Systematic development and validation of a predictive model for major postoperative complications in the Peri-operative Quality Improvement Project (PQIP) dataset.

Complications are common following major surgery and are associated with increased use of healthcare resources, disability and mortality. Continued reliance on mortality estimates risks harming patients and health systems, but existing tools for predicting complications are unwieldy and inaccurate. We aimed to systematically construct an accurate pre-operative model for predicting major postoperative complications; compare its performance against existing tools; and identify sources of inaccuracy in predictive models more generally. Complete patient records from the UK Peri-operative Quality Improvement Programme dataset were analysed. Major complications were defined as Clavien-Dindo grade ≥ 2 for novel models. In a 75% train:25% test split cohort, we developed a pipeline of increasingly complex models, prioritising pre-operative predictors using Least Absolute Shrinkage and Selection Operators (LASSO). We defined the best model in the training cohort by the lowest Akaike's information criterion, balancing accuracy and simplicity. Of the 24,983 included cases, 6389 (25.6%) patients developed major complications. Potentially modifiable risk factors (pain, reduced mobility and smoking) were retained. The best-performing model was highly complex, specifying individual hospital complication rates and 11 patient covariates. This novel model showed substantially superior performance over generic and specific prediction models and scores. We have developed a novel complications model with good internal accuracy, re-prioritised predictor variables and identified hospital-level variation as an important, but overlooked, source of inaccuracy in existing tools. The complexity of the best-performing model does, however, highlight the need for a step-change in clinical risk prediction to automate the delivery of informative risk estimates in clinical systems.

Development and internal validation of a model for postoperative morbidity in adults undergoing major elective colorectal surgery: the peri-operative quality improvement programme (PQIP) colorectal risk model.

Over 1.5 million major surgical procedures take place in the UK NHS each year and approximately 25% of patients develop at least one complication. The most widely used risk-adjustment model for postoperative morbidity in the UK is the physiological and operative severity score for the enumeration of mortality and morbidity. However, this model was derived more than 30 years ago and now overestimates the risk of morbidity. In addition, contemporary definitions of some model predictors are markedly different compared with when the tool was developed. A second model used in clinical practice is the American College of Surgeons National Surgical Quality Improvement Programme risk model; this provides a risk estimate for a range of postoperative complications. This model, widely used in North America, is not open source and therefore cannot be applied to patient populations in other settings. Data from a prospective multicentre clinical dataset of 118 NHS hospitals (the peri-operative quality improvement programme) were used to develop a bespoke risk-adjustment model for postoperative morbidity. Patients aged ≥ 18 years who underwent colorectal surgery were eligible for inclusion. Postoperative morbidity was defined using the postoperative morbidity survey at postoperative day 7. Thirty-one candidate variables were considered for inclusion in the model. Death or morbidity occurred by postoperative day 7 in 3098 out of 11,646 patients (26.6%). Twelve variables were incorporated into the final model, including (among others): Rockwood clinical frailty scale; body mass index; and index of multiple deprivation quintile. The C-statistic was 0.672 (95%CI 0.660-0.684), with a bootstrap optimism corrected C-statistic of 0.666 at internal validation. The model demonstrated good calibration across the range of morbidity estimates with a mean slope gradient of predicted risk of 0.959 (95%CI 0.894-1.024) with an index-corrected intercept of -0.038 (95%CI -0.112-0.036) at internal validation. Our model provides parsimonious case-mix adjustment to quantify risk of morbidity on postoperative day 7 for a UK population of patients undergoing major colorectal surgery. Despite the C-statistic of < 0.7, our model outperformed existing risk-models in widespread use. We therefore recommend application in case-mix adjustment, where incorporation into a continuous monitoring tool such as the variable life adjusted display or exponentially-weighted moving average-chart could support high-level monitoring and quality improvement of risk-adjusted outcome at the population level.

Human spermatozoa and temperature: the elephant in the room.

Men are notable for low sperm production, relative to that of other large mammals, and often inferior morphology and motility of their spermatozoa. The extent to which temperature plays a role in this picture has been a moot point. However, animal experiments suggest that an increased scrotal temperature of approximately +4°C brought by inguinal clothing has a negative impact on the germinal epithelium and on the epididymis in man. In two animal species with inguinal testes, their transposition to the abdomen, raising the testis temperature by a modest approximate 1.5°C brought reduced sperm production and abnormalities of spermiogenesis (distorted sperm nuclei, shared acrosomes), a picture seen commonly in man alongside morphologically normal spermatids. Reflection of the scrotal epididymis to the abdomen in laboratory animals did not inhibit sperm maturation there, but the consequences of this for other epididymal parameters are mirrored in several features seen in man. In addition to the typically puny form of the human cauda, these include often rapid epididymal sperm transit, rapid capacitation in vitro, a poor sperm reserve (as reflected in the steep decline in sperm numbers in successive ejaculates), and not least, the cauda's failure to maintain the viability of spermatozoa there (reflected in both their mixed potential for motility and the negative outcome of abstinence). Because the number of competent spermatozoa inseminated relates to prompt fertilization and/or incidence of pregnancy in some animal models, the negative effects of scrotal temperature may be an important factor in the need for an average of approximately five cycles of unprotected intercourse in order to establish pregnancy in human females.

Singular features of fertilization and their impact on the male reproductive system in eutherian mammals.

Therian (marsupial and eutherian) mammals have evolved a suite of novel reproductive features - seen variously in their gametes, the steps of fertilization and the male reproductive tract - whose adaptive significance remains unclear. Present evidence for the better-understood eutherian mammals suggests that the 'prime mover' in their evolution has been the character of the egg coat, with other such features being adaptations to the consequences of this. Its elastic thickness allows the zona pellucida to stretch to a variable degree and yet remain around the blastocyst during much or all of its expansion before implantation, but its character represents an unusual challenge for spermatozoa. Novel aspects of the acrosome related to this challenge enable it to maintain a relatively prolonged binding after the onset of the acrosome reaction, and the structure, shape and behaviour of the sperm head point to physical thrust as a major element of zona penetration - with the unique configuration of gamete fusion as a sequela of this strategy. In the male, such adaptations are reflected in sperm head formation in the testis and in sperm maturation in the epididymis involving at least the sperm head's structure, plasmalemma and acrosome. This complexity allied to a slow epididymal sperm transport, a relatively modest sperm production and the brief life span of mature spermatozoa kept above the cauda epididymidis could account for the evolution of the sperm storage function - a development seemingly linked, in turn, to the need for sperm capacitation and scrotal evolution.

From DNA damage to chromosome aberrations: joining the break.

Despite many years of experimental studies on radiation-induced chromosomal aberrations, and the recent progress in elucidating the molecular mechanisms of the DNA damage response, the link between DNA double-strand break repair and its expression as microscopically visible chromosomal rearrangements remains, in many ways, obscure. Some long standing controversies have partially been resolved to the satisfaction of most investigators, including the linearity of the dose-response for DNA double-strand break induction, the necessity of pairwise interaction of radiogenic damaged sites in the formation of exchange aberrations, and the importance of proximity between lesions in misrejoining. However, the contribution of different molecular DNA repair mechanisms (e.g., alternative end-joining pathways) and their impact on the kinetics of aberration formation is still unclear, as is the definition of "complex" radiogenic damaged sites - in either the chemical or spatial sense - which ostensibly lead to chromosome rearrangements. These topics have been recently debated by molecular biologists and cytogeneticists, whose opinions are summarized in this paper.

Probing the seismic cycle timing with coseismic twisting of subduction margins.

Assessing the timing of great megathrust earthquakes is together crucial for seismic hazard analysis and deemed impossible. Geodetic instrumentation of subduction zones has revealed unexpected deformation patterns at subduction segments adjacent to those that hosted recent mega-earthquakes: coastal sites move landward with faster velocities than before the earthquake. Here, we show observations from the largest and best-monitored megathrust earthquakes, and from a scaled analog model, to reveal that these events create coseismic and postseismic deformation patterns typical of a complete gear-like rotation about a vertical axis, hereafter called twisting. We find that such twisting alters the interseismic velocity field of adjacent subduction segments depending on the time since the last earthquake. Early interactions accelerate while late interactions decelerate local kinematics. This finding opens the possibility of using megathrust earthquakes, the characteristics of the twisting pattern, and the ensuing geodetic velocity changes, as a proxy for estimating the timing of the seismic cycle at unruptured segments along the margin.

Asymmetry of spermiation and sperm surface charge patterns over the giant acrosome in the musk shrew Suncus murinus.

Spermatozoa of the shrew Suncus murinus, a mammal with abdominal testes, exhibit four unusual features: a giant acrosome; a dorsoventral asymmetry of their spermiation; a dorsoventral asymmetry of their head surface character; and also apparent surface maturity as they enter the epididymis. A Sertoli cell-periacrosomal cisternal complex envelops the giant acrosome during spermatid maturation. Spermiation is heraled by asymmetrical disorganization of the subplasmalemmal components of this complex and is completed by retraction of the Sertoli cell from the ventral and then the dorsal face of the spermatid head. This sequence or release is correlated with an asynchronous acquisition of negative surface charges on the spermatid head-demonstrable on glutaraldehyde-stabilized cells by the binding at pH 1.8 of positively charged colloidal particles of ferric oxide. Mature epididymal spermatozoa exhibit an asymmetry in the patterns of distribution of bound colloid over the dorsal vs. ventral surfaces of the sperm head, as well as regional differences between the tail midpiece and principal piece. Surface distributions of anionic residues and lectin (Con A)-binding sites characteristic of mature Suncus spermatozoa are demonstrable within the testis, unlike the situation in most nannals where distinct modifications of the sperm surface occur during epididymal passage.

X-ray--induced breakage and rejoining of human interphase chromosomes.

A method was developed for the high-resolution measurement of breaks in prematurely condensed chromosomes at the G1 phase of the cell cycle. The dose response for fragments (breaks) produced immediately after x-irradiation of confluent cultures of normal human cells was linear down to 10.9 rad (0.109 Gy) and extrapolated to zero effect at zero dose. The curve had a slope of 0.063 breaks per cell per rad, which is at least an order of magnitude greater than that for breaks scored in the same cells after they have progressed to mitosis following subculture. When incubated at 37 degrees C half of the breaks disappeared in 2 hours. A slower, perhaps nonrejoining component was apparent at later incubation times. The initial rate of break rejoining was similar to the rate of increase in survival after incubation because of the repair of potentially lethal damage and is also in close agreement with recently reported values for the rejoining of double-strand breakage in DNA.

On the nature of a defect in cells from individuals with ataxia-telangiectasia.

The cells and tissues of patients with ataxia-telangiectasia (A-T), an inherited disease characterized by a high degree of proneness to cancer, are abnormally sensitive to ionizing radiation. Noncycling cultures of normal human and A-T fibroblasts were exposed to x-rays so that the breakage and rejoining of prematurely condensed chromosomes in the G1 phase could be compared. After a dose of 6.0 grays, both cell types had the same initial frequency of breaks and the same rate for rejoining of the breaks, but the fraction of breaks that did not rejoin was five to six times greater for the A-T cells. The results also show that progression of cells into the S phase is not a prerequisite for the increased frequency of chromosome fragments that appear in mitosis after A-T cells are irradiated in the G1 or G0 phase.

Rectal insemination modifies immune responses in rabbits.

Weekly deposition of pooled rabbit semen into the rectum in healthy male rabbits resulted in the appearance of immune complexes and antibodies to sperm and to peripheral blood lymphocyte antigens. It also led to a decreased ability to mount a humoral immune response to T lymphocyte-dependent antigens, keyhole limpet hemocyanin, and sheep red blood cells. These findings suggest that repeated rectal deposition of semen may compromise some aspects of the immune system.

Puzzles of mammalian fertilization--and beyond.

A complexity imposed on the events of conception during the evolution of eutherian mammals is reflected not only in the placenta but also in a series of gamete-related novelties that involve the design of sperm and eggs, their interactions leading to fertilization, epididymal function, and even the scrotal state. While their functional significance has been difficult to determine, I suggest on the basis of present evidence that the genesis of these novel features relates ultimately to changes in the egg associated with nidation, that they imply a new fertilization strategy, and that most are causally linked--a major first 'domino' being the formidable zona pellucida. The eutherian zona pellucida stands out by virtue of an elastic resilience and thickness which allow it to stretch around the expanding blastocyst. However, this quality of the zona together with its relative protease-insensitivity creates a physical challenge which appears to have determined the design of the sperm head, its behaviour at fertilization, and indirectly even the pattern of sperm maturation in the epididymis. In turn, that pattern appears to have evoked the development of the sperm storage function of the cauda region, with both sperm capacitation and the scrotal state as ultimate legacies of this. Coincidentally, the vulnerability of the small yolkless egg to polyspermy appears to have selected for a unique parsimonious pattern of sperm transport in the Fallopian tube, and possibly for the role of the cumulus oophorus as a sperm sequestering device. These ideas are supported generally by evidence from marsupials, as well as by the deviant patterns seen in some insectivorous mammals.

Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and ß) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-ß-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.

Review of hypofractionated small volume radiotherapy for early-stage non-small cell lung cancer.

A review of the technical aspects of high-dose hypofractionated radiotherapy for localised non-small cell lung cancer was carried out to allow correlation with outcome measures and with a consensus view of the technique. A Pubmed search carried out between January 2001 and April 2007 identified 15 studies for inclusion. The clinical and technical aspects of treatment were extracted and their effect on survival, progression-free survival and toxicity were assessed using the summary statistic of weighted means. A comparison was made with the RTOG 0236 consensus study protocol. The range of variables in the studies precluded correlation of outcome with tumour parameters, dose fractionation and technical aspects such as immobilisation, techniques dealing with breathing motion, beam number and arrangement and organ at risk dose constraints. Robust data to justify a consensus view were not found, which suggests that further studies are required. They should focus on developing the treatment technique of stereotactic body radiation therapy for early-stage non-small cell lung cancer and correlating it with outcome to provide a rational basis for future randomised trials, comparing the technique with conformal radiotherapy and surgery, and the introduction of the technique into routine clinical practice.

Direct-aperture optimization applied to selection of beam orientations in intensity-modulated radiation therapy.

Direct-aperture optimization (DAO) was applied to iterative beam-orientation selection in intensity-modulated radiation therapy (IMRT), so as to ensure a realistic segmental treatment plan at each iteration. Nested optimization engines dealt separately with gantry angles, couch angles, collimator angles, segment shapes, segment weights and wedge angles. Each optimization engine performed a random search with successively narrowing step sizes. For optimization of segment shapes, the filtered backprojection (FBP) method was first used to determine desired fluence, the fluence map was segmented, and then constrained direct-aperture optimization was used thereafter. Segment shapes were fully optimized when a beam angle was perturbed, and minimally re-optimized otherwise. The algorithm was compared with a previously reported method using FBP alone at each orientation iteration. An example case consisting of a cylindrical phantom with a hemi-annular planning target volume (PTV) showed that for three-field plans, the method performed better than when using FBP alone, but for five or more fields, neither method provided much benefit over equally spaced beams. For a prostate case, improved bladder sparing was achieved through the use of the new algorithm. A plan for partial scalp treatment showed slightly improved PTV coverage and lower irradiated volume of brain with the new method compared to FBP alone. It is concluded that, although the method is computationally intensive and not suitable for searching large unconstrained regions of beam space, it can be used effectively in conjunction with prior class solutions to provide individually optimized IMRT treatment plans.

gamma-H2AX foci after low-dose-rate irradiation reveal atm haploinsufficiency in mice.

We have investigated the use of the gamma-H2AX assay, reflecting the presence of DNA double-strand breaks (DSBs), as a possible means for identifying individuals who may be intermediate with respect to the extremes of hyper-radiosensitivity phenotypes. In this case, cells were studied from mice that were normal (Atm+/+), heterozygous (Atm+/-), or homozygous recessive (Atm-/-) for a truncating mutation in the Atm gene. After single acute (high-dose-rate) exposures, differences in mean numbers of gamma-H2AX foci per cell between samples from Atm+/+ and Atm-/- mice were clear at nearly all sampling times, but at no sampling time was there a clear distinction for cells from Atm+/+ and Atm+/- mice. In contrast, under conditions of low-dose-rate irradiation at 10 cGy/h, appreciable differences in the levels of gamma-H2AX foci per cell were observed in synchronized G1 cells derived from Atm+/- mice relative to cells from Atm+/+ mice. The levels were intermediate between those for cells from Atm+/+ and Atm-/- mice. After 24 h exposure at this dose rate, measurements in cells from four different mice for each genotype yielded mean frequencies of foci per cell of 1.77 +/- 0.13 (SEM) for Atm+/+ cells, 4.75 +/- 0.20 for the Atm+/- cells, and 11.10 +/- 0.33 for the Atm-/-cells. The distributions of foci per G1 cell were not significantly different from Poisson. To the extent that variations in sensitivity with respect to gamma-H2AX focus formation reflect variations in radiosensitivity for biological effects of concern, such as carcinogenesis, and that similar differences are seen for other genetic DNA DSB processing defects in general, this assay may provide a relatively straightforward means for distinguishing individuals who may be mildly hypersensitive to radiation such as we observed for Atm heterozygous mice.