Outcome of neoadjuvant treatment for pancreatic cancer in elderly patients: comparative, observational cohort study.

BACKGROUND: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. METHODS: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared. RESULTS: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor. CONCLUSION: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study.

BACKGROUND: Making trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials. METHODS: We used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online. RESULTS: We had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs. CONCLUSIONS: We identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of 'dos and don'ts' for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea.

Comparison of bursting pressure after scleral tunnel incision sealed with sutures or an adherent ocular bandage in human globes.

OBJECTIVE: To evaluate the efficiency of a hydrogel adherent ocular bandage for sealing of scleral tunnel incisions in human eye globes. METHODS: A 4-mm scleral tunnel incision was made in each of 10 globes and bursting pressure was measured using the Seidel test to check for wound leakage. Globes were sealed using either two interrupted 10-0 nylon sutures (n = 5) or an adherent ocular bandage in the form of polyethylene glycol hydrogel (n = 5). Bursting pressure was then measured for a second time. RESULTS: Bursting pressure was significantly higher after wound sealing in both groups. There were no statistically significant differences in bursting pressure between the two groups before or after sealing. CONCLUSIONS: The adherent ocular bandage successfully protected the incision in ex vivo human globes immediately after surgery, with a sealing efficiency comparable to two nylon sutures, suggesting that it is a safe and effective alternative to conventional suturing.

Perceptual and physiological responses to the visual complexity of fractal patterns.

Fractals have experienced considerable success in quantifying the complex structure exhibited by many natural patterns and have captured the imagination of scientists and artists alike. With ever widening appeal, they have been referred to both as "fingerprints of nature" and "the new aesthetics." Our research has shown that the drip patterns of the American abstract painter Jackson Pollock are fractal. In this paper, we consider the implications of this discovery. We first present an overview of our research from the past five years to establish a context for our current investigations of human response to fractals. We discuss results showing that fractal images generated by mathematical, natural and human processes possess a shared aesthetic quality based on visual complexity. In particular, participants in visual perception tests display a preference for fractals with mid-range fractal dimensions. We also present recent preliminary work based on skin conductance measurements that indicate that these mid-range fractals also affect the observer's physiological condition and discuss future directions based on these results.

Myosin VI is a processive motor with a large step size.

Myosin VI is a molecular motor involved in intracellular vesicle and organelle transport. To carry out its cellular functions myosin VI moves toward the pointed end of actin, backward in relation to all other characterized myosins. Myosin V, a motor that moves toward the barbed end of actin, is processive, undergoing multiple catalytic cycles and mechanical advances before it releases from actin. Here we show that myosin VI is also processive by using single molecule motility and optical trapping experiments. Remarkably, myosin VI takes much larger steps than expected, based on a simple lever-arm mechanism, for a myosin with only one light chain in the lever-arm domain. Unlike other characterized myosins, myosin VI stepping is highly irregular with a broad distribution of step sizes.

Static splinting of extensor tendon repairs.

In a prospective review we assessed the results of extensor tendon injuries managed postoperatively with a static splint. Thirty-three patients with 44 injured digits were assessed 4 months after primary tendon repair, using the Strickland-Glogovac criteria. Patients were managed in a static splint, the duration of which was guided by the zone of injury. Four months after repair, excellent or good results were obtained in 95%. Overall it was found that static splinting was an effective and safe method of management after extensor tendon repair.

Symptoms are a poor indication of severity of reflux in Barrett's oesophagus

AIMS: Patients with Barrett's oesophagus have increased acid and duodenogastric reflux and impaired motility compared with non-Barrett's patients with reflux disease. Impaired sensitivity to acid infusion and distension have also been described, but the relationship of this visceral response to symptoms is unclear. A symptom index was used to compare Barrett's and non-Barrett's patients with reflux. METHODS: Patients with reflux (DeMeester score above 14) were studied with 24-h pH monitoring and manometry. An event marker recorded symptom events. An event was positive if it corresponded to a period greater than 10 s within 2 min either side of the drop in pH. The symptom index was calculated as the number of symptoms with pH less than 4/total number of symptoms x 100. RESULTS: Eighteen patients with Barrett's oesophagus were compared with 58 non-Barrett's patients with significant reflux. CONCLUSIONS: Patients with Barrett's oesophagus have a low symptom index compared with non-Barrett's patients with reflux disease. This occurs despite a near 100 per cent increase in acid exposure in the Barrett's group. Symptoms are thus no guide to the severity of reflux in patients with Barrett's oesophagus. Proof of efficacy of therapeutic modalities may need physiological rather than symptom-based confirmation.

Nitric oxide synthase distribution during implantation in the mouse.

The peri-implantation period is a critical time during murine development. Although the importance of nitric oxide has been demonstrated during gestation, its role in implantation has not been fully defined. The aim of this study was to quantify (by Western blotting) two prominent nitric oxide synthase (NOS) isoforms, inducible (iNOS) and endothelial (eNOS) and localize all three forms [iNOS, eNOS, and neuronal (nNOS)] by immunohistochemistry in uterine tissue from days 4 through 8 of pregnancy. By day 6, iNOS values were significantly elevated in implantation sites compared with interimplantation regions and continued to rise through day 8. Analysis of eNOS was similar, but implantation site values peaked by days 6 and 7. Labelled iNOS cells were within the decidua, around myometrial vessels, and within the ectoplacental cone. At implantation, eNOS was conspicuous, displaying label adjacent to the embryo in vessels of the primary decidual zone. nNOS was localized mainly in the mesometrium and myometrium and did not appear to change throughout the peri-implantation period. The increased iNOS and eNOS values following implantation in the embryonic site may imply roles in tissue remodelling, immunosuppression and vasoregulation. Nitric oxide may play an important role in the mechanisms of implantation where these factors are keys to successful pregnancy.

Genome-scale cloning and expression of individual open reading frames using topoisomerase I-mediated ligation.

The in vitro cloning of DNA molecules traditionally uses PCR amplification or site-specific restriction endonucleases to generate linear DNA inserts with defined termini and requires DNA ligase to covalently join those inserts to vectors with the corresponding ends. We have used the properties of Vaccinia DNA topoisomerase I to develop a ligase-free technology for the covalent joining of DNA fragments to suitable plasmid vectors. This system is much more efficient than cloning methods that require ligase because the rapid DNA rejoining activity of Vaccinia topoisomerase I allows ligation in only 5 min at room temperature, whereas the enzyme's high substrate specificity ensures a low rate of vector-alone transformants. We have used this topoisomerase I-mediated cloning technology to develop a process for accelerated cloning and expression of individual ORFs. Its suitability for genome-scale molecular cloning and expression is demonstrated in this report.

Inducible nitric oxide synthase is present in the rat placenta at the fetal-maternal interface and decreases prior to labour.

The aim of this study was to investigate the expression and distribution patterns of the inducible isoform of nitric oxide synthase (iNOS) in rat placenta during gestation and term labour. The expression of iNOS isoform was assessed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting with monoclonal antibodies. Two specific bands were detected corresponding to 135 and 124 kDa in all placenta samples. The upper band (135 kDa) was identified as iNOS due to its correspondence with the band obtained with mouse macrophages (positive control). Compared with its concentrations on day 16, iNOS decreased steadily toward the end of gestation to approximately 37% on day 20, 20% on day 22 before labour and 12% during labour (p < 0.01). The lower band (124 kDa) drastically increased (to almost double) from day 16 to day 18 but returned to initial values on day 22, during delivery. Immunohistochemical staining of placentae at day 16 and 22 using rabbit polyclonal anti-iNOS antibody revealed labelling specifically concentrated in the trophospongial cell layer, at the fetal-maternal interface. The most conspicuous iNOS staining was associated with islands of cells referred to as vacuolated 'glycogen cells'. Staining was greatly decreased during labour. The changes in placental iNOS expression suggest a 'paracrine' role for NO in regulating uterine contractility, blood flow and immunosuppression required for pregnancy maintenance. NO withdrawal at term may also be involved in the initiation of labour.

Tobacco control activities of primary-care physicians in the Community Intervention Trial for Smoking Cessation. COMMIT Research Group.

OBJECTIVE: To compare tobacco control practices of physicians and their staff in Intervention communities with those in Comparison communities of the Community Intervention Trial for Smoking Cessation (COMMIT). DESIGN: COMMIT was a randomised trial testing community-based intervention for smoking cessation carried out over four years. SETTING: Eleven matched pairs of communities assigned randomly to Intervention and Comparison conditions. PARTICIPANTS AND INTERVENTIONS: Physicians in the Intervention communities participated in continuing medical education (CME). Training for office staff focused on tobacco control and office intervention "systems". OUTCOME MEASURES: Smoking control attitudes and practices reported by primary-care physicians in the 22 communities, smoking policies, and practices of 30 randomly selected medical offices in each community, and patient reports of physician intervention activities. RESULTS: Response rates to the physicians' mail survey were 45% and 42% in Intervention and Comparison communities, respectively. Telephone interviews of office staff had response rates of 84% in both conditions. Physicians in Intervention communities were more likely to attend training than those in Comparison communities (53% and 26%, respectively (P<0.0005)). In both conditions, training attendees perceived themselves as being better prepared to counsel smokers than non-attendees (P < or = 0.01) and reported more activity in smoking intervention. Intervention communities carried out more office-based tobacco control activities (P = 0.002). Smokers in Intervention communities were more likely to report receiving reading material about smoking from their physicians (P = 0.026). No other differences in physician intervention activities were reported by smokers between the Intervention and Comparison communities. CONCLUSIONS: The COMMIT intervention had a significant effect on some reported physician behaviours, office practices, and policies. However, most physicians still did not use state-of-the-art smoking intervention practices with their patients and there was little, or no, difference between patient reports of intervention activities of physicians in the Intervention and Comparison communities. Better systems and incentives are needed to attract physicians and their staff to CME and to encourage them to follow through on what they learn. The recently released Agency for Health Care Policy and Research clinical practice guideline for smoking cessation and other standards and policies outline these systems and offer suggestions for incentives to facilitate adoption of these practices by physicians.

Production of a recombinant bovine enterokinase catalytic subunit in the methylotrophic yeast Pichia pastoris.

We describe the heterologous expression of a 26.3 kD protein containing the catalytic domain of bovine enterokinase (EKL) in the methylotrophic yeast Pichia pastoris. A highly active protein is secreted and glycosylated, and it has the native amino-terminus of EKL. The cDNA encoding EKL was cloned with the KEX2 protease cleavage site following the alpha mating factor prepro secretion signal from Saccharomyces cerevisiae. The secreted EKL was easily purified from the few native proteins found in the P. pastoris fermentation supernatant, using ion exchange and affinity chromatography. The yield of the purified EKL was 6.3 mg per liter of fermentation culture. This is significantly higher than previous reports of expressions in E. coli and COS cells. The ability of this highly specific protease to cleave immediately after the carboxyl-terminal residue of the (Asp)4-Lys recognition sequence allows regeneration of native amino-terminal residues of recombinant proteins. Its application is demonstrated by the removal of thioredoxin (TrxA), and polyhistidine fusion partners from proteins of interest.

Accuracy of the tongue blade test in patients with suspected mandibular fracture.

The inter-observer reliability and accuracy of the tongue blade test (TBT) for the identification of patients with mandibular fracture was prospectively evaluated using radiographic diagnosis as the gold standard. A consecutive sample of 110 patients presenting to the emergency department of a teaching county hospital was studied. Patients with uninterpretable x-rays, known diagnosis of mandibular fracture, or inability to cooperate for the test were excluded. Bilateral ability to crack a wooden tongue blade held between the teeth was scored as a negative test. Fifty-three patients had mandibular fractures. In the study group, the TBT had a sensitivity of 95.7%; a specificity of 63.5%; a positive predictive value of 66.2%; a negative predictive value of 95.2%; and an accuracy of 77.3%. The TBT provided contributory evidence useful in screening patients for mandibular fracture.

The somatic patient.

A significant proportion of patients seen in the Emergency Department will present with somatic complaints for which there is no apparent physiologic cause. Such patients may be divided into two broad categories: (1) those with symptoms and signs consciously synthesized by the patient, either for obvious secondary gain (malingering) or as a result of more subtle and complex motivations (factitious disorders); and (2) those patients with symptoms that are the unconscious expression of psychological stress (somatoform disorders). The somatoform disorders include (1) somatization disorder (characterized by a chronic history of numerous and widely divergent somatic complaints), (2) psychogenic pain disorder (somatization expressed in terms of persistent pain), (3) hypochondriasis (a conviction that one is diseased and disabled in conjunction with a well-focused constellation of supporting symptoms), and (4) conversion disorder (a single, usually nonpainful neurologic symptom, often with identifiable coping value for the patient). The first three disorders have been aggregately termed the "common somatization syndrome." Management of the somatically focused patient includes the communication of a caring attitude to the patient in conjunction with a cautious and diligent search for treatable medical or psychiatric illness. Resocialization and development of patient links with ongoing, nurturing nonmedical as well as medical support systems is of benefit.

Necrotizing fasciitis in the pediatric age group: report of a case.

Necrotizing fasciitis is a rapidly progressive invasive soft tissue infection that is rarely seen in the pediatric population. In the majority of cases described in the medical literature, there has been an identifiable initiating event such as instrumentation or other trauma to the skin. Because of the rapid progression of the infection, the key to a successful outcome is early recognition and rapid initiation of definitive surgical management. A case is presented in which necrotizing fasciitis was seen in a child with no precipitating skin trauma.