An Expert Review of Chest Wall Fascial Plane Blocks for Cardiac Surgery.

The recent integration of regional anesthesia techniques into the cardiac surgical patient population has become a component of enhanced recovery after cardiac surgery pathways. Fascial planes of the chest wall enable single-injection or catheter-based infusions to spread local anesthetic over multiple levels of innervation. Although median sternotomy remains a common approach to cardiac surgery, minimally invasive techniques have integrated additional methods of performing cardiac surgery. Understanding the surgical approach and chest wall innervation is crucial to success in choosing the appropriate chest wall block. Parasternal intercostal plane techniques (previously termed "pectointercostal fascial plane" and "transversus thoracic muscle plane") provide anterior chest and ipsilateral sternal coverage. Anterolateral chest wall coverage is feasible with the interpectoral plane and pectoserratus plane blocks (previously termed "pectoralis") and superficial and deep serratus anterior plane blocks. The erector spinae plane block provides extensive coverage of the ipsilateral chest wall. Any of these techniques has the potential to provide bilateral chest wall analgesia. The relative novelty of these techniques requires ongoing research to be strategic, thoughtful, and focused on clinically meaningful outcomes to enable widespread evidence-based implementation. This review article discusses the key perspectives for performing and assessing chest wall blocks in a cardiac surgical population.

Fibrillar matrix, Echogenicity, Contour, Thickness, and Suture (FECTS) vs. Global: A comparison of 2 scales developed to assess ultrasound images post rotator cuff repair.

BACKGROUND: Ultrasound is commonly used to assess rotator cuff repair (RCR), but no standardized criterion exists to characterize the tendon. PURPOSE: The aims of this study were to (1) develop content validity for ultrasound specific criteria to grade the postoperative appearance of a tendon after RCR, (2) assess the reliability of the criteria, and (3) assess the feasibility to use these assessments. METHODOLOGY: Following expert consultation and literature review for content validity, 2 scales were created: 1) the Fibrillar matrix, Echogenicity, Contour, Thickness, and Suture (FECTS) scale and 2) the Rotator Cuff Repair-Investigator Global Assessment (RCR-IGA). A prospective cohort study was undertaken on patients who had received a RCR and serial B-mode ultrasound images. Four raters assessed the 64-ultrasound images using the scales created in a blinded fashion using intraclass correlation coefficients. RESULTS: The FECTS scale was a composite score with 5 key parameters and the RCR-IGA scale was a 5-point global score. The intrarater reliability for the FECTS scale was excellent for the most experienced rater (0.92) and fair for the rater with no experience (0.72). The intrarater reliability for the RCR-IGA scale was excellent for 3 of the 4 raters (0.80-0.87) and fair when used by the least experienced rater (0.56). Inter-rater testing for all the FECTS scale parameters had excellent reliability (0.82-0.92) except for Fibrillar matrix (0.73). The average time to complete the FECTS scale per image was 23 seconds and 11 seconds for the RCR-IGA scale. CONCLUSION: The FECTS scale and the RCR-IGA scale are reliable tools to assess the ultrasonic appearance of the repaired rotator cuff tendon. The FECTS scale was more reliable for less experienced assessors. The RCR-IGA scale was easier, more time efficient and reliable for those with experience.

More-Than-Human: A Cross-Sectional Study Exploring Children's Perceptions of Health and Health-Promoting Neighbourhoods in Aotearoa New Zealand.

A disconnect between children's ideas and their incorporation into environmental design, in the context of rapid urbanisation and climate crises, compelled us to reflect on children's meaningful participation in positive environmental change. Our research aimed to bring new knowledge to the fore using a participatory, child-centred approach to understanding children's perceptions of health and health-promoting neighbourhoods in Aotearoa New Zealand. The cross-sectional Neighbourhoods and Health study was conducted with 93 primary school-aged children (approximate ages 8 to 10 years) from two schools in Otepoti Dunedin and two schools in Tamaki Makaurau Auckland from June 2020 to August 2021. We present a framework of twelve child-centred topics of importance for health (Healthcare and 'not getting sick', 'How you feel', and Taking care of yourself), health-promoting neighbourhoods (Proximity, safety and feel, Range of 'places to go', 'Friendly streets', and 'No smoking'), and those common to both (Connections with other humans, Healthy food and drink, Exercising and playing sport 'to keep fit', 'Nature' and 'helping the environment', and Recreational activities). The more-than-human theory was used to situate our study findings, and we explored three threads evident in children's thinking: (1) care for humans and non-humans, (2) vital interdependence of human-non-human relations, and (3) understanding complex urban environments through everyday activities. We conclude that the thriving of humans and non-humans in urban environments is important to children in Aotearoa New Zealand. We affirm that children have clear and salient ideas about health and health-promoting neighbourhoods.

Recommendations on eliminating racial disparities in multiple myeloma therapies: a step toward achieving equity in healthcare.

African Americans are at higher risk of multiple myeloma (MM) yet underrepresented in clinical trials and reap less benefits from novel therapies of the disease. To improve representation of African Americans in MM clinical trials, researchers, providers, patients, industry partners and regulators at the FDA-AACR workshop developed recommendations to all stakeholders. The outlined principles offer a roadmap to addressing disparities broadly in clinical trials.

Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of Epithelial-to-Mesenchymal Transition in Human Right Ventricular Failure.

BACKGROUND: Right ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA sequencing of RV tissue from 2 clinically relevant animal models of PAH. METHODS: We performed RNA sequencing on RV from rats treated with monocrotaline or Sugen with hypoxia/normoxia. PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time polymerase chain reaction, immunofluorescence, and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5). RESULTS: We identified similar transcriptomic profiles of RV from monocrotaline- and Sugen with hypoxia-induced RV failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition, inflammation, and metabolism. Histological staining of human RV tissue from patients with RV failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition, as well as elevated cellular communication network factor 2 (top gene implicated in epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition) expression in perivascular areas compared with normal RV. CONCLUSIONS: Transcriptomic signature of RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from patients with PAH to demonstrate evidence of epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition and protein expression of cellular communication network factor 2 (CTGF [connective tissue growth factor]). Targeting specific molecular mechanisms responsible for RV failure in monocrotaline and Sugen with hypoxia models may identify novel therapeutic strategies for PAH-associated RV failure.

African American Patients With Multiple Myeloma: Optimizing Care to Decrease Racial Disparities.

The incidence of multiple myeloma in African Americans is two to three times higher than in other ethnicities and is the leading hematologic malignancy in African Americans. Despite the high incidence of multiple myeloma in African American individuals, a vast majority experience delays in diagnosis and reduced usage of effective therapies, including stem cell transplantation, as well as low participation in clinical trials. Racial disparities, social and financial health disparities, and barriers to earlier access to care can lead to poorer patient outcomes. There are also unique characteristics in the disease manifestation in African Americans with multiple myeloma that are imperative for oncology nurses to understand and recognize to provide optimal care.

General Utilization of Fluorescent Polyisoprenoids with Sugar Selective Phosphoglycosyltransferases.

The protective surfaces of bacteria are comprised of polysaccharides and are involved in host invasion and colonization, host immune system evasion, and antibacterial resistance. A major barrier to our fundamental understanding of these complex surface polysaccharides lies in the tremendous diversity in glycan composition among bacterial species. The polyisoprenoid bactoprenyl phosphate (or undecaprenyl phosphate) is an essential lipid carrier necessary for early stages of glycopolymer assembly. Because of the ubiquity of bactoprenyl phosphate in these critical processes, molecular probes appended to this lipid carrier simplify identification of enzymatic roles during polysaccharide bioassembly. A limited number of these probes exist in the literature or have been assessed with such pathways, and the limits of their use are not currently known. Herein, we devise an efficient method for producing fluorescently modified bactoprenyl probes. We further expand our previous efforts utilizing 2-nitrileaniline and additionally prepare nitrobenzoxadizol-tagged bactoprenyl phosphate for the first time. We then assess the enzyme promiscuity of these two probes utilizing four well-characterized initiating phosphoglycosyltransferases: CPS2E (Streptococcus pneumoniae), WbaP (Salmonella enterica), WecA (Escherichia coli), and WecP (Aeromonas hydrophilia). Both probes serve as substrates for these enzymes and could be readily used to investigate a wide range of bacterial glycoassembly pathways. Interestingly, we have also identified unique solubility requirements for the nitrobenzoxadizol moiety for efficient enzymatic utilization that was not observed for the 2-nitrileaniline.

Engaging with Aboriginal Shire Councils in remote Cape York communities to address smoke-free environments.

The high prevalence and health effect of tobacco smoking and secondhand smoke exposure among Aboriginal and Torres Strait Islander people is well known. Due to its significance, the responsibility of tackling smoking among Aboriginal and Torres Strait Islander people should not remain solely with health service providers. The creation of supportive environments and collaboration beyond the health sector are critical elements of comprehensive primary health care practised by Aboriginal Community Controlled Health Services. This paper discusses how Apunipima Cape York Health Council worked with three Aboriginal Shire Councils to create more smoke-free places, using local working groups, information sessions and community-based health promotion. The flexibility and the time allocated to the engagement process with councils, community leaders, organisations and community members were important. All three communities acknowledged the benefits of role modelling and working together to improve health, with addressing tobacco smoking seen as 'everyone's business' and 'not just service providers'. Aboriginal Shire Councils can play a critical role, in partnership with Aboriginal Community Controlled Health Services, in creating healthy places that enable healthy choices.

Effect of point-of-care CD4 cell count results on linkage to care and antiretroviral initiation during a home-based HIV testing campaign: a non-blinded, cluster-randomised trial.

BACKGROUND: HIV disease staging with referral laboratory-based CD4 cell count testing is a key barrier to the initiation of antiretroviral treatment (ART). Point-of-care CD4 cell counts can improve linkage to HIV care among people living with HIV, but its effect has not been assessed with a randomised controlled trial in the context of home-based HIV counselling and testing (HBCT). METHODS: We did a two-arm, cluster-randomised, controlled efficacy trial in two districts of western Kenya with ongoing HBCT. Housing compounds were randomly assigned (1:1) to point-of-care CD4 cell counts (366 compounds with 417 participants) or standard-of-care (318 compounds with 353 participants) CD4 cell counts done at one of three referral laboratories serving the study catchment area. In each compound, we enrolled people with HIV not engaged in care in the previous 6 months. All participants received post-test counselling and referral for HIV care. Point-of-care test participants received additional counselling on the result, including ART eligibility if CD4 was less than 350 cells per µL, the cutoff in Kenyan guidelines. Participants were interviewed 6 months after enrolment to ascertain whether they sought HIV care, verified through chart reviews at 23 local clinics. The prevalence of loss to follow-up at 6 months (LTFU) was listed as the main outcome in the study protocol. We analysed linkage to care at 6 months (defined as 1-LTFU) as the primary outcome. All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02515149. FINDINGS: We enrolled 770 participants between July 1, 2013, and Feb 28, 2014. 692 (90%) had verified linkage to care status and 78 (10%) were lost to follow-up. Of 371 participants in the point-of-care group, 215 (58%) had linked to care within 6 months versus 108 (34%) of 321 in the standard-of-care group (Cox proportional multivariable hazard ratio [HR] 2·14, 95% CI 1·67-2·74; log rank p<0·0001). INTERPRETATION: Point-of-care CD4 cell counts in a resource-limited HBCT setting doubled linkage to care and thereby improved ART initiation. Given the substantial economic and logistic hindrances to providing ART for all people with HIV in resource-limited settings in the near term, point of care CD4 cell counts might have a role in prioritising care and improving linkage to care. FUNDING: US Centers for Disease Control and Prevention.

Epidural analgesia does not increase the rate of inpatient falls after major upper abdominal and thoracic surgery: a retrospective case-control study.

PURPOSE: Postoperative epidural analgesia for major upper abdominal and thoracic surgery can provide significant benefits, including superior analgesia and reduced pulmonary dysfunction. Nevertheless, epidural analgesia may also be associated with decreased muscle strength, sympathetic tone, and proprioception that could possibly contribute to falls. The purpose of this retrospective case-control study was to search a large national database in order to investigate the possible relationship between postoperative epidural analgesia and the rate of inpatient falls. METHODS: Data from the nationwide inpatient sample for 2007-2011 were queried for adult patients who underwent elective major upper abdominal and thoracic surgery. Multiple International Classification of Diseases, Ninth Revision, Clinical Modification codes for inpatient falls and accidents were combined into one binary variable. Univariate analyses were used for initial statistical analysis. Logistic regression analyses and McNemar's tests were subsequently used to investigate the association of epidural analgesia with inpatient falls in a 1:1 case-control propensity-matched sample after adjustment of patients' demographics, comorbidities, and hospital characteristics. RESULTS: Forty-two thousand six hundred fifty-eight thoracic and 54,974 upper abdominal surgical procedures were identified. The overall incidence of inpatient falls in the thoracic surgery group was 6.54% with an increasing trend over the study period from 4.95% in 2007 to 8.11% in 2011 (P < 0.001). Similarly, the overall incidence of inpatient falls in the upper abdominal surgery group was 5.30% with an increasing trend from 4.55% in 2007 to 6.07% in 2011 (P < 0.001). Postoperative epidural analgesia was not associated with an increased risk for postoperative inpatient falls in the thoracic surgery group (relative risk [RR], 1.18; 95% confidence interval [CI], 0.95 to 1.47; P = 0.144) and in the upper abdominal surgery group (RR, 0.84; 95% CI 0.64 to 1.09; P = 0.220). Inpatient falls compared with non-falls were associated with a longer median (interquartile range) length of hospital stay in both the thoracic surgery group (11 [7-17] days vs 9 [6-16] days, respectively; P < 0.001) and the upper abdominal surgery group (12 [7-20] days vs 10 [6-17] days, respectively; P < 0.001). CONCLUSION: Our study suggests that postoperative epidural analgesia for patients undergoing major upper abdominal and thoracic surgery is not associated with an increased risk of inpatient falls.

Mortality Risk After AIDS-Defining Opportunistic Illness Among HIV-Infected Persons--San Francisco, 1981-2012.

OBJECTIVE: To examine whether improved human immunodeficiency virus (HIV) treatment was associated with better survival after diagnosis of AIDS-defining opportunistic illnesses (AIDS-OIs) and how survival differed by AIDS-OI. DESIGN: We used HIV surveillance data to conduct a survival analysis. METHODS: We estimated survival probabilities after first AIDS-OI diagnosis among adult patients with AIDS in San Francisco during 3 treatment eras: 1981-1986; 1987-1996; and 1997-2012. We used Cox proportional hazards models to determine adjusted mortality risk by AIDS-OI in the years 1997-2012. RESULTS: Among 20 858 patients with AIDS, the most frequently diagnosed AIDS-OIs were Pneumocystis pneumonia (39.1%) and Kaposi sarcoma (20.1%). Overall 5-year survival probability increased from 7% in 1981-1986 to 65% in 1997-2012. In 1997-2012, after adjustment for known confounders and using Pneumocystis pneumonia as the referent category, mortality rates after first AIDS-OI were highest for brain lymphoma (hazard ratio [HR], 5.14; 95% confidence interval [CI], 2.98-8.87) and progressive multifocal leukoencephalopathy (HR, 4.22; 95% CI, 2.49-7.17). CONCLUSIONS: Survival after first AIDS-OI diagnosis has improved markedly since 1981. Some AIDS-OIs remain associated with substantially higher mortality risk than others, even after adjustment for known confounders. Better prevention and treatment strategies are still needed for AIDS-OIs occurring in the current HIV treatment era.

Efficient single tobamoviral vector-based bioproduction of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 in Nicotiana benthamiana plants and utility of VRC01 in combination microbicides.

Broadly neutralizing monoclonal antibodies (bnMAbs) may offer powerful tools for HIV-1 preexposure prophylaxis, such as topical microbicides. However, this option is hampered due to expensive MAb biomanufacturing based on mammalian cell culture. To address this issue, we developed a new production system for bnMAb VRC01 in Nicotiana benthamiana plants using a tobamovirus replicon vector. Unlike conventional two-vector-based expression, this system was designed to overexpress full-length IgG1 from a single polypeptide by means of kex2p-like enzyme recognition sites introduced between the heavy and light chains. An enzyme-linked immunosorbent assay (ELISA) revealed that gp120-binding VRC01 IgG1 was maximally accumulated on 5 to 7 days following vector inoculation, yielding ~150 mg of the bnMAb per kg of fresh leaf material. The plant-made VRC01 (VRC01p) was efficiently purified by protein A affinity followed by hydrophobic-interaction chromatography. ELISA, surface plasmon resonance, and an HIV-1 neutralization assay demonstrated that VRC01p has gp120-binding affinity and HIV-1-neutralization capacity virtually identical to the human-cell-produced counterpart. To advance VRC01p's use in topical microbicides, we analyzed combinations of the bnMAb with other microbicide candidates holding distinct antiviral mechanisms in an HIV-1 neutralization assay. VRC01p exhibited clear synergy with the antiviral lectin griffithsin, the CCR5 antagonist maraviroc, and the reverse transcriptase inhibitor tenofovir in multiple CCR5-tropic HIV-1 strains from clades A, B, and C. In summary, VRC01p is amenable to robust, rapid, and large-scale production and may be developed as an active component in combination microbicides with other anti-HIV agents such as antiviral lectins, CCR5 antagonists, and reverse transcriptase inhibitors.

Interactive effects of cadmium and hypoxia on metabolic responses and bacterial loads of eastern oysters Crassostrea virginica Gmelin.

Pollution by toxic metals including cadmium (Cd) and hypoxia are important stressors in estuaries and coastal waters which may interactively affect sessile benthic organisms, such as oysters. We studied metabolic responses to prolonged hypoxic acclimation (2 weeks at 5% O2) in control and Cd-exposed (30 d at 50 µg L(-1) Cd) oysters Crassostrea virginica, and analyzed the effects of these stressors on abundance of Vibrio spp. in oysters. Hypoxia-acclimated oysters retained normal standard metabolic rates (SMR) at 5% O2, in contrast to a decline of SMR observed during acute hypoxia. However, oysters spent more time actively ventilating in hypoxia than normoxia resulting in enhanced Cd uptake and 2.7-fold higher tissue Cd burdens in hypoxia. Cd exposure led to a significant decrease in tissue glycogen stores, increase in free glucose levels and elevated activity of glycolytic enzymes (hexokinase and aldolase) indicating a greater dependence on carbohydrate catabolism. A compensatory increase in activities of two key mitochondrial enzymes (citrate synthase and cytochrome c oxidase) was found during prolonged hypoxia in control oysters but suppressed in Cd-exposed ones. Cd exposure also resulted in a significant increase in abundance of Vibrio parahaemolyticus and Vibrio vulnificus levels during normoxia and hypoxia, respectively. Overall, Cd- and hypoxia-induced changes in metabolic profile, Cd accumulation and bacterial flora of oysters indicate that these stressors can synergistically impact energy homeostasis, performance and survival of oysters in polluted estuaries and have significant consequences for transfer of Cd and bacterial pathogens to the higher levels of the food chain.

The Drosophila protein palmitoylome: characterizing palmitoyl-thioesterases and DHHC palmitoyl-transferases.

Palmitoylation is the post-translational addition of a palmitate moiety to a cysteine residue through a covalent thioester bond. The addition and removal of this modification is controlled by both palmitoyl acyl-transferases and thioesterases. Using bioinformatic analysis, we identified 22 DHHC family palmitoyl acyl-transferase homologs in the Drosophila genome. We used in situ hybridization,RT-PCR, and published FlyAtlas microarray data to characterize the expression patterns of all 22 fly homologs. Our results indicate that all are expressed genes, but several, including CG1407, CG4676, CG5620, CG6017/dHIP14, CG6618, CG6627 and CG17257 appear to be enriched in neural tissues suggesting that they are important for neural function. Furthermore, we have found that several may be expressed in a sex-specific manner with adult male specific expression of CG4483 and CG17195. Using tagged versions of the DHHC genes, we demonstrate that fly DHHC proteins are primarily located in either the Golgi Apparatus or Endoplasmic Reticulum in S2 cells, except for CG1407, which was found on the plasma membrane. We also characterized the subcellular localization and expression of the three known thioesterases: Palmitoyl-protein Thioesterase 1 (Ppt1), Palmitoyl-protein Thioesterase 2 (Ppt2)and Acyl-protein Thioesterase 1 (APT1). Our results indicate that Ppt1 and Ppt2 are the major lysosomal thioesterases while APT1 is the likely cytoplasmic thioesterase. Finally, in vivo rescue experiments show that Ppt2 expression cannot rescue the neural inclusion phenotypes associated with loss of Ppt1, further supporting distinct functions and substrates for these two thioesterases. These results will serve as the basis for a more complete understanding of the protein palmitoylome's normal cellular functions in the fly and will lead to further insights into the molecular etiology of diseases associated with the mis-regulation of palmitoylation.

Analysis of prostate-specific membrane antigen splice variants in LNCap cells.

The prostate-specific membrane antigen (PSMA), a product of the folate hydrolase (FOLH1) gene, is highly expressed as a largely extracellular membrane-anchored protein in malignant prostate tissues and in nonprostatic tumor neovasculature. Treatment of prostate cancer LNCap cells with spliceswitching oligonucleotides (SSOs) modulated splicing of FOLH1 pre-mRNA from the full-length PSMA splice variant to three splice variants: the cytoplasmic PSM', alternatively spliced at exon 1, and the previously unexamined PSMADelta6 and PSMADelta18 variants, which lack exons 6 and 18, respectively. Application of SSOs decreased membrane PSMA levels and increased PSM', PSMADelta6, and PSMADelta18 transcripts. As a result, PSM' protein was translocated to the cytoplasm, and switching to PSMADelta6 and PSMADelta18 downregulated PSMA expression. NAALADase assays showed that PSM' retained enzymatic activity. PSMADelta6 and PSMADelta18 were not active, presumably due to a change in a reading frame that eliminated the NAALDase active site or the dimerization domain or both in these proteins.

In vivo delivery of BCNU from a MEMS device to a tumor model.

A drug delivery micrcoelectromechanical systems (MEMS) device was used to locally deliver a chemotherapeutic agent (BCNU) to an experimental tumor in rats. This MEMS device consists of an array of reservoirs etched into the silicon substrate. The drug release is achieved by the electrochemical dissolution of the gold membranes covering the reservoirs. A new Pyrex package was developed to improve the BCNU release kinetics and enhance device capacity. Co-formulation of BCNU with polyethylene glycol (PEG) led to complete and rapid release of drug in vivo. BCNU delivered from the MEMS device showed dose-dependent inhibiting effect on the tumor growth in the BCNU dosage range of 0.67 approximately 2 mg. BCNU delivered from the activated devices was as effective as equipotent subcutaneous injections of BCNU in inhibiting tumor growth. Further optimization using this MEMS device to deliver BCNU in combination with other therapeutic agents against the tumor challenge is possible because of the unique capability of the device to precisely control the temporal release profiles of multiple substances.

RNA modulation, repair and remodeling by splice switching oligonucleotides.

Targeting splicing by antisense oligonucleotides allows RNA modifications that are not possible with RNA interference or other antisense techniques that destine the RNA for destruction. By changing the ratio of naturally occurring splice variants the expression of mRNA is modulated. By preventing the use of an aberrant splice site created by a mutation and enforcing re-selection of correct splice sites the RNA is repaired. Antisense induced skipping of the exon that carries a nonsense mutation remodels the mRNA and restores the reading frame of the defective protein. All of the above approaches have clinical applications. Modulation of splice variants is particularly important since close to 60% of all genes code for alternatively spliced pre-mRNA.

Modification of alternative splicing by antisense therapeutics.

Alternative splicing allows the production of several different proteins from a single pre-mRNA, resulting in an increased diversity of proteins derived from a relatively limited number of transcribed genes. Although it is necessary for normal development, alternative splicing and its aberrations are also implicated in disease states from thalassemia and cancer to neurodegenerative disorders. Techniques that trick the splicing machinery to alter the splicing pathways can be of high therapeutic value. Antisense technology, used mostly for RNA downregulation, recently has been adapted to alter the splicing process. The promise of this approach is now being realized as a result of chemical modification of oligonucleotides and improvements in their delivery in vivo.