Unwarranted variation and the goal of net zero for the NHS in England: exploring the link between efficiency working, patient outcomes and carbon footprint.

In 2020 the NHS in England set a target of reaching net zero carbon emissions by 2040. Progress has already been made towards this goal, with substantial reductions in the use of environmentally harmful anaesthetic gases, such as desflurane, in recent years. Where an effective replacement already exists, changing practice to use low carbon alternatives is relatively easy to achieve, but much greater challenges lie ahead. The Getting It Right First Time (GIRFT) programme is a clinically-led, data-driven clinical improvement initiative with a focus on reducing unwarranted variation in clinical practice and patient outcomes. Reducing unwarranted variation can improve patient care and service efficiency, and can also support the drive to net zero. In this article we set out what the GIRFT programme is doing to support sustainable healthcare in England, why it is uniquely positioned to support this goal and what the future challenges, barriers, enablers and opportunities are likely to be in the drive to net zero.

The acute effects of whole-body vibration on gait parameters in adults with cerebral palsy.

OBJECTIVES: As adults with cerebral palsy (CP) are surviving longer, interventions are needed to reduce spasticity and increase strength to improve mobility and life quality. Adults with CP are lacking a form of independent exercise that allows them to maintain or improve their ambulation skills. A new approach to increase muscle strength and flexibility called whole-body vibration (WBV) was assessed. METHODS: Using an individualized frequency (I-Freq) approach to WBV therapy the acute effects on gait in adults with CP was measured. In this study, eight adults with CP (age 20-51 years, two female) participated in two testing sessions: session one determined each individual's I-Freq; and session two included a 3D gait analysis before and after a WBV treatment. The WBV was administered in five, one minute bouts of vibration followed by one minute of rest. RESULTS: Following WBV exposure subjects experienced a significant increase in walking speed (P=0.047), stride length (P=0.017) and dynamic ankle range of motion (P=0.042). CONCLUSIONS: These data show that acute WBV treatments at I-Freq can improve measures of gait and mobility in adults with CP, however, future should assess potential long-term improvements.

Dural venous sinus thrombosis in anaplastic astrocytoma following concurrent temozolomide and focal brain radiotherapy plus bevacizumab.

Malignant gliomas have long been a therapeutic dilemma in neuro-oncology, with a poor overall prognosis. Standard treatment, consisting of primary resection, followed by radiation therapy and temozolomide, has improved prognosis. Recently, studies have looked at the addition of bevacizumab (Avastin), a humanized murine IgG1 monoclonal antibody against vascular endothelial growth factor-A, to conventional regiments. Bevacizumab gained US FDA approval for single agent use in recurrent glioblastoma in 2009. Known side effects of bevacizumab include increased risk of arterial and venous thromboembolism, as well as hemorrhage. With emerging data for the use of bevacizumab in malignant gliomas, the extent of risks such as bleeding and thrombosis in patients with primary brain tumors treated with bevacizumab remains unknown. Here, we present only the second reported case of dural venous sinus thrombosis during treatment with bevacizumab and the first reported case for a primary glioma treated with temozolomide, radiation, and bevacizumab.

The history and development of breast implants.

This review discusses the historical development of smooth and textured silicone gel filled implants, and examines the reasoning behind product development and aspects of surgical technique from a surgeon's perspective.

The growth of Japanese science and technology.

Several measures are used to delineate the remarkable growth in the Japanese technological position over the last decade. The share of U.S. patents issued to Japanese inventors has been rising at 1 percent per year. These patents are the most frequently cited patents in the U.S. system. By 1984, Japanese inventors obtained more U.S. patents than inventors in the United Kingdom, France, and West Germany combined, and the gap has been widening ever since. As measured by publications, the Japanese scientific position is more modest, with a 0.5 percent rise per year in papers and with barely average citation performance. These indicators characterize Japan as a technological powerhouse, with highly innovative technology, and an expanding but far less powerful scientific position.

Heritability of upper airway dimensions derived using acoustic pharyngometry.

Acoustic pharyngometry represents a simple, quick noninvasive method of measuring upper airway dimensions, which are predictive of sleep apnoea risk. The aim of the present study was to assess the genetic basis of upper airway size as determined using pharyngometry. Participants in the Cleveland Family Study aged >14 yrs underwent three acoustic pharyngometric measurements. Variance component models adjusted for age and sex were used to estimate the heritability of pharyngometry-derived airway measures. A total of 568 out of 655 (87%) subjects provided pharyngometric curves of sufficient quality. Although African-Americans tended to show narrower airways compared with white subjects, heritability patterns were similar in these two groups. The minimum cross-sectional area exhibited a heritability of 0.34 in white subjects and 0.39 in African-Americans, suggesting that 30-40% of the total variance in this measure is explained by shared familial factors. Estimates were unchanged after adjustment for body mass index or neck circumference. In contrast, oropharyngeal length did not show significant heritability in either ethnic group. The minimum cross-sectional area of the oropharynx is a highly heritable trait, suggesting the presence of an underlying genetic basis. These findings demonstrate the potential utility of acoustic pharyngometry in dissecting the genetic basis of sleep apnoea.

A numerical investigation and experimental verification of size effects in loaded bovine cortical bone.

In this paper, we present 2- and 3-dimensional finite element-based numerical models of loaded bovine cortical bone that explicitly incorporate the dominant microstructural feature: the vascular channel or Haversian canal system. The finite element models along with the representation of the microstructure within them are relatively simple: 2-dimensional models, consisting of a structured mesh of linear elastic planar elements punctuated by a periodic distribution of circular voids, are used to represent beam samples of cortical bone in which the channels are orientated perpendicular to the sample major axis, while 3-dimensional models, using a corresponding mesh of equivalent solid elements, represent those samples in which the canals are aligned with the axis. However, these models are exploited in an entirely novel approach involving the representation of material samples of different sizes and surface morphology. The numerical results obtained for the virtual material samples when loaded in bending indicate that they exhibit size effects not forecast by either classical (Cauchy) or more generalized elasticity theories. However, these effects are qualitatively consistent with those that we observed in a series of carefully conducted experiments involving the flexural testing of bone samples of different sizes. Encouraged by this qualitative agreement, we have identified appropriate model parameters, primarily void volume fraction but also void separation and matrix modulus by matching the computed size effects to those we observed experimentally. Interestingly, the parameter choices that provide the most suitable match of these effects broadly concur with those we actually observed in cortical bone.

Hematopoietic stem cell development: Using the zebrafish to identify extrinsic and intrinsic mechanisms regulating hematopoiesis.

Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic hierarchy, giving rise to each of the blood lineages found throughout the lifetime of the organism. Since the genetic programs regulating HSC development are highly conserved between vertebrate species, experimental studies in zebrafish have not only complemented observations reported in mammals but have also yielded important discoveries that continue to influence our understanding of HSC biology and homeostasis. Here, we summarize findings that have established zebrafish as an important conserved model for the study of hematopoiesis, and describe methods that can be utilized for future investigations of zebrafish HSC biology.

Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia.

PURPOSE: To quantify the incidence and severity of tumor lysis syndrome (TLS) as a consequence of fludarabine therapy in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: A retrospective review and questionnaire follow-up of clinical and laboratory data were performed on patients with intermediate or high-risk CLL on the National Cancer Institute Group C protocol or special exception mechanisms, or phase II trials of fludarabine, for whom adverse drug reports of TLS were available. Fludarabine was administered at a dose of 20 to 40 mg/m2 per day for 5 days at monthly intervals. RESULTS: Among the 6,137 patients, TLS was suspected in 26 (0.42%), with clinical and laboratory features consistent with TLS present in 20 (0.33%). Prophylaxis against TLS had been administered to 60% of these patients. Clinical or laboratory features were similar to patients who did not develop TLS. Of the patients with TLS, 90% had high-risk CLL, 60 months of prior disease duration, with a median pretreatment WBC of 109 x 10(9)/L, two prior regimens, lymphadenopathy in 89%, splenomegaly and/or hepatomegaly in 90%. TLS developed on approximately day 7 and lasted a median of 9.5 days. Dialysis was required in 30% during the TLS episode; 20% of patients died during cycle one of fludarabine therapy with renal failure, and another 20% died of infection or congestive heart failure. Six patients were retreated with fludarabine without recurrent TLS. CONCLUSION: TLS after fludarabine therapy is extremely uncommon, but may be associated with significant morbidity and mortality.

Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine.

PURPOSE: A phase II trial in patients with limited-stage small-cell lung cancer treated with induction etoposide/cisplatin plus twice-daily chest radiotherapy was conducted in an attempt to increase response rates and prolong survival. PATIENTS AND METHODS: Fifty-four previously untreated patients with limited-stage small-cell cancer were treated with etoposide/cisplatin and concurrent radiotherapy at 1.5 Gy twice daily for 3 weeks to a total dose of 45 Gy. Patients then received three more cycles of etoposide/cisplatin followed by four cycles of vincristine, doxorubicin, and cyclophosphamide or an individualized chemotherapy regimen. RESULTS: Nine patients are alive and free of cancer a median of 4 years (range, 2 to 7) from the start of treatment. Thirty-eight have had progression of their cancer at a median of 1.2 years (range, 0.5 to 5.4) and all have died of small-cell cancer. Thirteen of these 38 patients' (34%) only site of initial relapse was in the CNS and all died of CNS metastases. Five patients died during therapy or from its complications and two patients died of causes other than relapsed small-cell lung cancer and toxicity. The median survival time is 21.3 months, with an actual survival rate of 83% at 1 year, and actuarial survival rates of 43% at 2 years and 19% at 5 years. CONCLUSION: This combined modality regimen for patients with limited-stage small-cell lung cancer results in a 2-year survival rate of 43%, but the principal cause of death in these patients is still relapse of the original cancer. Isolated CNS metastases caused more than 30% of the cancer deaths.

Application of an algorithm for staging small-cell lung cancer can save one third of the initial evaluation costs.

OBJECTIVE: Design of a cost-effective algorithm for staging disease in patients with small-cell lung cancer. DESIGN: An algorithm was constructed by analyzing all permutations of a sequence of procedures required to stage disease in patients with small-cell lung cancer. Procedural costs were determined, and the model was applied to the small-cell lung cancer patient population treated at the National Cancer Institute, Bethesda, Md, from 1973 to 1989. The final algorithm was derived from the permutation with the lowest cost per accurately staged patient. SETTING: A single government institute, the National Cancer Institute. PATIENTS: Four hundred fifty-one patients with previously untreated, consecutive histologically documented small-cell lung cancer entered into therapeutic protocols at the National Cancer Institute from April 1973 through July 1989. Data were obtained from small-cell lung cancer protocol databases and patients' medical records. MAIN OUTCOME MEASURE: The cost per patient of each sequence of staging procedures when applied to the patient population. RESULTS: The least expensive sequence of procedures saved $1418 per patient when compared with application of a standard set of staging procedures to all patients. The major factor in reducing costs was the concept of stopping the staging procedures after a site of distant metastatic disease had been identified. CONCLUSIONS: An algorithm consisting of a set of sequential staging procedures can accurately stage disease in patients with small-cell lung cancer and save more than one third of the costs of an inclusive standard set of staging procedures.

Debrisoquine metabolism and lung cancer risk.

Previous reports of the association between the debrisoquine metabolic polymorphism and lung cancer risk have been conflicting. We examined the hypothesis that the genetically determined ability to metabolize debrisoquine identifies individuals at increased risk for lung cancer in a study designed to address some of the methodological criticisms of previous studies. A case-control study of 335 incident Caucasian lung cancer patients and 373 controls matched for age, race, sex, and hospital, was conducted at the National Naval Medical Center (Bethesda, MD) and at the Laval Hospital (Sainte-Foy, Quebec, Canada). Debrisoquine metabolic phenotype was determined by debrisoquine administration and analysis of debrisoquine and 4-hydroxydebrisoquine in the subsequent 8-h urine collected. Stratified and logistic regression analyses were used to evaluate the association between extensive or intermediate debrisoquine metabolism and lung cancer risk. We found no increased risk among extensive or intermediate metabolizers (odds ratio, 0.6; 95% confidence interval, 0.3-1.2). The lack of an association was not confounded by control diagnoses, medications used within 1 month of debrisoquine administration, smoking, stage, or histology of lung cancer. No relationship was found among either heavy smokers or light and nonsmokers. Our results do not support the role of debrisoquine metabolism as a marker for lung cancer risk. While the concept that polymorphisms of metabolism may account for differential susceptibility to lung cancer is sound, debrisoquine metabolic phenotype was not associated with lung cancer risk in these data.

Lung tumor resection does not affect debrisoquine metabolism.

Some authors have reported an association of extensive metabolism of debrisoquine with increased lung cancer risk, although others have found no association. Debrisoquine metabolism is controlled by a cytochrome P-450 isozyme encoded at the CYP2D6 locus, which is inducible by antipyrine and rifampicin. Because lung tumors may produce a variety of humoral substances, we wanted to determine whether the tumor induced debrisoquine metabolism. As part of a case-control study of lung cancer, debrisoquine metabolism was measured in patients with histologically confirmed non-small cell lung cancer before and after surgical resection with curative intent. One hundred four incident patients with curative intent. One hundred four incident patients with pathological stage I, II, or IIIA non-small cell lung cancer took debrisoquine (10 mg) orally at 10 p.m. and collected the subsequent 8-h urine both before and after surgery. We compared the values of the metabolic ratio, which is the percentage of the dose excreted as debrisoquine to the percentage of the dose excreted as the principal metabolite. The pre- and postoperative metabolic ratios were highly correlated (Pearson correlation coefficient = 0.96), and did not differ in value significantly (P = 0.88). Using traditional cutpoints (metabolic ratio, 1.0 and 12.6) to categorize the three metabolic phenotypes, the preoperative and postoperative phenotypes were well correlated (kappa = 0.78). These results show that the ability to metabolize debrisoquine is not induced by the presence of a primary lung tumor.

Genetic polymorphism of CYP2D6 and lung cancer risk.

Previous reports of the association of extensive debrisoquine metabolism, controlled by the cytochrome P450 CYP2D6, with increased lung cancer risk have been conflicting. We examined the hypothesis that genetic polymorphism at the CYP2D6 locus identifies individuals at increased risk for lung cancer in a case-control study of 98 incident Caucasian lung cancer patients and 110 age-, race-, and sex-matched controls conducted at the National Naval Medical Center, Bethesda, MD. Using germ line DNA, we identified inactivating mutations at the CYP2D6 locus (CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6A), as well as those mutations that impair but do not abolish enzyme activity (CYP2D6*9 and CYP2D6*10A). Compared to subjects with homozygous inactivating mutations, no association with lung cancer was observed for those with homozygous or heterozygous functional alleles (odds ratios were 0.4 and 0.7, respectively). Furthermore, no excess risk was seen in any histological group or smoking category, and adjustment for smoking and sociodemographic characteristics did not alter the findings. Although the concept that genetic polymorphisms may contribute to differential lung cancer susceptibility is sound, these data do not support the role of CYP2D6 as a marker for elevated lung cancer risk.

Clinical significance of the FV:Q506 mutation in unselected oncology patients.

PURPOSE: A common germline mutation in the factor V gene (FV:Q506) has been associated with hypercoagulability in families with heritable predisposition to thrombosis. We examined the prevalence and clinical significance of the FV:Q506 mutation in cancer patients. PATIENTS AND METHODS: We performed a retrospective cohort study by examining 353 consecutive, unselected patients in a general hematology/oncology clinic. We ascertained risk factors, obtained the clinical clotting history, and determined the heterozygous or homozygous presence of the FV:Q506 allele for each patient. RESULTS: We detected a germline mutation in 5.4% (19 of 353) of patients, of whom 18 were heterozygous and 1 was homozygous for the FV:Q506 mutant allele. In 17 of 18 heterozygous patients, there was no history of venous thrombosis or catheter-associated thrombosis. These asymptomatic patients included 13 patients who had been diagnosed with cancer or leukemia for a mean of 66.2 months (median 69) and had received a variety of local and systemic treatments. In contrast, 1 of 18 heterozygous and 1 of 1 homozygous patients had developed deep vein thrombosis that was associated, respectively, with either recurrent thrombotic events or a strong family history for pulmonary embolus. CONCLUSIONS: Routine screening for the FV:Q506 mutation in cancer patients without a personal or family history for venous thrombosis is not helpful in guiding management. In contrast, an episode of venous thrombosis in a patient with a mutant germline FV:Q506 allele was associated with recurrent thrombotic events. These findings suggest that patients heterozygous for the FV:Q506 allele may require an independent "susceptibility" element to manifest a venous hypercoagulable state. In addition, only 2 of 25 clinic patients with a venous clot carried the FV:Q506 allele suggesting this genetic defect plays a minor role in the hypercoagulable state of cancer.

T cell depletion of human bone marrow. Comparison of Campath-1 plus complement, anti-T cell ricin A chain immunotoxin, and soybean agglutinin alone or in combination with sheep erythrocytes or immunomagnetic beads.

The aim of this study was to compare the extent of in vitro T cell depletion and recovery of hematopoietic progenitor cells achieved with five methods of T cell depletion. Bone marrow samples from the same source were treated with monoclonal antibody Campath-1 (CP1) and human complement, XomaZyme-H65 (anti-T cell ricin A chain immunotoxin), or soybean agglutinin (SBA) alone or in combination with sheep erythrocytes (EAET) or a cocktail of immunomagnetic beads (B) directly coated with anti-CD2, anti-CD3, or anti-CD8 monoclonal antibodies. Residual T cells were enumerated by limiting dilution analysis, EAET rosetting, and proliferative responses to phytohemagglutinin. The results of this study demonstrated the following reductions in BM T cells as detected by limiting dilution analysis (mean % control): SBA+B (99.9%), SBA+EAET (99.8%), CP1+C' (99.4%), anti-T cell ricin A chain immunotoxin (99.0%), and SBA alone (94.2%). Neither PHA response nor enumeration of residual EAET rosettes provided discriminating differences in the degree of T cell depletion by treatment method when T cell reductions exceeded 99.0% by LDA. These results demonstrate the ability of CP1+C', XomaZyme-H65, and SBA plus sheep erythrocyte or magnetic bead depletion to achieve a greater than 99% reduction of BM T cells and the importance of limiting dilution analysis in defining differences in T cell numbers when depletion exceeded 99%.

Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute.

OBJECTIVE: To determine the outcome of all patients with small-cell lung cancer (SCLC) treated at the US National Cancer Institute between April 1973 and April 1993. DESIGN: We retrospectively analyzed a series of 594 consecutive patients with SCLC treated at a single institution during a 20-year period to assess changes in duration of survival and toxicity related to various treatment regimens. MATERIAL AND METHODS: For analysis, patients were grouped by decade, and the duration of survival of patients with limited- and extensive-stage SCLC was examined to assess whether patients treated during the first decade of the study (1973 through 1983), when cyclophosphamide-based regimens were used, had different outcomes than those treated during the second decade (1983 through 1993), when cisplatin-based regimens were used. Patients had a minimal follow-up of 2 years. RESULTS: No significant difference was found in the survival of patients with limited- or extensive-stage SCLC treated during the second decade in comparison with during the first decade of the study. Among patients with extensive-stage SCLC, performance status 3 or 4 and metastatic lesions of the liver and central nervous system had a significant adverse effect on survival in both the first and the second decade. Among patients with limited-stage disease, performance status 3 or 4 had the most significant adverse influence on survival during the overall study period. In addition, in a multivariate analysis, etoposide-cisplatin plus twice-daily chest radiotherapy was significantly associated with prolonged survival (P = 0.003). CONCLUSION: We noted no significant change in the duration of survival of patients with either limited-or extensive-stage SCLC treated at our institution during a 20-year period. A multivariate analysis showed that patients with limited-stage SCLC given a cisplatin-based regimen plus chest radiotherapy lived modestly longer than similar patients given cyclophosphamide regimens at our institution. No evidence was found of changes in pretreatment factors that would affect survival.

Frequency of the variant allele CYP2D6(C) among North American Caucasian lung cancer patients and controls.

Previous reports of the association between the debrisoquine polymorphism and lung cancer risk are conflicting. Following the report of an association between lung cancer risk and the variant allele CYP2D6(C), we examined the presence of this allele in 98 incident Caucasian lung cancer patients and 110 age, race, and sex matched hospital controls from a case-control study conducted at the National Naval Medical Center in Bethesda, MD. Debrisoquine metabolic phenotype was determined by debrisoquine administration and analysis of debrisoquine and 4-hydroxydebrisoquine in the subsequent 8 h urine collected. Genomic DNA was genotyped by a specific polymerase chain reaction amplification and subsequent restriction enzyme digestion, and Southern analysis. Twenty subjects were heterozygous for the CYP2D6(C) allele but none were homozygous for this allele. There was no significant difference in frequency of CYP2D6(C) between lung cancer patients and controls (5.61% and 4.09%, respectively), and there was no significant heterogeneity among cases by histologic type of lung cancer (P = 0.08). However, 7 of 11 cases (64%) with the CYP2D6(C) allele had small cell lung cancer, and none had squamous cell carcinoma. Carrying the CYP2D6(C) allele did not impair debrisoquine metabolism to the same degree as the known inactivating mutations, CYP2D6(A) and CYP2D6(B), or deletion of CYP2D6. Thus, the CYP2D6(C) allele does not encode a completely inactivating mutation, and the suggestion of a role for this variant allele in the risk for specific histologic types of lung cancer justifies further investigation.

Hydroxyapatite as a bone substitute in the jaws.

Densely sintered calcium hydroxyapatite has previously been shown to be biocompatible and stable. Its possible role in jaw surgery was investigated using a clinically analogous animal model. The apatite was implanted into the mandible of twelve dogs for 12 weeks, and the healing assessed radiologically and histologically. The new bone which was deposited directly onto the surface of the implants bonded them firmly to the adjacent tissues. There was no fibrous tissue between implant and bone. This material appears to be a suitable substitute for autogenous bone when used as inert 'space filler' in maxillo-facial surgical procedures.

Subperiosteal behaviour of alginate and cellulose wound dressing materials.

A histological comparison was undertaken of the tissue response to a new sodium calcium alginate material (Kaltostat) and an oxidized regenerated cellulose wound dressing (Surgicel) when implanted between bone and periosteum in the jaws at intervals of up to 24 wk. Both biomaterials caused a foreign body reaction, persisting up to 12 wk after surgery. New bone formation occurred along the surface of the mandible in some specimens, but was not apparently related to the implants. It was concluded that the implantation of Kaltostat or Surgicel between bone and periosteum in the jaws caused a delay in wound healing, and had no effect on bone induction.