Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex.

The development of neural circuits relies on axon projections establishing diverse, yet well-defined, connections between areas of the nervous system. Each projection is formed by growth cones-subcellular specializations at the tips of growing axons, encompassing sets of molecules that control projection-specific growth, guidance, and target selection1. To investigate the set of molecules within native growth cones that form specific connections, here we developed growth cone sorting and subcellular RNA-proteome mapping, an approach that identifies and quantifies local transcriptomes and proteomes from labelled growth cones of single projections in vivo. Using this approach on the developing callosal projection of the mouse cerebral cortex, we mapped molecular enrichments in trans-hemispheric growth cones relative to their parent cell bodies, producing paired subcellular proteomes and transcriptomes from single neuron subtypes directly from the brain. These data provide generalizable proof-of-principle for this approach, and reveal molecular specializations of the growth cone, including accumulations of the growth-regulating kinase mTOR2, together with mRNAs that contain mTOR-dependent motifs3,4. These findings illuminate the relationships between subcellular distributions of RNA and protein in developing projection neurons, and provide a systems-level approach for the discovery of subtype- and stage-specific molecular substrates of circuit wiring, miswiring, and the potential for regeneration.

A circuit-level biomarker of Rett syndrome based on ectopic phase-amplitude coupling during slow-wave-sleep.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of purposeful hand use and spoken language following an initial period of normal development. Although much is known about the genetic and molecular underpinnings of RTT, less is known about the circuit-level etiopathology. Coupling of oscillations during slow-wave-sleep (SWS) underlies important neurocognitive processes in adulthood, yet its emergence has yet to be described in early typical development (TD) or in RTT. We therefore addressed these unknowns by describing SWS cross-frequency coupling in both RTT and early TD using a retrospective study design. We found that in TD, phase-amplitude coupling (PAC) during SWS was dominated by coupling of slow-wave (0.5-2 Hz) phase to theta amplitude (5-8 Hz, "SW:T") as well as slow-wave to spindle-range (12-15 Hz, "SW:S"). Coupling exhibited characteristic vertex-prominent spatial topography, which emerged during an early developmental window. This topography failed to develop in patients with RTT due to persistent ectopic coupling. Furthermore, we found that subtypes of RTT exhibit distinct PAC topographic profiles, and that ectopic PAC correlates with clinical severity. These findings suggest that altered PAC dynamics and spatial organization during SWS may underlie the circuit-level pathophysiology of RTT and suggest that ectopic coupling may contribute to RTT pathogenesis.

A Two-Stage Injection Technique and Dose-Ranging Study Using High-Dose AbobotulinumtoxinA for Treating Platysmal Bands.

BACKGROUND: AbobotulinumtoxinA (aboBoNT-A) is useful for the treatment of platysmal banding. This study evaluated the efficacy and safety of a standardized 2-staged injection technique using high doses of AboBoNT-A for treating platysmal banding. METHODS: This was a randomized, double-blinded, dose-ranging prospective study. Subjects included adults with moderate-to-severe platysmal bands (grade 3 or 4 on the validated 5-point photographic scale), who received either 120 U (Cohort 1) or 180 U (Cohort 2) of aboBoNT-A, followed by an optional 90 U touch-up. The relatively higher on-label concentration of aboBoNT-A was used (1.5 mL/300 units) to reduce the volume injected and the risk of spread to adjacent muscles. Subjects were followed for 5 months, with safety and efficacy endpoints evaluated by the Investigator Live Assessment (ILA) and Subject Live Assessment (SLA). RESULTS: Twenty women were included in the analysis. Cohort 1 and Cohort 2 had 100% and 90% responder rates (achieved grade 1 or 2) during maximal contraction at month 1 with ILA. Cohort 2 had more subjects with 2 or greater grade improvement at maximal contraction using both ILA and SLA. Cohort 2 also had longer time to loss of grade 1 or 2 at maximal contraction compared with Cohort 1. No major adverse reactions occurred, but 3 subjects experienced transient positional neck weakness. CONCLUSION: We demonstrate a standardized 2-stage injection technique using aboBoNT-A for effectively treating moderate-to-severe platysmal banding. We used relatively higher doses while maintaining a good safety profile by using the more concentrated on-label volume of reconstitution for aboBoNT-A and by including a touch-up. J Drugs Dermatol. 2024;23(1):1311-1318.     doi:10.36849/JDD.7537.

Returning integrated genomic risk and clinical recommendations: The eMERGE study.

PURPOSE: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk. METHODS: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results. RESULTS: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022. CONCLUSION: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Recognizing thyrotoxic hypokalemic periodic paralysis.

Thyrotoxic hypokalemic periodic paralysis (THPP) is a rare but potentially serious complication of thyrotoxicosis. The resulting muscle weakness is profound, associated with more severe hypokalemia, yet reversible. However, clinicians must be cautious because patients can develop life-threatening hyperkalemia during treatment. Underlying causes should be investigated as repeated episodes of THPP may occur.

Fibrinolysis in Trauma: "Myth," "Reality," or "Something in Between".

The emphasis on fibrinolysis as an important contributor to trauma-induced coagulopathy (TIC) has led to a debate regarding the relative clinical significance of fibrinolysis in the setting of trauma. The debate has centered on two camps. The one camp defines fibrinolysis in trauma by standard coagulation tests as well as fibrin split products, D-dimers, and plasmin/antiplasmin levels. This camp favors a more liberal use of tranexamic acid and attributes more significance to hyperfibrinolysis in TIC. The other camp favors a definition of fibrinolysis based on the viscoelastic tests (VET), rotational thromboelastometry (ROTEM), and thromboelastography (TEG). These whole blood assays define hyperfibrinolysis at a higher threshold than plasma-based tests. Therefore, this VET camp reserves antifibrinolytic treatment for patients who demonstrate severe coagulopathy associated with hyperfibrinolysis. This bimodal attribution of the clinical relevance of fibrinolysis in trauma suggests that there may be an underlying "Myth" of the concept of TIC that was historically defined by plasma-based tests and a future "Reality" of the concept of TIC that is grounded on an understanding of TIC based on a VET-defined "fibrinolytic spectrum" of TIC. This narrative review explores this "Myth" and "Reality" of fibrinolysis in TIC and proposes a direction that will allow a "Future" interpretation of TIC that incorporates both the past "Myth" and present "Reality" of fibrinolysis TIC.

Tranexamic Acid for Trauma Resuscitation in the United States of America.

The utilization of tranexamic acid (TXA) for the management of bleeding trauma patients has been a subject of much debate on both sides of the Atlantic and in Australia. As a result of the large randomized controlled study called the Clinical Randomization of an Antifibrinolytic in Severe Hemorrhage (CRASH-2), there was an initial enthusiasm for the use of TXA to treat bleeding patients. However, the adoption of TXA in the United States was delayed by concerns of "knowledge and evidence gaps" of the CRASH-2 study and because of a lack of mechanistic rationale that would explain the survival benefit noted in the study. Subsequent nonrandomized controlled trials questioned the liberal use of TXA in trauma patients. This narrative review explores the historical as well as clinical and theoretical grounds for the more measured use of TXA in the United States and proposes a clinical and point-of-care guided utilization of TXA, blood components, and adjunctive hemostatic agents in bleeding trauma patients.

Intra-amniotic transient transduction of the periderm with a viral vector encoding TGFß3 prevents cleft palate in Tgfß3(-/-) mouse embryos.

Cleft palate is a developmental defect resulting from the failure of embryonic palatal shelves to fuse with each other at a critical time. Immediately before and during palatal fusion (E13-E15 in mice), transforming growth factor ß3 (TGFß3) is expressed in the palatal shelf medial edge epithelium (MEE) and plays a pivotal role in palatal fusion. Using Tgfß3(-/-) mice, which display complete penetrance of the cleft palate phenotype, we tested the hypothesis that intra-amniotic gene transfer could be used to prevent cleft palate formation by restoring palatal midline epithelial function. An adenoviral vector encoding Tgfß3 was microinjected into the amniotic sacs of mouse embryos at successive developmental stages. Transduced Tgfß3(-/-) fetuses showed efficient recovery of palatal fusion with mesenchymal confluence following injection at E12.5 (100%), E13.5 (100%), E14.5 (82%), and E15.5 (75%). Viral vectors injected into the amniotic sac transduced the most superficial and transient peridermal cell layer but not underlying basal epithelial cells. TGFß3 transduction of the peridermdal cell layer was sufficient to induce adhesion, fusion, and disappearance of the palatal shelf MEE in a cell nonautonomous manner. We propose that intra-amniotic gene transfer approaches have therapeutic potential to prevent cleft palate in utero, especially those resulting from palatal midline epithelial dysfunction.

Symmetry in levels of axon-axon homophilic adhesion establishes topography in the corpus callosum and development of connectivity between brain hemispheres.

Specific and highly diverse connectivity between functionally specialized regions of the nervous system is controlled at multiple scales, from anatomically organized connectivity following macroscopic axon tracts to individual axon target-finding and synapse formation. Identifying mechanisms that enable entire subpopulations of related neurons to project their axons with regional specificity within stereotyped tracts to form appropriate long-range connectivity is key to understanding brain development, organization, and function. Here, we investigate how axons of the cerebral cortex form precise connections between the two cortical hemispheres via the corpus callosum. We identify topographic principles of the developing trans-hemispheric callosal tract that emerge through intrinsic guidance executed by growing axons in the corpus callosum within the first postnatal week in mice. Using micro-transplantation of regionally distinct neurons, subtype-specific growth cone purification, subcellular proteomics, and in utero gene manipulation, we investigate guidance mechanisms of transhemispheric axons. We find that adhesion molecule levels instruct tract topography and target field guidance. We propose a model in which transcallosal axons in the developing brain perform a "handshake" that is guided through co-fasciculation with symmetric contralateral axons, resulting in the stereotyped homotopic connectivity between the brain's hemispheres.

The Efficacy of Physical Therapy to Alleviate Symptomatic Thoracic Radiculopathy: A Systematic Review and Meta-Narrative Analysis.

To evaluate the efficacy of physical therapy (PT) to alleviate symptomatic thoracic radiculopathy (TR) without the use of invasive procedures. Database search was conducted by an experienced medical librarian from inception until January 27, 2023, in EBSCO CINAHL with Full Text, Ovid Cochrane Central Register of Controlled Trials, Ovid Embase, Ovid MEDLINE, Scopus, and Web of Science Core Collection. Inclusion criteria included studies that involved adult patients (age≥18) who had a magnetic resonance imaging-confirmed TR and underwent a structured, supervised PT program of any length. All types of studies were included. Study quality and risk of bias were assessed using the National Heart, Lung, and Blood Institute (NHLBI) Study Quality of Assessment Tool. Certainty in evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. A meta-analysis was not performed. A total of 1,491 studies were screened and 7 studies met inclusion criteria, 5 case studies and 2 cohort studies. All studies showed improvement or resolution of the TR with PT. Quantitative improvements were not noted in most studies and PT regimens were sparsely described. Overall quality assessment demonstrated 3 studies had "good," 1 "fair," and 3 "poor" quality evidence. Certainty of evidence was "low" due to risk of bias. A dedicated PT program may help to alleviate symptomatic TR; however due to limited evidence, risk of bias, and low certainty in evidence, the data is too weak to support a definite conclusion.

Platelet dysfunction is an early marker for traumatic brain injury-induced coagulopathy.

BACKGROUND: The goal of this study is to determine the presence of platelet dysfunction in patients with traumatic brain injury (TBI). The mechanisms underlying the coagulopathy associated with TBI remain elusive. The question of platelet dysfunction in TBI is unclear. METHODS: This was a prospective observational study conducted at Memorial Hospital of South Bend, IN, and Denver Health Medical Center, CO. A total of 50 patients sustaining TBI, and not under treatment with anticoagulants or platelet inhibitors, were analyzed utilizing modified thromboelastography (TEG) with platelet mapping (TEG/PM), along with standard coagulation tests. RESULTS: Compared to normal controls, patients with severe TBI had a significantly increased percentage of platelet ADP and arachidonic acid (AA) receptor inhibition. Furthermore, the percentage of ADP inhibition distinguished between survivors and non-survivors in patients with TBI (Mann-Whitney test, P = 0.035). ADP inhibition correlates strongly with severity of TBI (Mann-Whitney test, P = 0.014), while AA inhibition did not. CONCLUSION: These data indicate that early platelet dysfunction is prevalent after severe TBI, can be measured in a point-of-care setting using TEG/PM, and correlates with mortality. The mechanism responsible for this platelet dysfunction and associated implications for TBI management remains to be defined.

Variation in cardiopulmonary restoration due to bodily posture post-submaximal exercise in collegiate athletes.

BACKGROUND: The body's anatomical position can influence the autonomic response to return to homeostasis following high intensity exercise. Discrepancies exist as to which body position is considered optimal and practical. This study intends to examine three recovery positions post submaximal exercise to determine which body position would be the most efficient in terms of excess post-exercise oxygen consumption and heart rate recovery. METHODS: NCAA Division I athletes (N.=17) from multiple sport teams completed three submaximal exercise tests utilizing the Bruce Protocol. Excess post-exercise oxygen consumption and heart rate recovery were measured at peak exercise and at 1-, 5-, and 10-minute time intervals during the recovery phase while assuming a recovery position: supine, trunk forward leaning, and standing vertical. RESULTS: Statistical analysis showed the 1-minute excess post-exercise oxygen consumption associated with supine recovery (1725±348 mL/kg) was significantly greater than standing vertical (1578±340 mL/kg, P=0.024). At 5 minutes, supine excess post-exercise oxygen consumption (3557±760 mL/kg) was significantly less than trunk forward leaning (4054±777 mL/kg, P=0.0001) and trunk forward leaning was significantly greater than standing vertical (3776±700 mL/kg, P=0.008). At 10 minutes, supine excess post-exercise oxygen consumption (5246±961 mL/kg) was significantly less than both the standing vertical position (5878±1042 mL/kg, P=0.0099), and the trunk forward leaning position (6749±1223 mL/kg, P<0.0001). Supine had the highest heart rate recovery at 1-, 5-, and 10-minutes post exercise. CONCLUSIONS: The supine position proved to be the most optimal during the 10-minute recovery period, while the trunk forward leaning position showed to be a more advantageous position for short-term recovery.

Effects of Different Percentages of Blood Flow Restriction on Muscle Oxygen Saturation While Walking.

The purpose of this investigation was to determine the effect of different relative pressures of blood flow restriction (BFR) on muscle oxygen saturation (SmO2) while walking at 3.0 mph (4.83 kph). Fifteen physically active healthy adults performed seven 5-minute stages of walking at 3.0 mph with a blood flow restriction cuff applied to the proximal portion of the left or right leg while bilateral SmO2 changes were measured using near infra-red spectroscopy (NIRS) on the medial head of the gastrocnemius (GM) and vastus lateralis (VL) muscles. Other measurements including heart rate (HR), blood pressure (BP), rating of perceived exertion (RPE), and ground contact time balance (GCTB) were also collected. SmO2 measurements were analyzed using two-way repeated measures (RM) ANOVA while other measurements were analyzed using one-way RM ANOVA. We observed a significant main effect of LOP% (limb occlusion pressure) on the difference in total area of desaturation that occurred during each occlusion stage (ADS), p < 0.0001 η2 = .336, early ΔSmO2, p < 0.0001 in both the GAS η2 = .132 and VL η2 = .335. The results suggest that there are significant differences in SmO2 desaturation between 40%, 80%, and 100% LOP. Our findings suggest that incremental increases in LOP will bring about greater SmO2 desaturation during walking and may therefore induce a larger adaptive response on the muscles. However, increased LOP% may intensify perception of effort.

Impact of a near-peer teaching program within a college of pharmacy on interest in mentoring roles.

BACKGROUND AND PURPOSE: Near-peer teaching within healthcare education has numerous benefits, but there is limited literature to assess the impact that these experiences have on skill development and future teaching roles. This study describes the impact of serving as a near-peer teaching assistant on both former and current pharmacy students. EDUCATIONAL ACTIVITY AND SETTING: The University of Texas at Austin College of Pharmacy implemented the Academic Assistant (AA) program in 2009 to provide an opportunity for students to participate as near-peer educators in a variety of courses. To determine the impact of these AA positions on current and former students, participants from five years of the program were surveyed regarding the impact of the program on skill development and current or future interest in teaching/mentoring. FINDINGS: Current students in the AA program reported that participation increased the likelihood of pursuing a career with teaching/mentoring roles. A majority (65%) of alumni who participated in the program reported being in a current teaching/mentoring role with 42% responding that the AA program was impactful to their career choice. The qualitative analysis showed that direct impact to respondents included validating career goals and increasing interests in teaching/mentoring roles. Those who reported no direct impact on their career still gained valuable professional skills that included: public speaking, time management, broadened perspectives, and increased understanding of academia career expectations. SUMMARY: Providing opportunities for pharmacy students to serve in near-peer teaching roles increased students' interest in pursuing teaching/mentoring roles and offered valuable professional experiences.

Rapid modeling of an ultra-rare epilepsy variant in wild-type mice by in utero prime editing.

Generating animal models for individual patients within clinically-useful timeframes holds great potential toward enabling personalized medicine approaches for genetic epilepsies. The ability to rapidly incorporate patient-specific genomic variants into model animals recapitulating elements of the patient's clinical manifestations would enable applications ranging from validation and characterization of pathogenic variants to personalized models for tailoring pharmacotherapy to individual patients. Here, we demonstrate generation of an animal model of an individual epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A, without the need for germline transmission and breeding. Using in utero prime editing in the brain of wild-type mice, our approach yielded high in vivo editing precision and induced frequent, spontaneous seizures which mirrored specific elements of the patient's clinical presentation. Leveraging the speed and versatility of this approach, we introduce PegAssist, a generalizable workflow to generate bedside-to-bench animal models of individual patients within weeks. The capability to produce individualized animal models rapidly and cost-effectively will reduce barriers to access for precision medicine, and will accelerate drug development by offering versatile in vivo platforms to identify compounds with efficacy against rare neurological conditions.

Safety, effectiveness and tolerability of sublingual ketamine in depression and anxiety: A retrospective study of off-label, at-home use.

Intravenous and intranasal ketamine have been shown to be effective therapeutic options in patients suffering from treatment-resistant depression (TRD). The use of sublingual (SL), rapid dissolve ketamine tablets (RDT) offers a novel approach for delivery for mental health indications. This study assessed the effectiveness and safety of self-administration of off-label, SL, rapid dissolve ketamine tablets (RDT) at-home for depression and anxiety. Intake scores on the Generalized Anxiety Disorder Screener (GAD-7) and Patient Health Questionnaire (PHQ-9) were compared to scores after treatments of three doses of ketamine RDT, and after six doses of ketamine RDT. After three doses of SL ketamine, 47.6% of patients showed a significant decrease in PHQ-9 scores, and 47.6% of patients showed a significant reduction in GAD-7 scores. Reduction rates were higher in those patients who completed a clinically recommended six doses of RDT ketamine. This study demonstrates that SL ketamine is a novel, safe, and effective treatment for TRD and treatment-resistant anxiety. SL ketamine offers an alternative therapeutic approach to IV ketamine when treating those with TRD.

CoreGenes5.0: An Updated User-Friendly Webserver for the Determination of Core Genes from Sets of Viral and Bacterial Genomes.

The determination of core genes in viral and bacterial genomes is crucial for a better understanding of their relatedness and for their classification. CoreGenes5.0 is an updated user-friendly web-based software tool for the identification of core genes in and data mining of viral and bacterial genomes. This tool has been useful in the resolution of several issues arising in the taxonomic analysis of bacteriophages and has incorporated many suggestions from researchers in that community. The webserver displays result in a format that is easy to understand and allows for automated batch processing, without the need for any user-installed bioinformatics software. CoreGenes5.0 uses group protein clustering of genomes with one of three algorithm options to output a table of core genes from the input genomes. Previously annotated "unknown genes" may be identified with homologues in the output. The updated version of CoreGenes is able to handle more genomes, is faster, and is more robust, providing easier analysis of custom or proprietary datasets. CoreGenes5.0 is accessible at coregenes.org, migrating from a previous site.

Blood glutamine synthetase signaling in alcohol use disorder and racial disparity.

As of 2018, 14.4 million adults ages 18 and older in the U.S had alcohol use disorder (AUD). However, only about 8% of adults who had AUD in the past year received treatment. Surveys have also shown racial disparities regarding AUD treatments. Thus, it is imperative to identify racial disparities in AUD patients, as it may indicate a specific underlying pathophysiology in an AUD subpopulation. To identify racial disparity in AUD, we enrolled 64 cohorts, including 26 AUD participants and 38 healthy controls, from Northwest Louisiana using community-based enrollment. Then, we used psychometric scales to assess alcohol drinking patterns and measured blood metabolites change using LC-MS/MS. Alcohol-related scales from the questionnaires did not differ between the Caucasian AUD participants and African-American AUD participants. From blood metabolomics analyses, we identified that 6 amino acids were significantly different by AUD status and or race. Interestingly, Caucasian AUD participants had a higher glutamate metabolism mediated by glutamine synthetase (GS). The correlation between blood glutamate/glutamine ratio and GS activity was only significant in the Caucasian AUD group whereas no changes were observed in African-American AUD group or controls. Taken together, our findings from this sample population demonstrate that blood GS is a potential biomarker associated with Caucasian AUD, which is an important step towards the application of a new pharmacological treatment for AUD.

Use of Thromboelastography and Rotational Thromboelastometry in Otolaryngology: A Narrative Review.

In the field of otolaryngology-head and neck surgery (ENT), coagulopathies present unique diagnostic and therapeutic challenges. In both hyper- and hypocoagulable patients, management of coagulopathies requires intricate attention to the nature of hemostatic competence. Common coagulation tests (CCTs) offer only a snapshot of hemostatic competence and do not provide a clear insight into the patient's real-time hemostatic condition. Viscoelastic tests (VETs) offer a holistic and concurrent picture of the coagulation process. Although VETs have found prominent utilization in hepatic transplants, obstetrics, and emergent surgical settings, they have not been fully adopted in the realm of otolaryngology. The objective of this manuscript is to provide an overview of the literature evaluating the current utilization and possible future uses of VETs in the field of otolaryngology. The authors performed a comprehensive literature search of the utilization of VETs in otolaryngology and identified applicable studies that included descriptions of viscoelastic testing. Twenty-five studies were identified in this search, spanning topics from head and neck oncology, microvascular free flap reconstruction, obstructive sleep apnea, adenotonsillectomy, facial trauma, and epistaxis. The applicability of VETs has been demonstrated in head and neck oncology and microvascular free flap management, although their pervasiveness in practice is limited. Underutilization of VETs in the field of otolaryngology may be due to a lack of familiarity of the tests amongst practitioners. Instead, most otolaryngologists continue to rely on CCTs, including PT, PTT, INR, CBC, fibrinogen levels, and thrombin time. Learning to perform, interpret, and skillfully employ VETs in clinical and operative practice can greatly improve the management of coagulopathic patients who are at increased risk of bleeding or thrombosis.

Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource.

BACKGROUND: Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development. RESULTS: Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. CONCLUSIONS: Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/ .