The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial.

BACKGROUND: Acetaminophen inhibits cell-free hemoglobin-induced lipid peroxidation and improves renal function in severe falciparum malaria but has not been evaluated in other infections with prominent hemolysis, including Plasmodium knowlesi malaria. METHODS: PACKNOW was an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ≥5 years with knowlesi malaria of any severity. The primary end point was change in creatinine at 72 hours. Secondary end points included longitudinal changes in creatinine in patients with severe malaria or acute kidney injury (AKI), stratified by hemolysis. RESULTS: During 2016-2018, 396 patients (aged 12-96 years) were randomized to acetaminophen (n = 199) or no acetaminophen (n = 197). Overall, creatinine fell by a mean (standard deviation) 14.9% (18.1) in the acetaminophen arm vs 14.6% (16.0) in the control arm (P = .81). In severe disease, creatinine fell by 31.0% (26.5) in the acetaminophen arm vs 20.4% (21.5) in the control arm (P = .12), and in those with hemolysis by 35.8% (26.7) and 19% (16.6), respectively (P = .07). No difference was seen overall in patients with AKI; however, in those with AKI and hemolysis, creatinine fell by 34.5% (20.7) in the acetaminophen arm vs 25.9% (15.8) in the control arm (P = .041). Mixed-effects modeling demonstrated a benefit of acetaminophen at 72 hours (P = .041) and 1 week (P = .002) in patients with severe malaria and with AKI and hemolysis (P = .027 and P = .002, respectively). CONCLUSIONS: Acetaminophen did not improve creatinine among the entire cohort but may improve renal function in patients with severe knowlesi malaria and in those with AKI and hemolysis. CLINICAL TRIALS REGISTRATION: NCT03056391.

Variability in detection of SARS-CoV-2-specific antibody responses following mild infection: a prospective multicentre cross-sectional study, London, United Kingdom, 17 April to 17 July 2020.

IntroductionImmunoassays targeting different SARS-CoV-2-specific antibodies are employed for seroprevalence studies. The degree of variability between immunoassays targeting anti-nucleocapsid (anti-NP; the majority) vs the potentially neutralising anti-spike antibodies (including anti-receptor-binding domain; anti-RBD), particularly in mild or asymptomatic disease, remains unclear.AimsWe aimed to explore variability in anti-NP and anti-RBD antibody detectability following mild symptomatic or asymptomatic SARS-CoV-2 infection and analyse antibody response for correlation with symptomatology.MethodsA multicentre prospective cross-sectional study was undertaken (April-July 2020). Paired serum samples were tested for anti-NP and anti-RBD IgG antibodies and reactivity expressed as binding ratios (BR). Multivariate linear regression was performed analysing age, sex, time since onset, symptomatology, anti-NP and anti-RBD antibody BR.ResultsWe included 906 adults. Antibody results (793/906; 87.5%; 95% confidence interval: 85.2-89.6) and BR strongly correlated (ρ = 0.75). PCR-confirmed cases were more frequently identified by anti-RBD (129/130) than anti-NP (123/130). Anti-RBD testing identified 83 of 325 (25.5%) cases otherwise reported as negative for anti-NP. Anti-NP presence (+1.75/unit increase; p < 0.001), fever (≥ 38°C; +1.81; p < 0.001) or anosmia (+1.91; p < 0.001) were significantly associated with increased anti-RBD BR. Age (p = 0.85), sex (p = 0.28) and cough (p = 0.35) were not. When time since symptom onset was considered, we did not observe a significant change in anti-RBD BR (p = 0.95) but did note decreasing anti-NP BR (p < 0.001).ConclusionSARS-CoV-2 anti-RBD IgG showed significant correlation with anti-NP IgG for absolute seroconversion and BR. Higher BR were seen in symptomatic individuals, particularly those with fever. Inter-assay variability (12.5%) was evident and raises considerations for optimising seroprevalence testing strategies/studies.

How can gastro-intestinal tuberculosis diagnosis be improved? A prospective cohort study.

BACKGROUND: Gastrointestinal tuberculosis (TB) is diagnostically challenging; therefore, many cases are treated presumptively. We aimed to describe features and outcomes of gastrointestinal TB, determine whether a clinical algorithm could distinguish TB from non-TB diagnoses, and calculate accuracy of diagnostic tests. METHODS: We conducted a prospective cohort study of hospitalized patients in Kota Kinabalu, Malaysia, with suspected gastrointestinal TB. We recorded clinical and laboratory characteristics and outcomes. Tissue samples were submitted for histology, microscopy, culture and GeneXpert MTB/RIF®. Patients were followed for up to 2 years. RESULTS: Among 88 patients with suspected gastrointestinal TB, 69 were included in analyses; 52 (75%) had a final diagnosis of gastrointestinal TB; 17 had a non-TB diagnosis. People with TB were younger (42.7 versus 61.5 years, p = 0.01) and more likely to have weight loss (91% versus 64%, p = 0.03). An algorithm using age < 44, weight loss, cough, fever, no vomiting, albumin > 26 g/L, platelets > 340 × 109/L and immunocompromise had good specificity (96.2%) in predicting TB, but very poor sensitivity (16.0%). GeneXpert® performed very well on gastrointestinal biopsies (sensitivity 95.7% versus 35.0% for culture against a gold standard composite case definition of confirmed TB). Most patients (79%) successfully completed treatment and no treatment failure occurred, however adverse events (21%) and mortality (13%) among TB cases were high. We found no evidence that 6 months of treatment was inferior to longer courses. CONCLUSIONS: The prospective design provides important insights for clinicians managing gastrointestinal TB. We recommend wider implementation of high-performing diagnostic tests such as GeneXpert® on extra-pulmonary samples.

Prognostic Modeling of COVID-19 Using Artificial Intelligence in the United Kingdom: Model Development and Validation.

BACKGROUND: The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency and the case fatality rate in the United Kingdom is significant. Although there appear to be several early predictors of outcome, there are no currently validated prognostic models or scoring systems applicable specifically to patients with confirmed SARS-CoV-2. OBJECTIVE: We aim to create a point-of-admission mortality risk scoring system using an artificial neural network (ANN). METHODS: We present an ANN that can provide a patient-specific, point-of-admission mortality risk prediction to inform clinical management decisions at the earliest opportunity. The ANN analyzes a set of patient features including demographics, comorbidities, smoking history, and presenting symptoms and predicts patient-specific mortality risk during the current hospital admission. The model was trained and validated on data extracted from 398 patients admitted to hospital with a positive real-time reverse transcription polymerase chain reaction (RT-PCR) test for SARS-CoV-2. RESULTS: Patient-specific mortality was predicted with 86.25% accuracy, with a sensitivity of 87.50% (95% CI 61.65%-98.45%) and specificity of 85.94% (95% CI 74.98%-93.36%). The positive predictive value was 60.87% (95% CI 45.23%-74.56%), and the negative predictive value was 96.49% (95% CI 88.23%-99.02%). The area under the receiver operating characteristic curve was 90.12%. CONCLUSIONS: This analysis demonstrates an adaptive ANN trained on data at a single site, which demonstrates the early utility of deep learning approaches in a rapidly evolving pandemic with no established or validated prognostic scoring systems.

Comparison of deep learning with regression analysis in creating predictive models for SARS-CoV-2 outcomes.

BACKGROUND: Accurately predicting patient outcomes in Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could aid patient management and allocation of healthcare resources. There are a variety of methods which can be used to develop prognostic models, ranging from logistic regression and survival analysis to more complex machine learning algorithms and deep learning. Despite several models having been created for SARS-CoV-2, most of these have been found to be highly susceptible to bias. We aimed to develop and compare two separate predictive models for death during admission with SARS-CoV-2. METHOD: Between March 1 and April 24, 2020, 398 patients were identified with laboratory confirmed SARS-CoV-2 in a London teaching hospital. Data from electronic health records were extracted and used to create two predictive models using: (1) a Cox regression model and (2) an artificial neural network (ANN). Model performance profiles were assessed by validation, discrimination, and calibration. RESULTS: Both the Cox regression and ANN models achieved high accuracy (83.8%, 95% confidence interval (CI) 73.8-91.1 and 90.0%, 95% CI 81.2-95.6, respectively). The area under the receiver operator curve (AUROC) for the ANN (92.6%, 95% CI 91.1-94.1) was significantly greater than that of the Cox regression model (86.9%, 95% CI 85.7-88.2), p = 0.0136. Both models achieved acceptable calibration with Brier scores of 0.13 and 0.11 for the Cox model and ANN, respectively. CONCLUSION: We demonstrate an ANN which is non-inferior to a Cox regression model but with potential for further development such that it can learn as new data becomes available. Deep learning techniques are particularly suited to complex datasets with non-linear solutions, which make them appropriate for use in conditions with a paucity of prior knowledge. Accurate prognostic models for SARS-CoV-2 can provide benefits at the patient, departmental and organisational level.

Adult Bowel Preparations for Colonoscopy.

Colon cancer is the third leading cause of cancer among men and women in the United States. Colonoscopy is largely used as a screening tool to detect pre-cancerous polyps and to detect colorectal cancers early. Optimal bowel preparation prior to colonoscopy allows the endoscopist the ability to increase adenoma detection rates and perform the procedure more safely. This article reviews the various bowel preparations on the market today with evidence based findings on optimal use, safety profiles, timing and adjuncts.

Case series of perianal and pelvic MRI imaging findings in monkeypox.

Monkeypox is a viral infection historically rarely seen in humans, but currently the focus of international attention due to a multi-country outbreak outside endemic countries of Central and West Africa, where cases are typically confined. Perianal pain and lesions have recently been recognised as a feature of monkeypox. We present a case series of the imaging findings of patients with monkeypox, including active proctitis, anal canal inflammation, and perianal inflammation. The aim is to increase awareness of perianal and rectal monkeypox MRI imaging features during this current outbreak.

Hybrid immunity in older adults is associated with reduced SARS-CoV-2 infections following BNT162b2 COVID-19 immunisation.

BACKGROUND: Older adults, particularly in long-term care facilities (LTCF), remain at considerable risk from SARS-CoV-2. Data on the protective effect and mechanisms of hybrid immunity are skewed towards young adults precluding targeted vaccination strategies. METHODS: A single-centre longitudinal seroprevalence vaccine response study was conducted with 280 LCTF participants (median 82 yrs, IQR 76-88 yrs; 95.4% male). Screening by SARS-CoV-2 polymerase chain reaction with weekly asymptomatic/symptomatic testing (March 2020-October 2021) and serology pre-/post-two-dose Pfizer-BioNTech BNT162b2 vaccination for (i) anti-nucleocapsid, (ii) quantified anti-receptor binding domain (RBD) antibodies at three time-intervals, (iii) pseudovirus neutralisation, and (iv) inhibition by anti-RBD competitive ELISA were conducted. Neutralisation activity: antibody titre relationship was assessed via beta linear-log regression and RBD antibody-binding inhibition: post-vaccine infection relationship by Wilcoxon rank sum test. RESULTS: Here we show neutralising antibody titres are 9.2-fold (95% CI 5.8-14.5) higher associated with hybrid immunity (p < 0.00001); +7.5-fold (95% CI 4.6-12.1) with asymptomatic infection; +20.3-fold, 95% (CI 9.7-42.5) with symptomatic infection. A strong association is observed between antibody titre: neutralising activity (p < 0.00001) and rising anti-RBD antibody titre: RBD antibody-binding inhibition (p < 0.001), although 18/169 (10.7%) participants with high anti-RBD titre (>100BAU/ml), show inhibition <75%. Higher RBD antibody-binding inhibition values are associated with hybrid immunity and reduced likelihood of infection (p = 0.003). CONCLUSIONS: Hybrid immunity in older adults was associated with considerably higher antibody titres, neutralisation and inhibition capacity. Instances of high anti-RBD titre with lower inhibition suggests antibody quantity and quality as independent potential correlates of protection, highlighting added value of measuring inhibition over antibody titre alone to inform vaccine strategy.

Older adults continue to be at risk of COVID-19, particularly in residential care home settings. We investigated the effect of infection and vaccination on antibody development and subsequent SARS-CoV-2 infection in older adults. Antibodies are proteins that the immune system produces on infection or vaccination that can help respond to subsequent infection with SARS-CoV-2. We found that older adults produce antibodies to SARS-CoV-2 after 2-doses of Pfizer BioNTech BNT162b2 vaccine. The strongest immune responses were seen among those older adults who also had prior history of infection. The results highlight the importance of both antibody quality and quantity when considering possible indicators of protection against COVID-19 and supports the need for a third, booster, vaccination in this age group..

Clinical features and novel presentations of human monkeypox in a central London centre during the 2022 outbreak: descriptive case series.

OBJECTIVE: To characterise the clinical features of monkeypox infection in humans. DESIGN: Descriptive case series. SETTING: A regional high consequences infectious disease centre with associated primary and secondary care referrals, and affiliated sexual health centres in south London between May and July 2022. PARTICIPANTS: 197 patients with polymerase chain reaction confirmed monkeypox infection. RESULTS: The median age of participants was 38 years. All 197 participants were men, and 196 identified as gay, bisexual, or other men who have sex with men. All presented with mucocutaneous lesions, most commonly on the genitals (n=111 participants, 56.3%) or in the perianal area (n=82, 41.6%). 170 (86.3%) participants reported systemic illness. The most common systemic symptoms were fever (n=122, 61.9%), lymphadenopathy (114, 57.9%), and myalgia (n=62, 31.5%). 102/166 (61.5%) developed systemic features before the onset of mucocutaneous manifestations and 64 (38.5%) after (n=4 unknown). 27 (13.7%) presented exclusively with mucocutaneous manifestations without systemic features. 71 (36.0%) reported rectal pain, 33 (16.8%) sore throat, and 31 (15.7%) penile oedema. 27 (13.7%) had oral lesions and 9 (4.6%) had tonsillar signs. 70/195 (35.9%) participants had concomitant HIV infection. 56 (31.5%) of those screened for sexually transmitted infections had a concomitant sexually transmitted infection. Overall, 20 (10.2%) participants were admitted to hospital for the management of symptoms, most commonly rectal pain and penile swelling. CONCLUSIONS: These findings confirm the ongoing unprecedented community transmission of monkeypox virus among gay, bisexual, and other men who have sex with men seen in the UK and many other non-endemic countries. A variable temporal association was observed between mucocutaneous and systemic features, suggesting a new clinical course to the disease. New clinical presentations of monkeypox infection were identified, including rectal pain and penile oedema. These presentations should be included in public health messaging to aid early diagnosis and reduce onward transmission.

Clinical Utility and Functionality of an Artificial Intelligence-Based App to Predict Mortality in COVID-19: Mixed Methods Analysis.

BACKGROUND: The artificial neural network (ANN) is an increasingly important tool in the context of solving complex medical classification problems. However, one of the principal challenges in leveraging artificial intelligence technology in the health care setting has been the relative inability to translate models into clinician workflow. OBJECTIVE: Here we demonstrate the development of a COVID-19 outcome prediction app that utilizes an ANN and assesses its usability in the clinical setting. METHODS: Usability assessment was conducted using the app, followed by a semistructured end-user interview. Usability was specified by effectiveness, efficiency, and satisfaction measures. These data were reported with descriptive statistics. The end-user interview data were analyzed using the thematic framework method, which allowed for the development of themes from the interview narratives. In total, 31 National Health Service physicians at a West London teaching hospital, including foundation physicians, senior house officers, registrars, and consultants, were included in this study. RESULTS: All participants were able to complete the assessment, with a mean time to complete separate patient vignettes of 59.35 (SD 10.35) seconds. The mean system usability scale score was 91.94 (SD 8.54), which corresponds to a qualitative rating of "excellent." The clinicians found the app intuitive and easy to use, with the majority describing its predictions as a useful adjunct to their clinical practice. The main concern was related to the use of the app in isolation rather than in conjunction with other clinical parameters. However, most clinicians speculated that the app could positively reinforce or validate their clinical decision-making. CONCLUSIONS: Translating artificial intelligence technologies into the clinical setting remains an important but challenging task. We demonstrate the effectiveness, efficiency, and system usability of a web-based app designed to predict the outcomes of patients with COVID-19 from an ANN.

An Evaluation of Commonly Used Surrogate Baseline Creatinine Values to Classify AKI During Acute Infection.

INTRODUCTION: Classification of acute kidney injury (AKI) requires a premorbid baseline creatinine, often unavailable in studies in acute infection. METHODS: We evaluated commonly used surrogate and imputed baseline creatinine values against a "reference" creatinine measured during follow-up in an adult clinical trial cohort. Known AKI incidence (Kidney Disease: Improving Global Outcomes [KDIGO] criteria) was compared with AKI incidence classified by (1) back-calculation using the Modification of Diet in Renal Disease (MDRD) equation with and without a Chinese ethnicity correction coefficient; (2) back-calculation using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation; (3) assigning glomerular filtration rate (GFR) from age and sex-standardized reference tables; and (4) lowest measured creatinine during admission. Back-calculated distributions were performed using GFRs of 75 and 100 ml/min. RESULTS: All equations using an assumed GFR of 75 ml/min underestimated AKI incidence by more than 50%. Back-calculation with CKD-EPI and GFR of 100 ml/min most accurately predicted AKI but misclassified all AKI stages and had low levels of agreement with true AKI diagnoses. Back-calculation using MDRD and assumed GFR of 100 ml/min, age and sex-reference GFR values adjusted for good health, and lowest creatinine during admission performed similarly, best predicting AKI incidence (area under the receiver operating characteristic curves [AUC ROCs] of 0.85, 0.87, and 0.85, respectively). MDRD back-calculation using a cohort mean GFR showed low total error (22%) and an AUC ROC of 0.85. CONCLUSION: Current methods for estimating baseline creatinine are large sources of potential error in acute infection studies. Preferred alternatives include MDRD equation back-calculation with a population mean GFR, age- and sex-specific GFR values corrected for "good health," or lowest measured creatinine. Studies using surrogate baseline creatinine values should report specific methodology.

Investigating the association between ethnicity and health outcomes in SARS-CoV-2 in a London secondary care population.

BACKGROUND: Black, Asian and minority ethnic (BAME) populations are emerging as a vulnerable group in the severe acute respiratory syndrome coronavirus disease (SARS-CoV-2) pandemic. We investigated the relationship between ethnicity and health outcomes in SARS-CoV-2. METHODS AND FINDINGS: We conducted a retrospective, observational analysis of SARS-CoV-2 patients across two London teaching hospitals during March 1 -April 30, 2020. Routinely collected clinical data were extracted and analysed for 645 patients who met the study inclusion criteria. Within this hospitalised cohort, the BAME population were younger relative to the white population (61.70 years, 95% CI 59.70-63.73 versus 69.3 years, 95% CI 67.17-71.43, p<0.001). When adjusted for age, sex and comorbidity, ethnicity was not a predictor for ICU admission. The mean age at death was lower in the BAME population compared to the white population (71.44 years, 95% CI 69.90-72.90 versus, 77.40 years, 95% CI 76.1-78.70 respectively, p<0.001). When adjusted for age, sex and comorbidities, Asian patients had higher odds of death (OR 1.99: 95% CI 1.22-3.25, p<0.006). CONCLUSIONS: BAME patients were more likely to be admitted younger, and to die at a younger age with SARS-CoV-2. Within the BAME cohort, Asian patients were more likely to die but despite this, there was no difference in rates of admission to ICU. The reasons for these disparities are not fully understood and need to be addressed. Investigating ethnicity as a clinical risk factor remains a high public health priority. Studies that consider ethnicity as part of the wider socio-cultural determinant of health are urgently needed.

Point-of-care serological assays for delayed SARS-CoV-2 case identification among health-care workers in the UK: a prospective multicentre cohort study.

BACKGROUND: Health-care workers constitute a high-risk population for acquisition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Capacity for acute diagnosis via PCR testing was limited for individuals with mild to moderate SARS-CoV-2 infection in the early phase of the COVID-19 pandemic and a substantial proportion of health-care workers with suspected infection were not tested. We aimed to investigate the performance of point-of-care and laboratory serology assays and their utility in late case identification, and to estimate SARS-CoV-2 seroprevalence. METHODS: We did a prospective multicentre cohort study between April 8 and June 12, 2020, in two phases. Symptomatic health-care workers with mild to moderate symptoms were eligible to participate 14 days after onset of COVID-19 symptoms, as per the Public Health England (PHE) case definition. Health-care workers were recruited to the asymptomatic cohort if they had not developed PHE-defined COVID-19 symptoms since Dec 1, 2019. In phase 1, two point-of-care lateral flow serological assays, the Onsite CTK Biotech COVID-19 split IgG/IgM Rapid Test (CTK Bitotech, Poway, CA, USA) and the Encode SARS-CoV-2 split IgM/IgG One Step Rapid Test Device (Zhuhai Encode Medical Engineering, Zhuhai, China), were evaluated for performance against a laboratory immunoassay (EDI Novel Coronavirus COVID-19 IgG ELISA kit [Epitope Diagnostics, San Diego, CA, USA]) in 300 samples from health-care workers and 100 pre-COVID-19 negative control samples. In phase 2 (n=6440), serosurveillance was done among 1299 (93·4%) of 1391 health-care workers reporting symptoms, and in a subset of asymptomatic health-care workers (405 [8·0%] of 5049). FINDINGS: There was variation in test performance between the lateral flow serological assays; however, the Encode assay displayed reasonable IgG sensitivity (127 of 136; 93·4% [95% CI 87·8-96·9]) and specificity (99 of 100; 99·0% [94·6-100·0]) among PCR-proven cases and good agreement (282 of 300; 94·0% [91·3-96·7]) with the laboratory immunoassay. By contrast, the Onsite assay had reduced sensitivity (120 of 136; 88·2% [95% CI 81·6-93·1]) and specificity (94 of 100; 94·0% [87·4-97·8]) and agreement (254 of 300; 84·7% [80·6-88·7]). Five (7%) of 70 PCR-positive cases were negative across all assays. Late changes in lateral flow serological assay bands were recorded in 74 (9·3%) of 800 cassettes (35 [8·8%] of 400 Encode assays; 39 [9·8%] of 400 Onsite assays), but only seven (all Onsite assays) of these changes were concordant with the laboratory immunoassay. In phase 2, seroprevalence among the workforce was estimated to be 10·6% (95% CI 7·6-13·6) in asymptomatic health-care workers and 44·7% (42·0-47·4) in symptomatic health-care workers. Seroprevalence across the entire workforce was estimated at 18·0% (95% CI 17·0-18·9). INTERPRETATION: Although a good positive predictive value was observed with both lateral flow serological assays and ELISA, this agreement only occurred if the pre-test probability was modified by a strict clinical case definition. Late development of lateral flow serological assay bands would preclude postal strategies and potentially home testing. Identification of false-negative results among health-care workers across all assays suggest caution in interpretation of IgG results at this stage; for now, testing is perhaps best delivered in a clinical setting, supported by government advice about physical distancing. FUNDING: None.

Incorporation of photo-carbon monoxide releasing materials into electrospun scaffolds for vascular tissue engineering.

Hyper-proliferation of smooth muscle cells (SMCs) and a reduction in endothelial cell function are reasons for poor patency rates of current tissue engineered small-diameter vascular grafts. The controlled delivery of carbon monoxide (CO), a gasotransmitter involved in cell signaling, could improve vascular cell function in these grafts. Current CO releasing molecules (CORMs) can improve endothelialization of injured vessels with appropriate doses, but they still have limitations. The goal of this project was to generate a novel tissue engineered scaffold that includes a non-toxic and photoactivatable CORM. This is the first use of a CORM for tissue engineering. The results demonstrated that CORM-loaded, electrospun poly(ɛ-caprolactone) scaffolds can be photo-activated and release CO. The fluorescence that develops after CO release can be used to non-destructively track the extent of reaction. Further, activation can occur when both dry and incubated in cell culture conditions. However, incubation in serum protein-containing media decreases the time frame for activation, demonstrating the importance of testing the release profile in culture conditions. Rat SMCs were able to attach, grow, and express contractile SMC markers on activated CORM-loaded meshes and controls. Overall, these findings demonstrate that CORM-loaded electrospun scaffolds provide a promising delivery system for vascular tissue engineering.

Health disparities in colorectal cancer among racial and ethnic minorities in the United States.

In the 2010 Census, just over one-third of the United States (US) population identified themselves as being something other than being non-Hispanic white alone. This group has increased in size from 86.9 million in 2000 to 111.9 million in 2010, representing an increase of 29 percent over the ten year period. Per the American Cancer Society, racial and ethnic minorities are more likely to develop cancer and die from it when compared to the general population of the United States. This is particularly true for colorectal cancer (CRC). The primary aim of this review is to highlight the disparities in CRC among racial and ethnic minorities in the United States. Despite overall rates of CRC decreasing nationally and within certain racial and ethnic minorities in the US, there continue to be disparities in incidence and mortality when compared to non-Hispanic whites. The disparities in CRC incidence and mortality are related to certain areas of deficiency such as knowledge of family history, access to care obstacles, impact of migration on CRC and paucity of clinical data. These areas of deficiency limit understanding of CRC's impact in these groups and when developing interventions to close the disparity gap. Even with the implementation of the Patient Protection and Affordable Healthcare Act, disparities in CRC screening will continue to exist until specific interventions are implemented in the context of each of racial and ethnic group. Racial and ethnic minorities cannot be viewed as one monolithic group, rather as different segments since there are variations in incidence and mortality based on natural history of CRC development impacted by gender, ethnicity group, nationality, access, as well as migration and socioeconomic status. Progress has been made overall, but there is much work to be done.

Accelerated mortality from hydrocephalus and pneumonia in mice with a combined deficiency of SPAG6 and SPAG16L reveals a functional interrelationship between the two central apparatus proteins.

SPAG6 and SPAG16L are proteins localized to the "9+2" axoneme central apparatus. Both are essential for sperm motility and male fertility. These two proteins are also expressed in other tissues containing ciliated cells, such as brain and lung. To study the effects of combined deficiency of these two proteins, a double mutant mouse model was created. The double mutant mice displayed a more profound phenotype of growth retardation and hydrocephalus compared to mice nullizygous for SPAG6 and SPAG16L alone. The double mutant mice died younger, and mortality was significantly higher than in single mutant mice. In addition, the double mutant mice demonstrated pneumonia and its complications, including hemorrhage, edema, and atelectasis, phenotypes not observed in mice nullizygous for mutations in the individual genes. No other cilia-related phenotypic change was detected in double mutant mice including lateralization defects. The ultrastructure of cilia in both the brain and lung of the double mutant mice appeared normal. This model of combined SPAG6 and SPAG16L deficiency provides a new platform to study primary ciliary dyskinesia. The findings also demonstrate that SPAG6 and SPAG16L have related roles in controlling the function of cilia in the brain and lung.

Deficiency of SPAG16L causes male infertility associated with impaired sperm motility.

The axonemes of cilia and flagella contain a "9+2" structure of microtubules and associated proteins. Proteins associated with the central doublet pair have been identified in Chlamydomonas that result in motility defects when mutated. The murine orthologue of the Chlamydomonas PF20 gene, sperm-associated antigen 16 (Spag16), encodes two proteins of M(r) approximately 71 x 10(3) (SPAG16L) and M(r) approximately 35 x 10(3) (SPAG16S). In sperm, SPAG16L is found in the central apparatus of the axoneme. To determine the function of SPAG16L, gene targeting was used to generate mice lacking this protein but still expressing SPAG16S. Mutant animals were viable and showed no evidence of hydrocephalus, lateralization defects, sinusitis, bronchial infection, or cystic kidneys-symptoms typically associated with ciliary defects. However, males were infertile with a lower than normal sperm count. The sperm had marked motility defects, even though ultrastructural abnormalities of the axoneme were not evident. In addition, the testes of some nullizygous animals showed a spermatogenetic defect, which consisted of degenerated germ cells in the seminiferous tubules. We conclude that SPAG16L is essential for sperm flagellar function. The sperm defect is consistent with the motility phenotype of the Pf20 mutants of Chlamydomonas, but morphologically different in that the mutant algal axoneme lacks the central apparatus.