Second surgery for progressive glioblastoma: a multi-centre questionnaire and cohort-based review of clinical decision-making and patient outcomes in current practice.

PURPOSE: Glioblastoma prognosis is poor. Treatment options are limited at progression. Surgery may benefit, but no quality guidelines exist to inform patient selection. We sought to describe variations in surgical management at progression, highlight where further evidence is needed, and build towards a consensus strategy. METHODS: Current practice in selection of patients with progressive GBM for second surgery was surveyed online amongst specialists in the UK and Europe. We complemented this with an assessment of practice in a retrospective cohort study from six United Kingdom neurosurgical units. We used descriptive statistics to analyse the data. RESULTS: 234 questionnaire responses were received. Maintaining or improving patient quality of life was key to decision making, with variation as to whether patient age, performance status or intended extent of resection was relevant. MGMT methylation status was not important. Half considered no minimum time after first surgery. 288 patients were reported in the cohort analysis. Median time to second surgery from first surgery 390 days. Median overall survival 815 days, with no association between time to second surgery and time to death (p = 0.874). CONCLUSIONS: This is the most wide-ranging examination of contemporaneous practice in management of GBM progression. Without evidence-based guidelines, the variation is unsurprising. We propose consensus guidelines for consideration, to reduce heterogeneity in decision making, support data collection and analysis of factors influencing outcomes, and to inform clinical trials to establish whether second surgery improves patient outcomes, or simply selects to patients already performing well.

Quantum Quenches in Isolated Quantum Glasses out of Equilibrium.

In this work, we address the question of how a closed quantum system thermalizes in the presence of a random external potential. By investigating the quench dynamics of the isolated quantum spherical p-spin model, a paradigmatic model of a mean-field glass, we aim to shed new light on this complex problem. Employing a closed-time Schwinger-Keldysh path integral formalism, we first initialize the system in a random, infinite-temperature configuration and allow it to equilibrate in contact with a thermal bath before switching off the bath and performing a quench. We find evidence that increasing the strength of either the interactions or the quantum fluctuations can act to lower the effective temperature of the isolated system and stabilize glassy behavior.

Resection of biliary mucinous cystic neoplasms of the liver: a prospective cohort series of 13 consecutive patients.

BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are uncommon neoplastic septated intrahepatic cysts which are often incorrectly diagnosed and have the potential for malignant transformation. OBJECTIVE: To assess the outcome of surgical resection of BMCNs. METHOD: A prospective liver surgery database was used to identify patients who underwent surgery at Groote Schuur Hospital Complex for BMCN from 1999 to 2015. Demographic variables including age and gender were documented as well as detailed preoperative imaging, location and size, operative treatment, extent of resection, histology, postoperative complications and outcome. RESULTS: Thirteen female patients (median age 45 years) had surgery. Eleven were diagnosed by imaging for symptoms. Two were jaundiced. One cyst was found during an elective cholecystectomy. Five cysts were located centrally in the liver. Before referral three cysts were treated with percutaneous drainage and two were treated with operative deroofing. Six patients had anatomical liver resections and seven patients had non anatomical liver resections of which two needed ablation of residual cyst wall. One patient needed a biliary-enteric reconstruction to treat a fistula. Median operative time was 183 minutes (range: 130-375). No invasive carcinoma was found. There was no operative mortality. One surgical site infection and one intra-abdominal collection were treated. Two patients developed recurrent BMCN after 24 months. CONCLUSION: BMCNs should be considered in middle aged women who have well encapsulated multilocular liver cysts. Treatment of large central BMCNs adjacent to vascular and biliary structures may require technically complex liver resections and are best managed in a specialised hepato-pancreatico-biliary unit.

Gene expression profiles predictive of cold-induced sweetening in potato.

Cold storage (2-4 °C) used in potato production to suppress diseases and sprouting during storage can result in cold-induced sweetening (CIS), where reducing sugars accumulate in tuber tissue leading to undesirable browning, production of bitter flavors, and increased levels of acrylamide with frying. Potato exhibits genetic and environmental variation in resistance to CIS. The current study profiles gene expression in post-harvest tubers before cold storage using transcriptome sequencing and identifies genes whose expression is predictive for CIS. A distance matrix for potato clones based on glucose levels after cold storage was constructed and compared to distance matrices constructed using RNA-seq gene expression data. Congruence between glucose and gene expression distance matrices was tested for each gene. Correlation between glucose and gene expression was also tested. Seventy-three genes were found that had significant p values in the congruence and correlation tests. Twelve genes from the list of 73 genes also had a high correlation between glucose and gene expression as measured by Nanostring nCounter. The gene annotations indicated functions in protein degradation, nematode resistance, auxin transport, and gibberellin response. These 12 genes were used to build models for prediction of CIS using multiple linear regression. Nine linear models were constructed that used different combinations of the 12 genes. An F-box protein, cellulose synthase, and a putative Lax auxin transporter gene were most frequently used. The findings of this study demonstrate the utility of gene expression profiles in predictive diagnostics for severity of CIS.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

Straight-to-test colonoscopy for 2-week-wait referrals improves time to diagnosis of colorectal cancer and is feasible in a high-volume unit.

AIM: We have introduced 'straight-to-test' (STT) colonoscopy as part of our 2-week-wait (2WW) pathway to address increasing numbers of urgent referrals for colorectal cancer (CRC) within the National Health Service. In this study we evaluated the ability of this initiative to shorten the time to diagnosis of CRC. METHOD: We amended our 2WW referral form to include performance status and comorbidities. General practitioners were asked to provide data on estimated glomerular filtration rate and full blood count/ferritin. Our 2WW referrals were screened by a colorectal consultant and a nurse specialist. Those deemed unsuitable for STT were offered outpatient assessment (OPA). RESULTS: Of 553 2WW referrals screened, 352 were considered suitable, 65 of whom failed a telephone assessment or were uncontactable, and accordingly 287 were offered the STT pathway. The STT group was significantly younger than the OPA group (median 65.9 years vs 78.7 years; P < 0.0001). STT colonoscopy significantly reduced the time to first test (13 days vs 22 days; P < 0.0001) and tissue diagnosis from the referral date (17 days vs 24.5 days; P < 0.0001). Thirty-seven (6.8%) CRCs were detected. Proportionately fewer patients in the STT pathway were managed with 'best supportive care only' compared with patients attending OPA (one of 15 vs six of 22, respectively). STT colonoscopy obviated the need for clinic attendance before testing in 287 patients, representing a potential net cost benefit of at least £48 500 in 4 months. CONCLUSION: STT colonoscopy was safe and effective for selecting out a group of symptomatic patients who could proceed straight to endoscopic examination and receive a diagnosis more rapidly.

Predictors of emergency colectomy in patients admitted with acute severe ulcerative colitis.

BACKGROUND: Acute Severe Ulcerative Colitis (ASUC) is a life-threatening condition which requires urgent and aggressive medical therapy to reduce mortality, morbidity and avoid surgery. To facilitate this process, it is essential to identify patients at high risk of poor outcomes and emergency colectomy. Numerous such risk factors have been described in Western literature, however there is no local data addressing this issue. As such it is unclear if these predictors are applicable in our setting. The aim of this study is thus to identify risk factors for emergency colectomy in patients admitted to Groote Schuur Hospital with ASUC. METHOD: A retrospective cohort study of 98 patients admitted with ASUC between January 2003 and January 2013 was performed. Clinical, demographic, laboratory and endoscopic factors on admission and 3 days thereafter were analysed as predictors of colectomy by univariate and multivariate analysis. RESULTS: Twenty-five percent of the cohort underwent emergency colectomy. On univariate analysis, factors predicting colectomy on admission were exposure to oral corticosteroids (p=0.01), megacolon (p=0.049) or mucosal islands (p=0.04) on abdominal X-ray, and a short duration from UC diagnosis until presentation with ASUC (p=0.04). The only variable that was significantly associated with colectomy on day 3 was serum albumin (p=0.01). This was also the only variable to remain significant on multivariate analysis (OR 0.79, 95% CI 0.65-0.97, p=0.01). CONCLUSION: ASUC is a medical emergency and predicting colectomy risk aids in therapeutic management. The only variable significantly associated with the need for surgery in our study was hypoalbuminaemia on day 3. Given the small study numbers a larger prospective study would be of value.

Auditing surgical service provision at a South African tertiary institution: Implications for the development of district services.

BACKGROUND: The optimal management of resources within South African state hospitals has been hampered by a paucity of data due to a lack of robust auditing information systems. This study reviews the use of a Hybrid Electronic Medical Record (HEMR) system to capture and aggregate data pertaining to the inpatient service demands on a South African tertiary surgical service. This dataset was used to analyse the appropriateness of tertiary surgical resource utilisation. METHOD: The HEMR system was implemented at Greys Hospital, in the city of Pietermaritzburg, Kwa-Zulu Natal, South Africa on 1 January 2013. Inpatient data pertaining to surgical admissions and operative interventions were captured prospectively. Following an 18-month study period, the data were extracted, aggregated and analysed. The district referral hospitals were mapped, and district surgical procedures performed within the tertiary center were identified and quantified. Results: 7314 patients were admitted and managed by the tertiary surgical service during the study period. The median patient age was 33 years (IQR 6.5-42.4 years). 59.7% were male and 40.3% were female. General, trauma and paediatric surgical admissions constituted 54.8%, 28.6% and 16.6% respectively. Emergency admissions constituted 62.4% and elective admissions 37.6%. Referral sources were captured for 6653 (91%) of the cohort. 4338 (65.2%) patients were referred from district hospitals. The district hospital (Northdale) closest to Greys Hospital was responsible for 1675 (25.2%) of surgical referrals. 4174 operative procedures were performed during the study period, 54.7% performed as an emergency, 34.1% electively and 11.2% semi-electively. The median waiting time for emergency operative intervention was 535 minutes (IQR 130-663). A total of 1272 (30.5%) operative procedures performed were assessed as district-level operations. The time intervals of 07:00-07:59 and 17:00-17:59 were identified as the time periods during which the least number of emergency procedures were performed in the operating theatres. CONCLUSION: The HEMR system enabled the Pietermaritzburg Metropolitan Department of Surgery to quantify the burden of surgical disease and map district referral patterns. Thirty percent of operative procedures performed were assessed as district-level operations. Potentially correctable deficits identified within the tertiary center were lengthy delays to emergency surgery and non-optimal theatre utilisation periods.

Primary seromucinous cystadenocarcinoma of the mesentery.

A 72-year-old woman presented with a slow growing mass on the left side of the abdomen, which was found to originate from the mesentery of the descending colon. Histopathology revealed a seromucinous cystadenocarcinoma of the mesentery, a rare clinical entity occurring most often in females. There are only 20 cases reported in the literature. It is postulated that these tumours develop as a result of serous or mucinous metaplasia of pre-existing coelomic mesothelium. Surgical excision remains the mainstay of successful management.

Incidence and management of postoperative bile leaks: A prospective cohort analysis of 467 liver resections.

BACKGROUND: Bile leaks from the parenchymal transection margin are a major cause of morbidity following major liver resections. The aim of this study was to benchmark the incidence and identify the risk factors for postoperative bile leakage after hepatic resection. PATIENTS AND METHODS: A prospective database of 467 consecutive liver resections performed by the University of Cape Town HPB surgical unit between January 1990 and January 2016 was analysed. The relationship of demographic, clinical and perioperative factors to the development of bile leakage was determined. Bile leak and postoperative complications severity were graded using the International Study Group of Liver Surgery and Accordion classifications. RESULTS: Overall morbidity was 24% (n = 112), with bile leaks occurring in 25 (5.4%) patients. Significantly more bile leaks occurred in patients who had major resections (≥ 3 segments) and longer total operative times (p < 0.05). There were 5 Grade A bile leaks which stopped spontaneously. Seventeen Grade B leaks required a combination of percutaneous drainage (n = 15), endoscopic biliary stenting (n = 8) and percutaneous transhepatic biliary drainage (n = 3). All 3 Grade C leaks required laparotomy for definitive drainage. Median hospital stay in the 442 patients without a bile leak was 8 days (IQR 1-98) compared with 12 days (IQR 6-30) for the 25 with bile leaks (p < 0.05) with no mortality. Major resections (≥ 3 segments) and total operative time (> 180mins) were significantly associated with bile leaks. CONCLUSION: The incidence of bile leakage was 5.4% and occurred after major liver resections with longer operative times and resulted in significantly extended hospitalisation. Most were effectively treated nonoperatively by percutaneous drainage of the collection and/or endoscopic or percutaneous biliary drainage without mortality.

Sound-producing voice prostheses: 150 years of research.

Advanced laryngeal cancer sometimes necessitates the removal of the complete larynx. This procedure involves suturing the trachea to an opening in the neck, the most disturbing consequence of which is the loss of voice. Since 1859, several devices have been developed for voice restoration, based mainly on a vibrating reed element. However, the resulting sound is very monotonous and thus unpleasant. Presently the most successful way of voice restoration is the placement of a one-way shunt valve in the tracheo-esophageal wall, thus preventing aspiration and allowing air to flow from the lungs to the esophagus, where soft tissues start to vibrate for substitute voicing. However, the quality of this voice is often poor. New artificial vocal folds to be placed within the shunt valve have been developed, and a membrane-principle concept appears very promising, owing to the self-cleaning construction and the high voice quality. Future developments will include electronic voice sources. Hopefully these developments will result in a high-quality voice, after 150 years of research.

From parent to 'peer facilitator': a qualitative study of a peer-led parenting programme.

BACKGROUND: Peer-led interventions are increasingly common in community health settings. Although peer-led approaches have proven benefits for service users, relatively little is known about the process and outcomes of participation for peer leaders. This study investigated experiences of parents who had participated as 'peer facilitators' in Empowering Parents, Empowering Communities (EPEC), a peer-led programme designed to improve access to evidence-based parenting support in socially disadvantaged communities. METHOD: A qualitative cross-sectional design was used. Semi-structured interviews were conducted with 14 peer facilitators and scrutinized using thematic analysis. RESULTS: Peer facilitators developed their knowledge and skills through personal experience of receiving parenting support, participation in formal training and supervised practice, access to an intervention manual, and peer modelling. Peer facilitators described positive changes in their own families, confidence and social status. Transformative personal gains reinforced peer facilitators' role commitment and contributed to a cohesive 'family' identity among EPEC staff and service users. Peer facilitators' enthusiasm, openness and mutual identification with families were seen as critical to EPEC's effectiveness and sustainability. Peer facilitators also found the training emotionally and intellectually demanding. There were particular difficulties around logistical issues (e.g. finding convenient supervision times), managing psychosocial complexity and child safeguarding. CONCLUSIONS: The successful delivery and sustained implementation of peer-led interventions requires careful attention to the personal qualities and support of peer leaders. Based on the findings of this study, support should include training, access to intervention manuals, regular and responsive supervision, and logistical/administrative assistance. Further research is required to elaborate and extend these findings to other peer-led programmes.

A prospective audit of the use of diagnostic laparoscopy to establish the diagnosis of abdominal tuberculosis.

BACKGROUND: The incidence of abdominal tuberculosis is much higher in an HIV-positive cohort. The use of laparoscopy in the diagnostic work-up of suspected abdominal tuberculosis is underutilized and its use and efficacy in the context of HIV co-infection has never been examined. METHODS: A prospective clinical audit of the use of diagnostic laparoscopy was conducted in patients with clinically suspected abdominal tuberculosis but histologically or microbiologically unconfirmed tuberculosis at any site. RESULTS: From January 2008 to June 2010, 81 patients underwent diagnostic laparoscopy; 34 were male and 47 were female, with a mean age of 33 years, and 77 % were HIV-positive. Fifty-five patients (68 %) had positive histology or culture for tuberculosis. In 15 patients (19 %), histology revealed non-specific inflammation, no pathology was found in one patient, and no specimen was taken from one patient. Eighty percent of peritoneal deposits and 77 % of lymph nodes were positive for tuberculosis, whereas 35 % of ascitic fluid cultures were positive. In nine patients (11 %) an alternative diagnosis was found; nine patients (11 %) had conversion to laparotomy. There was no procedure-related death. Nine patients (11 %) died during the 2-month follow-up period. CONCLUSIONS: Diagnostic laparoscopy avoids the morbidity and mortality of laparotomy in chronically ill patients, and reduces the rate of misdiagnosis of other abdominal conditions and unnecessary long-term therapy. Diagnostic laparoscopy and tissue sampling is a viable and reliable strategy in patients with suspected abdominal tuberculosis.

The windows of the inner ear.

The oval and round windows of the inner ear are important structures for the transmission of sound and may be affected by a variety of disease entities. The anatomy of this small area is one that often causes the radiology trainee some difficulty, but there are certain disease states that can be easily diagnosed when knowing where and how to look. As this area is very important to the otologist in a variety of preoperative settings, accurate assessment of the windows and recognition of important and potentially complex intra-operative anomalies, will greatly aid our surgical colleagues.

Lessons from emergency laparotomy for abdominal tuberculosis in the HIV/AIDS era.

BACKGROUND: The rising incidence of HIV/AIDS has resulted in a resurgence of abdominal tuberculosis (TB) in HIV-positive patients in South Africa. These often debilitated patients frequently present with acute complications requiring surgery. METHODS: A prospective audit of all patients with abdominal TB undergoing emergency laparotomy was conducted. From January 2008 to June 2010, 49 patients had emergency laparotomy and specimens obtained from them were diagnostic of TB. Twenty-five were males and 24 females, with a median age of 32 years (range 2 - 62). Thirty-nine patients were HIV-positive (79.6%). RESULTS: Intra-operative findings were bowel perforations in 13 cases, small-bowel obstruction in seven, a frozen abdomen in ten, and enlarged lymph nodes and an ileocaecal mass in 19. Eleven patients (22.4%) underwent small-bowel resection and eight (16.3%) right hemicolectomy. Eighteen patients (36.7%) ended up with stomas, 14 (28.6%) had re-laparotomies, and 18 (36.7%) were admitted to the intensive care unit. Twenty-three patients (46.9%) required blood transfusion and 15 (30.6%) total parenteral nutrition. Three patients (6.1%) developed an enterocutaneous fistula and 19 (38.8%) died. Pre-operative illness severity indices of acidosis, anaemia and hypo-albuminaemia were significant predictors of death, but mode of presentation and surgical interventions were not. CONCLUSION: Laparotomy as currently practised for the 'acute abdomen' in patients with suspected HIV and abdominal TB is associated with very high morbidity and mortality, which is related to pre-operative severity indices. More liberal use of imaging may define cases in which a more conservative approach could improve outcome.

Predicting gallstone pancreatitis in HIV infected patients.

BACKGROUND: Human immunodeficiency virus (HIV) infection, low cluster of differentiation (CD)4 counts and antiretroviral therapy can cause cholestasis and raised transaminases. In acute pancreatitis, this may render biochemical predictors of a gallstone aetiology inaccurate. METHODS: In a prospective observational study, acute pancreatitis was diagnosed by standard criteria. Cholecystolithiasis and bile duct diameter were diagnosed by ultrasound. Cholestasis was defined as two of the following: bilirubin ≥ 21 umol/l, γ glutamyl transferase ≥ 78 U/l, alkaline phosphatase ≥ 121 U/l. Cholangitis was defined as cholestasis and any two sepsis criteria: (temperature > 38˚C, WCC > 12.6 ×109/L, pulse > 90 beats/min). Cholangitis, cholestasis, and bile duct diameter greater that 1 cm were indications for endoscopic retrograde cholangiopancreatography (ERCP). These parameters' ability to predict gallstone pancreatitis (GSP) and choledocholithiasis were compared in HIV+ve and HIV-ve patients. RESULTS: Sixty-two (26%) of 216 patients had GSP. Twenty four were HIV+ve patients. More HIV+ve patients had cholestasis (p = 0.059) and ERCP (p = 0.004). In HIV+ve patients alanine aminotransferase (ALT) > 100 U/L, gamma glutamyl transferase (GGT) > 2 upper limit of normal and cholestasis had a negative predictive value of 92%, 96.7% and 95.2% respectively. In HIV-ve patients, negative predictive value (NPV) was 84%, 83.8% and 84.6% respectively. Bile duct stones were demonstrated at ERCP in 6 (25%) and 3 (8%) of HIV+ve and HIV-ve patients respectively (p = 0.077). Five of 14 ERCP patients had no bile duct stones. HIV+ve and HIV-ve groups had two deaths each. CONCLUSION: Absence at presentation of the abnormal parameters analysed were good predictors of a non-gallstone aetiology particularly in HIV+ve patients. Prior, magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) would reduce the number of non-therapeutic ERCPs.

Association between chronic pancreatitis and pancreatic cancer at a central hospital in KwaZulu-Natal, South Africa.

BACKGROUND: The frequency of histological chronic pancreatitis (CP) evidence in the resident pancreas of resected periampullary cancers (PACs) has never been studied in Africa. This study aims to describe the spectrum of pathology and outcomes of pancreatic surgeries and address this deficit from a South African central hospital cohort. METHODS: A retrospective audit of patients undergoing pancreatic surgery at Inkosi Albert Luthuli Central Hospital (IALCH) between 2003 and 2023 was conducted. The patient demographics, human immunodeficiency virus (HIV) status, histological subtypes, type and extent of surgery, and 30-day and overall mortality were captured from medical records. The presence of CP in the resident pancreas of patients resected for pancreatic and PAC was obtained from the pathology reports. RESULTS: Of the cohort, 72% were Africans, presenting at an earlier average age than other races. Surgery was performed on 126 (107 for cancer, 19 for CP) patients. Of these, 77 were pancreaticoduodenectomy (PD), of which 34 were for pancreatic ductal adenocarcinoma (PDAC). The prevalence of CP in the resident pancreas was 29.9%, and 55.9% in PDAC. Age was the only factor significantly associated with 30-day mortality, as well as long-term survival amongst patients with pancreatic and PAC. The overall median survival for patients with PAC was seven months; 11 patients are alive. CONCLUSION: In a predominantly African cohort undergoing pancreatic surgery, PDAC presents at a younger age. The high perioperative mortality and low overall survival (OS) in the setting of high CP prevalence in the resident pancreas requires further investigation of its role in the aetiopathogenesis and prognosis in PDAC.

ebrain: the electronic learning platform for clinical neuroscience.

ebrain (www.ebrainjnc.com) is a comprehensive e-learning platform for the clinical neurosciences. It is owned by the Joint Neurosciences Council which is formed from the UK neuroscience specialty associations including the Society of British Neurosurgeons. ebrain has been developed in association with the European Neurology Associations and University College London. The content was written in 2010/11 and the programme was launched in November 2011. It is now one year old. This article reviews the history of the development, its progress since launch, and the plans for the future of this project.

Cystic fibrosis transmembrane conductance regulator splice variants are not conserved and fail to produce chloride channels.

In the human CFTR only the rare exon 4- splice variant is conserved in mice. We have discovered two novel murine variants, exon 5- and exon 11b+. The exon 5- variant represents up to 40% of mRNA in all CFTR-expressing tissues and leaves the reading frame intact. The exon 11b+ variant inserts a novel exon between exons 11 and 12 with expression restricted to the testis. Two variants of 11b have been found and both introduce premature stop codons. When we expressed human CFTR variants lacking either exon 5 or exon 9 in HeLa cells, they failed to generate cAMP-mediated chloride transport, due to defective intracellular processing. The lack of conservation of splice variants between species and the inability of the more abundant splice variants to generate protein that is correctly processed argue against a physiological role and may simply represent aberrant splicing that is tolerated by the cell and organism.