power settings used, the type of tissue being cauterized, and the duration of the procedure. Furthermore, we discuss the potential health risks associated with long-term exposure to electrocautery smoke, including the possibility of respiratory conditions, cardiovascular effects, and carcinogenicity. Our analysis also addresses the importance of implementing appropriate smoke evacuation systems and optimizing operating room ventilation to minimize the concentration of smoke particles in the surgical environment. Overall, this comprehensive analysis provides valuable insights into the impact of electrocautery smoke in surgical settings and the varying levels of protection offered by different masks.

Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

A Geospatial Analysis of the Availability, Distribution, and Accessibility of Neurosurgical Facilities, Workforce, and Infrastructure in Nigeria; and Projection Towards 2050.

OBJECTIVE: There has been a modest but progressive increase in the neurosurgical workforce, training, and service delivery in Nigeria in the last 2 decades. However, these resources are unevenly distributed. This study aimed to quantitatively assess the availability and distribution of neurosurgical resources in Nigeria while projecting the needed workforce capacity up to 2050. METHODS: An online survey of Nigerian neurosurgeons and residents assessed the country's neurosurgical infrastructure, workforce, and resources. The results were analyzed descriptively, and geospatial analysis was used to map their distribution. A projection model was fitted to predict workforce targets for 2022-2050. RESULTS: Out of 86 neurosurgery-capable health facilities, 65.1% were public hospitals, with only 17.4% accredited for residency training. Dedicated hospital beds and operating rooms for neurosurgery make up only 4.0% and 15.4% of the total, respectively. The population disease burden is estimated at 50.2 per 100,000, while the operative coverage was 153.2 cases per neurosurgeon. There are currently 132 neurosurgeons and 114 neurosurgery residents for a population of 218 million (ratio 1:1.65 million). There is an annual growth rate of 8.3%, resulting in a projected deficit of 1113 neurosurgeons by 2030 and 1104 by 2050. Timely access to neurosurgical care ranges from 21.6% to 86.7% of the population within different timeframes. CONCLUSIONS: Collaborative interventions are needed to address gaps in Nigeria's neurosurgical capacity. Investments in training, infrastructure, and funding are necessary for sustainable development and optimized outcomes.

The Epidemiology of Spinal Neurosurgery in Nigeria: A Systematic Review and Patient-Level Analysis.

OBJECTIVE: Spinal pathologies are prevalent in Nigeria, though epidemiological data remains sparse. This systematic review used pooled patient-level data from across the country to generate a standardized epidemiological reference. METHODS: Four research databases and gray literature sources were searched. Risk of bias assessment was conducted using Risk of Bias in Non-Randomised Studies - of Interventions and Cochrane's risk of bias tool. We descriptively analyzed all article metrics and statistically analyzed relevant data variables via paired t-test and χ2 independence tests (α = 0.05). RESULTS: One hundred twenty-seven articles, comprising a patient cohort of 8425 patients, were analyzed. Most were retrospective cohort studies (46.5%) and case reports/series (31.5%), with an overall moderate-high risk of bias. Most studies were published in the last 20 years. Most patients were male (∼2.5 males per female), with an average age of 43.2 years (±16.4). Clinical diagnoses spanned the breadth of spinal neurosurgery. Approximately 45.0% of patients had complete spinal impairment. Pain (41.7%) was the most reported presenting feature. X-ray (45.1%) was the most common investigation used. Intervertebral disc herniation (18.9%) was the most prevalent imaging finding on MRI. Most patients were managed nonoperatively (57.8%), with a favorable outcome in 27.4% of patients. Posttreatment complications included pressure sores, infection, and motor deficits. CONCLUSIONS: This systematic review and pooled analysis provide an epidemiological overview of spinal neurosurgery in Nigeria over the last 60 years and serves as a useful reference to direct future global research in this arena.

The Epidemiological Burden of Neurovascular Pathology in Nigeria: A Systematic Review and Pooled Patient-Level Analysis.

OBJECTIVE: Vascular neurosurgery has developed significantly in Nigeria, but its burden and challenges remain unclear. This study systematically reviewed vascular neurosurgical literature from Nigeria. METHODS: Four research databases and gray literature sources were searched from 1962-2021. ROBINS-I tool was used to assess risk of bias. Descriptive, narrative, and statistical analyses were conducted on all variables. Where appropriate, paired t-tests and Chi-squared independence tests were used (α = 0.05). RESULTS: 56 articles were included and 3203 patients pooled for analysis. Risk of bias was moderate-high. Most articles were published over the last 20 years with retrospective cohort studies and case reports being the most common study designs. The cohort had a relatively even gender split and an average age of 49 years (±22). Cerebrovascular accidents accounted for over 85% of diagnoses, with most etiologies being traumatic. Headache and motor deficit were the most prevalent clinical features. X-ray and carotid angiography were the most commonly reported imaging modalities, closely followed by computed tomography (CT) and CT angiography. The top two radiological diagnoses were ischemic cerebrovascular disease and intracerebral hematoma. Aneurysmal clipping and hematoma evacuation were the most commonly reported treatment modalities. Outcome at last follow-up was favorable in 48%. The mortality rate was 6%. Post-treatment complications included chest infection and rebleeding. CONCLUSIONS: This study illustrates the epidemiological burden of neurovascular pathology (based on the available data in published literature) in Nigeria, and raises awareness amongst service providers and researchers of the attendant challenges and epochal trends seen within vascular neurosurgery in Nigeria.

Assessing the Neurosurgical Capacity in Nigeria Using the Modified Neuro-PIPES Tool.

BACKGROUND: Like many low- and-middle-income countries in Africa, documented assessment of the neurosurgical workforce, equipment, infrastructure, and scope of service delivery in Nigeria is lacking. This study aimed to assess the capacity for the delivery of neurosurgical services in Nigeria. METHODS: An 83-question survey was disseminated to neurosurgeons and residents in Nigeria. We report the findings from the capacity assessment section of the survey, which used the modified neurological-PIPES (personnel, infrastructure, procedures, equipment, and supplies) (MN-PIPES) tool to evaluate the availability of neurosurgical personnel, infrastructure, procedures, equipment, and supplies. A comparative analysis was done using the domain and total MN-PIPES scores and MN-PIPES index. RESULTS: The national average MN-PIPES score and index were 176.4 and 9.8, respectively. Overall, the southwest and northwest regions had the highest scores and frequently had high subscores. The survey respondents reported that the main challenges impeding neurosurgery service delivery were a lack of adjunctive supplies (75.2%), a dearth of diagnostic and interventional equipment (72.4%), and an absence of a dedicated intensive care unit (72.4%). CONCLUSIONS: The availability of workforce, infrastructure, equipment, and supplies needed to provide optimal neurosurgical care is uneven in many institutions in Nigeria. Although major strides have been made in recent years, targeted collaborative interventions at local, national, regional, and international levels will further improve neurosurgical service delivery in Nigeria and will have positive ripple effects on the rest of the healthcare system.

Perceived Barriers to Pursuing a Career in Neurosurgery in Nigeria: A Cross-Sectional Survey of Nigerian Medical Students and Unspecialized Physicians.

BACKGROUND: Nigeria has an inadequate number of neurosurgeons to meet the population's demand for neurosurgical care. Furthermore, few Nigerian neurosurgeons are female. This study sought to evaluate perceived barriers to pursuing neurosurgery among Nigerian trainees. METHODS: A 60-question survey was distributed electronically to medical students at the College of Medicine, University of Ibadan, and unspecialized intern physicians at the University College Hospital, Ibadan, Nigeria. Participation was voluntary. RESULTS: One hundred fifty-seven respondents participated in the survey. A greater proportion of males indicated an interest in neurosurgery than females (40% vs. 18%, P = 0.010). Over 75% of respondents identified decreased family and personal time, long work hours, and limited access to maternity or paternity leave as potential barriers to neurosurgery, with no differences by gender. Respondents overall saw being female and low-income as disadvantageous to pursuing neurosurgery in Nigeria. Although they universally viewed research as important in neurosurgery, 59% of respondents reported inadequate access to research opportunities; this did not vary by gender. However, 65% of female respondents reported that having a female neurosurgery mentor would increase their interest in neurosurgery (vs. 37% of males, P = 0.001). CONCLUSIONS: Nigerian medical trainees perceived the time commitment of neurosurgery as a major barrier to pursuing the specialty. Regardless of gender, they also reported low exposure to neurosurgery and inadequate access to research and mentorship opportunities. However, we found that enhanced female representation among neurosurgery mentors and improved work-life balance could increase interest in neurosurgery and help expand Nigeria's neurosurgical workforce.

Epidemiology and Management Trends of Neuro-Oncology in Nigeria: A Systematic Review and Pooled Analysis.

OBJECTIVE: Access to neuro-oncologic care in Nigeria has grown exponentially since the first reported cases in the mid-1960s. In this systematic review and pooled analysis, we characterize the growth of neurosurgical oncology in Nigeria and build a reference paper to direct efforts to expand this field. METHODS: We performed an initial literature search of several article databases and gray literature sources. We included and subsequently screened articles published between 1962 and 2021. Several variables were extracted from each study, including the affiliated hospital, the number of patients treated, patient sex, tumor pathology, the types of imaging modalities used for diagnosis, and the interventions used for each individual. Change in these variables was assessed using Chi-squared independence tests and univariate linear regression when appropriate. RESULTS: A total of 147 studies were identified, corresponding to 5,760 patients. Over 4000 cases were reported in the past 2 decades from 21 different Nigerian institutions. The types of tumors reported have increased over time, with increasingly more patients being evaluated via computed tomography (CT) and magnetic resonance imaging (MRI). There is also a prevalent use of radiotherapy, though chemotherapy remains an underreported treatment modality. CONCLUSIONS: This study highlights key trends regarding the prevalence and management of neuro-oncologic pathologies within Nigeria. Further studies are needed to continue to learn and guide the future growth of this field in Nigeria.

Women in Nigerian Neurosurgery: A Cross-Sectional Survey.

BACKGROUND: Although women have made remarkable strides in several medical specialties in Sub-Saharan Africa, their presence and contribution to the development of neurosurgery remain limited. We sought to study the gender differences within Nigerian neurosurgery, identify challenges resulting from these differences, and recommend how African female neurosurgeons can maximize their effects in neurosurgery. METHODS: A structured online survey captured data on neurosurgical infrastructural capacity, workforce, and training from neurosurgical consultants and residents in neurosurgical centers in Nigeria. All the collected data were coded and analyzed. RESULTS: Altogether, 82 neurosurgical consultants and 67 neurosurgical residents from 50 primary medical institutions in Nigeria completed the online survey. Only 8 of the respondents (5.4%) were women, comprising 3 consultants, 2 senior residents, and 3 junior residents. Although 40.2% of the respondents did not believe that being female affected the decision of whether to specialize in neurosurgery, 46.3% believed that being female was a disadvantage. Most did not believe that being female affected admission (57.8%), completion of a neurosurgery residency (58.5%), or life working as a neurosurgeon after graduation (63.4%). The most common challenges women face while navigating through neurosurgery training and practice are erosion of family and social life, lack of female mentors, and lack of a work-life balance. CONCLUSIONS: There is a deficit of both female consultants and trainees among Nigerian neurosurgeons. Identifying female medical students with a strong interest in neurosurgery and providing early mentorship might increase the number of female neurosurgeons.

Epidemiological Burden of Neurotrauma in Nigeria: A Systematic Review and Pooled Analysis of 45,763 Patients.

OBJECTIVE: Neurotrauma is a significant cause of morbidity and mortality in Nigeria. We conducted this systematic review to generate nationally generalizable reference data for the country. METHODS: Four research databases and gray literature sources were electronically searched. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions and Cochrane's risk of bias tools. Descriptive analysis, narrative synthesis, and statistical analysis (via paired t-tests and χ2 independence tests) were performed on relevant article metrics (α = 0.05). RESULTS: We identified a cohort of 45,763 patients from 254 articles. The overall risk of bias was moderate to high. Most articles employed retrospective cohort study designs (37.4%) and were published during the last 2 decades (81.89%). The cohort's average age was 32.5 years (standard deviation, 20.2) with a gender split of ∼3 males per female. Almost 90% of subjects were diagnosed with traumatic brain injury, with road traffic accidents (68.6%) being the greatest cause. Altered consciousness (48.4%) was the most commonly reported clinical feature. Computed tomography (53.5%) was the most commonly used imaging modality, with skull (25.7%) and vertebral fracture (14.1%) being the most common radiological findings for traumatic brain injury and traumatic spinal injury, respectively. Two-thirds of patients were treated nonoperatively. Outcomes were favorable in 63.7% of traumatic brain injury patients, but in only 20.9% of traumatic spinal injury patients. Pressure sores, infection, and motor deficits were the most commonly reported complications in the latter. CONCLUSIONS: This systematic review and pooled analysis demonstrate the significant burden of neurotrauma across Nigeria.

Neurosurgical Practice, Training, and Research Capacity Assessment in Nigeria: A Methodological Approach.

OBJECTIVE: There has been a progressive growth of neurosurgery in Nigeria over the past 6 nulldecades. This study aims to comprehensively evaluate the state of neurosurgical practice, training, and research in the country. METHODS: We used a mixed-methods approach that combined a survey of neurosurgery providers and a systematic review of the neurosurgical literature in Nigeria. The 83-question online survey had 3 core sections for assessing capacity, training, and gender issues. The systematic review involved a search of 4 global databases and gray literature over a 60-year period. RESULTS: One hundred and forty-nine respondents (95% male) completed the survey (65.4%). Their age ranged from 20 to 68 years, with a mean of 41.8 (±6.9) years. Majority were from institutions in the nation's South-West region; 82 (55.0%) had completed neurosurgery residency training, with 76 (51%) employed as consultants; 64 (43%) identified as residents in training, 56 (37.6%) being senior residents, and 15 (10.1%) each held academic appointments as lecturers or senior lecturers. The literature review involved 1,023 peer-reviewed journal publications: 254 articles yielding data on 45,763 neurotrauma patients, 196 on 12,295 pediatric neurosurgery patients, and 127 on 8,425 spinal neurosurgery patients. Additionally, 147 papers provided data on 5,760 neuro-oncology patients, and 56 on 3,203 patients with neuro-vascular lesions. CONCLUSIONS: Our mixed-methods approach provided significant insights into the historical, contemporary, and future trends of neurosurgery in Nigeria. The results could form the foundation for policy improvement; health-system strengthening; better resource-planning, prioritization, and allocation; and more purposive collaborative engagement in Nigeria and other low- and middle-income countries.

In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Revisiting Textbook Azide-Clock Reactions: A "Propeller-Crawling" Mechanism Explains Differences in Rates.

An ongoing challenge to chemists is the analysis of pathways and kinetics for chemical reactions in solution, including transient structures between the reactants and products that are difficult to resolve using laboratory experiments. Here, we enabled direct molecular dynamics simulations of a textbook series of chemical reactions on the hundreds of ns to µs time scale using the weighted ensemble (WE) path sampling strategy with hybrid quantum mechanical/molecular mechanical (QM/MM) models. We focused on azide-clock reactions involving addition of an azide anion to each of three long-lived trityl cations in an acetonitrile-water solvent mixture. Results reveal a two-step mechanism: (1) diffusional collision of reactants to form an ion-pair intermediate; (2) "activation" or rearrangement of the intermediate to the product. Our simulations yield not only reaction rates that are within error of experiment but also rates for individual steps, indicating the activation step as rate-limiting for all three cations. Further, the trend in reaction rates is due to dynamical effects, i.e., differing extents of the azide anion "crawling" along the cation's phenyl-ring "propellers" during the activation step. Our study demonstrates the power of analyzing pathways and kinetics to gain insights on reaction mechanisms, underscoring the value of including WE and other related path sampling strategies in the modern toolbox for chemists.

Reducing target binding affinity improves the therapeutic index of anti-MET antibody-drug conjugate in tumor bearing animals.

Many oncology antibody-drug conjugates (ADCs) have failed to demonstrate efficacy in clinic because of dose-limiting toxicity caused by uptake into healthy tissues. We developed an approach that harnesses ADC affinity to broaden the therapeutic index (TI) using two anti-mesenchymal-epithelial transition factor (MET) monoclonal antibodies (mAbs) with high affinity (HAV) or low affinity (LAV) conjugated to monomethyl auristatin E (MMAE). The estimated TI for LAV-ADC was at least 3 times greater than the HAV-ADC. The LAV- and HAV-ADCs showed similar levels of anti-tumor activity in the xenograft model, while the 111In-DTPA studies showed similar amounts of the ADCs in HT29 tumors. Although the LAV-ADC has ~2-fold slower blood clearance than the HAV-ADC, higher liver toxicity was observed with HAV-ADC. While the SPECT/CT 111In- and 124I- DTPA findings showed HAV-ADC has higher accumulation and rapid clearance in normal tissues, intravital microscopy (IVM) studies confirmed HAV mAb accumulates within hepatic sinusoidal endothelial cells while the LAV mAb does not. These results demonstrated that lowering the MET binding affinity provides a larger TI for MET-ADC. Decreasing the affinity of the ADC reduces the target mediated drug disposition (TMDD) to MET expressed in normal tissues while maintaining uptake/delivery to the tumor. This approach can be applied to multiple ADCs to improve the clinical outcomes.