Isotope-Edited Variable Temperature Infrared Spectroscopy for Measuring Transition Temperatures of Single A-T Watson-Crick Base Pairs in DNA Duplexes.

Experimental methods to determine transition temperatures for individual base pair melting events in DNA duplexes are lacking despite intense interest in these thermodynamic parameters. Here, we determine the dimensions of the thymine (T) C2═O stretching vibration when it is within the DNA duplex via isotopic substitutions at other atomic positions in the structure. First, we determined that this stretching state was localized enough to specific atoms in the molecule to make submolecular scale measurements of local structure and stability in high molecular weight complexes. Next, we develop a new isotope-edited variable temperature infrared method to measure melting transitions at various locations in a DNA structure. As an initial test of this "sub-molecular scale thermometer", we applied our T13C2 difference infrared signal to measure location-dependent melting temperatures (TmL) in a DNA duplex via variable temperature attenuated total reflectance Fourier transform infrared (VT-ATR-FTIR) spectroscopy. We report that the TmL of a single Watson-Crick A-T base pair near the end of an A-T rich sequence (poly T) is ∼34.9 ± 0.7°C. This is slightly lower than the TmL of a single base pair near the middle position of the poly T sequence (TmL ∼35.6±0.2°C). In addition, we also report that the TmL of a single Watson-Crick A-T base pair near the end of a 50% G-C sequence (12-mer) is ∼52.5 ± 0.3°C, which is slightly lower than the global melting Tm of the 12-mer sequence (TmL ∼54.0±0.9°C). Our results provide direct physical evidence for end fraying in DNA sequences with our novel spectroscopic methods.

COVID-19 associated with universities in England, October 2020-February 2022.

OBJECTIVES: The aim of this study was to describe the epidemiology of COVID-19 cases at universities in England (October 2020-February 2022) and investigate factors associated with rates of COVID-19 among students during autumn/winter of 2021/22. STUDY DESIGN: The study was an observational retrospective study using routine contact tracing data. METHODS: Estimates of COVID-19 cases among students and staff at universities were described. Student cases aged 18-24 years were calculated as a percentage of all cases within that age group. Count regression was used to explore university characteristics associated with case numbers. RESULTS: We identified 102,382 cases among students and 28,639 among staff. Student cases reflected trends in the wider population of the same age group, but the observed fraction aged 18-24 years who were students was consistently below the expected level (32%). Phased reopening of universities in March-May 2021 was associated with small peaks but low absolute numbers. Russell group membership, campus universities, and higher student proportions in halls of residence were all associated with increased case numbers. CONCLUSIONS: COVID-19 case numbers among students in England varied considerably. At no time were the observed case numbers as high as expected from community prevalence. Characteristics of universities associated with higher case rates can inform future guidance for higher education settings.

Equity analysis audit of access and utilisation of Special Care Dental Services by ethnicity and social demographic markers.

OBJECTIVE: To identify and investigate any differences in utilisation of the, Sussex Community NHSFT, Special Care Dental Service (SCDS) across multiple demographic factors, including ethnicity, socio-economic groups and age in the Crawley area. METHOD: Data were audited for all new patients seen at the Crawley Special Care Dental Centre from November 2020-October 2021. Demographic data were compared to population data from the 2011 Census. Deprivation data, using Index of Multiple Deprivation, were also examined against utilisation and failure to attend appointments. RESULTS: A total of 1250 new patients accessed the Crawley SCDS between November 2020 and October 2021. The data suggests good equity to the service being utilised by the local community; the proportions of patients utilising the service over the course of a year from different ethnic groups reflected the demographic profile of Crawley. The proportion of failed appointments showed no correlation with deprivation decile. There was also no association between ethnic group and proportion of failed appointments. CONCLUSION: Ensuring equal utilisation of healthcare for all population groups has become a priority for healthcare providers. This audit found minimal inequities in utilisation of the Special Care Dental Service at Crawley.

Molecular simulation of glycerol-derived triether podands for lithium ion solvation.

Solvate ionic liquids (ILs) are promising candidates for several applications due to their stability, high coulombic efficiency, and low volatility. In this work, we investigate the solvation of lithium-bistriflimide by different glycerol-derived triether solvents, using molecular dynamics simulations. Very strong interactions between Li+ and the solvent oxygen sites are found, leading to significant conformational changes in the solvent. By comparing the conformation of the neat solvents with their IL mixtures at different concentrations and temperatures, we find that the presence of Li+ induces a distinct crown-like structure in the solvent molecules. The Li+ cations and the surrounding solvent form a podand complex, which is stable even at elevated temperatures. These glycerol-derived solvents exhibit distinct interactions with Li+ cations which may be exploited in electrolytic applications or lithium recovery processes.

HIV Care Engagement Among Trans Women of Color in San Francisco Bay Area Demonstration Projects: Findings from the Brandy Martell Project and TransAccess.

In the San Francisco Bay Area (SFBA), trans women of color are disproportionately affected by HIV and have poor HIV care outcomes. The Brandy Martell Project and TransAccess were two demonstration projects aimed at increasing HIV care engagement and retention among trans women of color in the SFBA. Both projects took place in clinics with a long history of providing trans health care and social services. Both also relied on peer navigation to address systems barriers and promote HIV care linkage and engagement. Our analysis was to identify associations between intervention exposure and primary HIV care visits, ART prescription, and retention in HIV care. Using GEE, we estimated the association between intervention exposure measures (receipt of intervention, intervention dose, intervention provider, and peer dose) and any primary HIV care visit or ART prescription over the 12-month period. Overall, the Brandy Martell Project and TransAccess interventions had significantly positive associations with HIV care outcomes measured. Peer navigation also had a significantly positive association with HIV care outcomes. These interventions demonstrate promise for engaging and retaining trans women of color in HIV care, and call for future investment in this highly underserved community.

A laboratory study to assess the formation of effluent volatile compounds and disinfection by-products during chemomechanical preparation of infected root canals and application of activated carbon for their removal.

AIM: To assess in a laboratory setting using extracted teeth the formation of volatile compounds (VOCs) and disinfection by-products (DBPs) in effluent aliquots, during chemomechanical preparation of artificially infected root canal specimens, and determine the role of silver-impregnated activated carbon (Ag-AC) in their removal. METHODOLOGY: Single-rooted human teeth were decoronated to obtain 15 mm-long root specimens and a nutrient-stressed multispecies biofilm was grown in the root canals. Specimens were randomly assigned into three groups [Group 1; instrumentation with rotary files and irrigation with sterile saline, Groups 2 and 3; instrumentation with rotary files and irrigation with 2.5% NaOCl and 17% EDTA]. A portable medical suction device was used to collect the effluent aliquots during root canal irrigation. In Groups 1 and 2, the reaction products of the collected effluents were analysed by selected ion flow tube mass spectrometry (SIFT-MS). The effluents from Group 3 were treated with Ag-AC prior to SIFT-MS analysis, to assess the removal capacity of Ag-AC against the reaction products. The synthesis of Ag-AC was characterized with scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS). Two-way analysis of variance (anova) with post hoc Tukey tests was used for data analysis and determination of a significant difference (P < 0.05). RESULTS: In Group 1, effluent VOCs and DBPs were detectable at very low levels. In Group 2, the collected effluent aliquots released high concentrations of methanol, propanol, ammonia, chloroform and formaldehyde, which were significantly greater compared to Group 1 (P < 0.001). SEM/EDS analysis confirmed impregnation of Ag within the AC matrix. The treatment of effluent aliquots with Ag-AC (Group 3) resulted in a significant reduction in concentrations of acetone, acetic acid, propanol, acetaldehyde, acetonitrile and chloroform, compared to Group 2 (P < 0.001). The concentration levels of ethanol, methanol, ammonia and formaldehyde remained unaffected (P > 0.05). CONCLUSIONS: In this laboratory setting using extracted human teeth, the chemomechanical preparation of artificially infected root canals resulted in the formation of toxic VOCs and DBPs as effluent suspensions. Their release during aspiration with dental suction indicates that potential environmental hazards should be investigated. The use of silver-impregnated activated carbon had potential for the point-of-use treatment of post-irrigation effluent aliquots.

Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy.

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.

Molecular insight into the anion effect and free volume effect of CO2 solubility in multivalent ionic liquids.

For many years, experimental and theoretical studies have investigated the solubility of CO2 in a variety of ionic liquids (ILs), but the overarching absorption mechanism is still unclear. Currently, two different factors are believed to dominate the absorption performance: (a) the fractional free volume (FFV) accessible for absorption; and (b) the nature of the CO2 interactions with the anion species. The FFV is often more influential than the specific choice of the anion, but neither mechanism provides a complete picture. Herein, we have attempted to decouple these mechanisms in order to provide a more definitive molecular-level perspective of CO2 absorption in IL solvents. We simulate a series of nine different multivalent ILs comprised of imidazolium cations and sulfonate/sulfonimide anions tethered to benzene rings, along with a comprehensive analysis of the CO2 absorption and underlying molecular-level features. We find that the CO2 solubility has a very strong, linear correlation with respect to FFV, but only when comparisons are constrained to a common anion species. The choice of anion results in a fundamental remapping of the correlation between CO2 solubility and FFV. Overall, the free volume effect dominates in the ILs with smaller FFV values, while the choice of anion becomes more important in the systems with larger FFVs. Our proposed mechanistic map is intended to provide a more consistent framework for guiding further IL design for gas absorption applications.

Streptococcal superantigen-induced expansion of human tonsil T cells leads to altered T follicular helper cell phenotype, B cell death and reduced immunoglobulin release.

Streptococcal pyrogenic exotoxin (Spe) A expression is epidemiologically linked to streptococcal tonsillo-pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantage to Streptococcus pyogenes are unclear. S. pyogenes is an exclusively human pathogen. As the leucocyte profile of tonsil is unique, the impact of SpeA production on human tonsil cell function was investigated. Human tonsil cells from routine tonsillectomy were co-incubated with purified streptococcal superantigens or culture supernatants from isogenic streptococcal isolates, differing only in superantigen production. Tonsil cell proliferation was quantified by tritiated thymidine incorporation, and cell surface characteristics assessed by flow cytometry. Soluble mediators including immunoglobulin were measured using enzyme-linked immunosorbent assay. Tonsil T cells proliferated in response to SpeA and demonstrated typical release of proinflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7 days. In contrast, marked B cell apoptosis and abrogation of total immunoglobulin (Ig)A, IgM, and IgG production occurred in the presence of SpeA and other superantigens. In SpeA-stimulated cultures, T follicular helper (Tfh) cells showed a reduction in C-X-C chemokine receptor (CXCR)5 (CD185) expression, but up-regulation of OX40 (CD134) and inducible T cell co-stimulator (ICOS) (CD278) expression. The phenotypical change in the Tfh population was associated with impaired chemotactic response to CXCL13. SpeA and other superantigens cause dysregulated tonsil immune function, driving T cells from Tfh to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen-producing bacteria with a probable survival advantage.

Moderators and predictors of outcomes in telephone delivered compared to face-to-face cognitive behaviour therapy for paediatric obsessive-compulsive disorder: preliminary evidence from a non-inferiority RCT.

This study provides a preliminary exploration of factors which differentially predict treatment response to telephone-delivered cognitive behavioural therapy (TCBT) compared to face-to-face CBT (CBT) in a randomised non-inferiority controlled trial of 72 children (aged 11-18 years) with obsessive-compulsive disorder (OCD). Potential moderator variables, their interaction with treatment group (CBT, TCBT) and baseline levels of OCD severity were entered into separate regression models where the primary outcome measure was the post-intervention Children's Yale-Brown Obsessive-Compulsive Scale total score (CYBOCS). Separate regressions were also used to test associations between predictors and outcome controlling for pretreatment CYBOCS. Only pretreatment level of parent-rated child peer problems moderated the effects of the two interventions on CYBOCS severity at post-treatment. After controlling for baseline CYBOCS, only family accommodation rated by mothers predicted poorer outcomes in both groups. While CBT and TCBT may be equally effective for adolescents with OCD, the current results tentatively suggest that higher baseline level of peer problems strengthened the response to therapy for youth receiving TCBT and the predictor analyses reinforce the importance of directly addressing family accommodation during CBT for paediatric OCD regardless of delivery mode. Limitations of the current findings and directions for future work are discussed.

Applying adaptive management and lessons learned from national assessments to address logistical challenges in the National Wetland Condition Assessment.

The National Wetland Condition Assessment (NWCA) is one of a series of probability-based National Aquatic Resource Surveys (NARS) conducted by the U.S. Environmental Protection Agency (USEPA) to provide a comprehensive assessment of the condition of the Nation's waters. Randomized design and standardized training and protocols allow USEPA to analyze data that are nationally consistent and regionally relevant. Each NARS assessment was preceded by careful consideration of key logistical elements that included pre-survey planning, training, sampling logistics, and laboratory analysis. Numerous state, tribal, and contractor crews were supported across the country for each assessment; sampling and sample analyses were tracked from initiation; laboratory analyses were completed at USEPA, state, regional, and contract laboratories; and the data analyses and reporting were completed by USEPA-led workgroups, states, and contractors. The complexity and difficulty of each step offered unique challenges and provided lessons learned for each of the NARS assessments. Major logistical elements for implementing large scale assessments that are constrained by sampling period and number and duration of visits are covered in this paper. These elements include sample transport, equipment and supplies, sampling and sample tracking, information management regional technical expertise, and a sound field training program. This paper describes how lessons from previous assessments were applied to the NWCA and how new challenges faced in the NWCA were addressed and carried forward into future surveys.

Sodalis glossinidius presence in wild tsetse is only associated with presence of trypanosomes in complex interactions with other tsetse-specific factors.

BACKGROUND: Susceptibility of tsetse flies (Glossina spp.) to trypanosomes of both humans and animals has been associated with the presence of the endosymbiont Sodalis glossinidius. However, intrinsic biological characteristics of the flies and environmental factors can influence the presence of both S. glossinidius and the parasites. It thus remains unclear whether it is the S. glossinidius or other attributes of the flies that explains the apparent association. The objective of this study was to test whether the presence of Trypanosoma vivax, T. congolense and T. brucei are related to the presence of S. glossinidius in tsetse flies when other factors are accounted for: geographic location, species of Glossina, sex or age of the host flies. RESULTS: Flies (n = 1090) were trapped from four sites in the Shimba Hills and Nguruman regions in Kenya. Sex and species of tsetse (G. austeni, G. brevipalpis, G. longipennis and G. pallidipes) were determined based on external morphological characters and age was estimated by a wing fray score method. The presence of trypanosomes and S. glossinidius was detected using PCR targeting the internal transcribed spacer region 1 and the haemolysin gene, respectively. Sequencing was used to confirm species identification. Generalised Linear Models (GLMs) and Multiple Correspondence Analysis (MCA) were applied to investigate multivariable associations. The overall prevalence of trypanosomes was 42.1%, but GLMs revealed complex patterns of associations: the presence of S. glossinidius was associated with trypanosome presence but only in interactions with other factors and only in some species of trypanosomes. The strongest association was found for T. congolense, and no association was found for T. vivax. The MCA also suggested only a weak association between the presence of trypanosomes and S. glossinidius. Trypanosome-positive status showed strong associations with sex and age while S. glossinidius-positive status showed a strong association with geographic location and species of fly. CONCLUSIONS: We suggest that previous conclusions about the presence of endosymbionts increasing probability of trypanosome presence in tsetse flies may have been confounded by other factors, such as community composition of the tsetse flies and the specific trypanosomes found in different regions.

De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review.

De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work-up and management of this recently described ID syndrome.

Housing and income effects on HIV-related health outcomes in the San Francisco Bay Area - findings from the SPNS transwomen of color initiative.

Transwomen of color are disproportionately impacted by HIV and may have worse health outcomes than other populations. This analysis was conducted to examine structural factors associated with poor health outcomes among transwomen of color living with HIV in the San Francisco Bay Area (N = 159). Univariate and multivariable analyses were conducted to determine if structural factors were associated with poor HIV-related health outcomes. A majority of participants were Black or African American (110/159, 69.2%), 32 (20.1%) identified their primary race/ethnicity as Hispanic or Latino/a or Spanish, and 17 (10.7%) identified as another race/ethnicity. Transwomen of color in our sample faced extreme structural barriers, including residential transience, extreme low income, high prevalence of running out of money in the last six months, high rates of food insecurity, high prevalence of income via entitlement programs, engagement in sex work and other illicit activities for income. Unstable housing was the structural factor most consistently associated with poor health outcomes along the HIV care continuum and may explain engagement in other sources of income generation. Interventions are needed that go beyond the individual and health care-level to address needs for housing and economic opportunities to improve HIV care outcomes among transwomen of color living with HIV in the San Francisco Bay Area.

Indirect neonatal hyperbilirubinemia in hospitalized neonates on the Thai-Myanmar border: a review of neonatal medical records from 2009 to 2014.

BACKGROUND: Indirect neonatal hyperbilirubinemia (INH) is a common neonatal disorder worldwide which can remain benign if prompt management is available. However there is a higher morbidity and mortality risk in settings with limited access to diagnosis and care. The manuscript describes the characteristics of neonates with INH, the burden of severe INH and identifies factors associated with severity in a resource-constrained setting. METHODS: We conducted a retrospective evaluation of anonymized records of neonates hospitalized on the Thai-Myanmar border. INH was defined according to the National Institute for Health and Care Excellence guidelines as 'moderate' if at least one serum bilirubin (SBR) value exceeded the phototherapy threshold and as 'severe' if above the exchange transfusion threshold. RESULTS: Out of 2980 records reviewed, 1580 (53%) had INH within the first 14 days of life. INH was moderate in 87% (1368/1580) and severe in 13% (212/1580). From 2009 to 2011, the proportion of severe INH decreased from 37 to 15% and the mortality dropped from 10% (8/82) to 2% (7/449) coinciding with the implementation of standardized guidelines and light-emitting diode (LED) phototherapy. Severe INH was associated with: prematurity (< 32 weeks, Adjusted Odds Ratio (AOR) 3.3; 95% CI 1.6-6.6 and 32 to 37 weeks, AOR 2.2; 95% CI 1.6-3.1), Glucose-6-phosphate dehydrogenase deficiency (G6PD) (AOR 2.3; 95% CI 1.6-3.3), potential ABO incompatibility (AOR 1.5; 95% CI 1.0-2.2) and late presentation (AOR 1.8; 95% CI 1.3-2.6). The risk of developing severe INH and INH-related mortality significantly increased with each additional risk factor. CONCLUSION: INH is an important cause of neonatal hospitalization on the Thai-Myanmar border. Risk factors for severity were similar to previous reports from Asia. Implementing standardized guidelines and appropriate treatment was successful in reducing mortality and severity. Accessing to basic neonatal care including SBR testing, LED phototherapy and G6PD screening can contribute to improve neonatal outcomes.

Baraitser-Winter cerebrofrontofacial syndrome.

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) (BRWS; MIM #243310, 614583) is a rare developmental disorder affecting multiple organ systems. It is characterised by intellectual disability (mild to severe) and distinctive facial appearance (metopic ridging/trigonocephaly, bilateral ptosis, hypertelorism). The additional presence of cortical malformations (pachygyria/lissencephaly) and ocular colobomata are also suggestive of this syndrome. Other features include moderate short stature, contractures, congenital cardiac disease and genitourinary malformations. BWCFF is caused by missense mutations in the cytoplasmic beta- and gamma-actin genes ACTB and ACTG1. We provide an overview of the clinical characteristics (including some novel findings in four recently diagnosed patients), diagnosis, management, mutation spectrum and genetic counselling.

Molecular Simulation of Ionic Polyimides and Composites with Ionic Liquids as Gas-Separation Membranes.

Polyimides are at the forefront of advanced membrane materials for CO2 capture and gas-purification processes. Recently, ionic polyimides (i-PIs) have been reported as a new class of condensation polymers that combine structural components of both ionic liquids (ILs) and polyimides through covalent linkages. In this study, we report CO2 and CH4 adsorption and structural analyses of an i-PI and an i-PI + IL composite containing [C4mim][Tf2N]. The combination of molecular dynamics (MD) and grand canonical Monte Carlo (GCMC) simulations is used to compute the gas solubility and the adsorption performance with respect to the density, fractional free volume (FFV), and surface area of the materials. Our results highlight the polymer relaxation process and its correlation to the gas solubility. In particular, the surface area can provide meaningful guidance with respect to the gas solubility, and it tends to be a more sensitive indicator of the adsorption behavior versus only considering the system density and FFV. For instance, as the polymer continues to relax, the density, FFV, and pore-size distribution remain constant while the surface area can continue to increase, enabling more adsorption. Structural analyses are also conducted to identify the nature of the gas adsorption once the ionic liquid is added to the polymer. The presence of the IL significantly displaces the CO2 molecules from the ligand nitrogen sites in the neat i-PI to the imidazolium rings in the i-PI + IL composite. However, the CH4 molecules move from the imidazolium ring sites in the neat i-PI to the ligand nitrogen atoms in the i-PI + IL composite. These molecular details can provide critical information for the experimental design of highly selective i-PI materials as well as provide additional guidance for the interpretation of the simulated adsorption systems.

Laparoscopic ventral rectopexy for rectal prolapse and rectal intussusception using a biological mesh.

AIM: Laparoscopic ventral rectopexy (LVR) is a nerve-sparing technique for the treatment of rectal prolapse. Concerns about the use of synthetic meshes in the pelvis and the associated risk of erosion have led to the recent use of biological meshes in some colorectal units. This retrospective study aims to assess the outcomes of patients undergoing LVR using a noncross-linked nondermal biological mesh. METHOD: The medical notes of all patients who underwent LVR between 1 December 2011 and 31 May 2014 were reviewed. The rate of obstructed defaecation before surgery was retrospectively determined from medical records using the Rome III criteria. The rates of obstructed defaecation and faecal incontinence following surgery were determined using a self-reported questionnaire. RESULTS: A total of 51 patients had LVR between 1 December 2011 and 31 May 2014. Their mean age was 57.3 ± 2.5 years and the mean follow-up was 23 ± 1 months. There were seven (13.7%) postoperative complications. In total, 45 (88%) patients completed the functional outcome questionnaires. Before surgery, 33 (73.3%) patients complained of symptoms of obstructed defaecation. At the end of follow-up, 22 (48.8%, P = 0.001) patients continued to have some symptoms of obstructed defaecation. Before surgery, 12 (26.7%) patients complained of faecal incontinence. At the end of follow-up, only three (6.7%, P = 0.004) patients reported faecal incontinence. At the end of follow-up, recurrence of symptoms had occurred in six (13.3%) patients. CONCLUSION: LVR using a biological mesh is safe and results in significant reduction in symptoms associated with external rectal prolapse and rectal intussusception.

A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).