Dynamic physiological temperature and pressure sensing with phase-resolved low-coherence interferometry.

We report the development and characterisation of highly miniaturised fibre-optic sensors for simultaneous pressure and temperature measurement, and a compact interrogation system with a high sampling rate. The sensors, which have a maximum diameter of 250 µm, are based on multiple low-finesse optical cavities formed from polydimethylsiloxane (PDMS), positioned at the distal ends of optical fibres, and interrogated using phase-resolved low-coherence interferometry. At acquisition rates of 250 Hz, temperature and pressure changes of 0.0021 °C and 0.22 mmHg are detectable. An in vivo experiment demonstrated that the sensors had sufficient speed and sensitivity for monitoring dynamic physiological pressure waveforms. These sensors are ideally suited to various applications in minimally invasive surgery, where diminutive lateral dimensions, high sensitivity and low manufacturing complexities are particularly valuable.

Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy.

Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake. Incorporation of ICG in PGA nanoparticles provided the NIR-absorbing agent with time-dependent altered optical properties in the presence of cathepsin B. Having minimal dark toxicity, the formulation exhibited significant cytotoxicity upon NIR exposure. Combined use of the formulation with saporin, a ribosome-inactivating protein, resulted in synergistically enhanced cytotoxicity attributed to the photo-induced release of saporin from endo/lysosomes. The results suggest that this therapeutic approach can offer significant therapeutic benefit in the treatment of superficial malignancies, such as head and neck tumours.

Photodynamic therapy: Inception to application in breast cancer.

Photodynamic therapy (PDT) is already being used in the treatment of many cancers. This review examines its components and the new developments in our understanding of its immunological effects as well as pre-clinical and clinical studies, which have investigated its potential use in the treatment of breast cancer.

The Yield of Fever, Inflammatory Markers and Ultrasound in the Diagnosis of Acute Cholecystitis: A Validation of the 2013 Tokyo Guidelines.

BACKGROUND: Each year, 1-4 % of people with known gallstones become symptomatic, either presenting with biliary colic or as acute cholecystitis. The distinction between both diagnoses remains challenging. To aid the proper diagnosis, the revised 2013 Tokyo Guidelines (TG 2013) were proposed with a self-acclaimed diagnostic accuracy of over 90 %. However, this accuracy has not been verified by others so far. OBJECTIVE: To determine the accuracy of the TG 2013 guidelines in the diagnosis of acute cholecystitis both in its single components of fever, inflammatory markers and US features and of the combined application of the TG 2013 guidelines as a whole. METHODS: A 5-year retrospective analysis equal to the TG 2013 validation process of all emergency cholecystectomies for acute cholecystitis or persistent biliary pain with an ultrasound performed during the same admission. Acute cholecystitis at histology was the golden standard. RESULTS: Inclusion criteria were met by 169 patients with a prevalence of acute cholecystitis of 52.7 %. The individual features of fever, gallbladder wall thickening and probe tenderness were not significant in univariate analysis. In multivariate analysis only, neutrophil count was an independent predictor. The combined application of the TG 2013 guidelines led to a better sensitivity of 83.1 % at the cost a reduced specificity of 37.5 % compared to neutrophil count alone. The accuracy was therefore only 60.3 %, which was well below the TG 2013 report. CONCLUSION: The 2013 Tokyo Guidelines were slightly better in predicting acute cholecystitis but over diagnosed two-thirds of normal gallbladders compared to neutrophil count alone.

Minimal residual disease testing after stem cell transplantation for multiple myeloma.

Increased use of novel agents and autologous stem cell transplantation has led to a significant improvement in PFS and overall survival in patients with multiple myeloma. Despite improved treatment strategies, most patients eventually relapse due to persistent low levels of disease in the bone marrow. Increasingly sensitive methods to measure or detect such disease have been evaluated, including multi-parametric flow cytometry, PCR, next-generation sequencing and imaging modalities. The following literature review examines current methods for detecting and monitoring minimal or measurable residual disease (MRD) in the post-transplant setting. Improved methods for detecting MRD will refine the current definitions of remission and could guide treatment approaches.

Music-of-light stethoscope: a demonstration of the photoacoustic effect.

In this paper we present a system aimed at demonstrating the photoacoustic (PA) effect for educational purposes. PA imaging is a hybrid imaging modality that requires no contrast agent and has a great potential for spine and brain lesion characterisation, breast cancer and blood flow monitoring notably in the context of fetal surgery. It relies on combining light excitation with ultrasound reception. Our brief was to present and explain PA imaging in a public-friendly way suitable for a variety of ages and backgrounds. We developed a simple, accessible demonstration unit using readily available materials. We used a modulated light emitting diode (LED) torch and an electronic stethoscope. The output of a music player was used for light modulation and the chest piece of the stethoscope covered by a black tape was used as an absorbing target and an enclosed chamber. This demonstration unit was presented to the public at the Bloomsbury Festival On Light in October 2015. Our stall was visited by over 100 people of varying ages. Twenty families returned in-depth evaluation questionnaires, which show that our explanations of the photoacoustic effect were well understood. Their interest in biomedical engineering was increased.

Implementation of tuberculosis infection prevention and control in Mozambican health care facilities.

SETTING: District and urban health care facilities in three provinces (Manica, Sofala, Tete) in central Mozambique. OBJECTIVE: To assess the level of implementation of selected tuberculosis infection prevention and control (TB-IPC) measures. DESIGN: In a cross-sectional study of TB-IPC implementation in 29 health care facilities, we assessed TB clinics, laboratories, out-patient departments and medical and TB wards. Assessment included selected managerial, administrative and environmental measures and the availability and use of respiratory protective equipment (N95 respirators). RESULTS: Guidelines for diagnosis and treatment of (presumptive) TB patients were not present in all facilities. Staff instructed patients on sputum collection in 91%, but only 4% observed it. Using a pragmatic '20% rule', 52% of the rooms assessed had adequate ventilation. Potentially, this could be increased to 76%. Three quarters of the health care workers had N95 respirators. Only 36% knew how to use it correctly. CONCLUSION: Implementation of TB-IPC measures showed wide variations within health care facilities. Relatively simple measures to improve TB-IPC include the availability of guidelines, opening doors and windows to improve ventilation, and training and support on correct N95 respirator use. However, even relatively simple measures are challenging to implement, and require careful attention in and evaluation of the implementation process.

Treatment practices in patients with suspected malaria in Provincial Hospital of Tete, Mozambique.

BACKGROUND: Nowadays, parasite-based diagnosis by microscopy or malaria rapid diagnostic tests (RDT) is universally promoted before malaria treatment. However, studies on adherence of primary caregivers to malaria test results have provided conflicting results. METHODS: The antimalarial and antibiotic prescription rates in patients with suspected malaria at Provincial Hospital of Tete, Mozambique, and the features associated with antibiotic prescription in non-severely ill parasite-negative patients were assessed. RESULTS: In March and April 2010, Plasmodium falciparum malaria was diagnosed by microscopy or RDT in 728 (27.2%) of 2672 patients tested. Almost all malaria patients were prescribed antimalarials and 20% were also given antibiotics. Of 1944 parasite-negative patients, 126 (6.5%) were prescribed antimalarials and 1213 (62.4%) antibiotics. Among non-severely ill parasite-negative patients with complete information (n = 1607), the antibiotic prescription rate was 68.8% and was more frequent with respiratory symptoms and leukocyte counts >10 000/µL (adjusted OR = 1.62, 95% CI 1.18-2.23 and adjusted OR = 2.12, 95% CI 1.66-2.71, respectively). CONCLUSIONS: Adherence to malaria test results was good in this reference setting, but antibiotic prescription was relatively frequent in clinically stable non-malaria patients. Optimal management of parasite-negative patients must be further defined along with programmatic deployment of the parasite-based strategy.

A randomised controlled trial of ALA vs. Photofrin photodynamic therapy for high-grade dysplasia arising in Barrett's oesophagus.

Photofrin photodynamic therapy (PDT) is a licenced treatment for Barrett's oesophagus (BE) with high-grade dysplasia (HGD) but causes strictures and photosensitivity and complete reversal of dysplasia (CR-HGD) by 50 % at 5 years. 5-Aminolaevulinic acid (ALA) is an alternative treatment with non-randomised data suggesting 85 % CR-HGD and a low risk of side effects. We aimed to compare efficacy and side effect profile between the drugs. A single-centre randomised controlled trial was conducted. Presence of HGD was confirmed on three occasions by two specialist GI pathologists. Stratification was by length of BE and extent of dysplasia. Standard protocols for ALA and Photofrin-PDT were followed. Endoscopic follow-up with 2-cm four-quadrant biopsy was at 6 weeks, 4 months, and then annually. All adverse event data were collected. Sixty four patients were randomised, 34 ALA and 30 Photofrin-PDT. Median follow-up is 24 months. On intention-to-treat analysis, CR-HGD was 16/34 (47 %) with ALA-PDT and 12/30 (40 %) with Photofrin-PDT. The overall cancer incidence was 14 % (9/64). On sub-group log-rank analysis, for BE ≤ 6 cm, CR-HGD was significantly higher with ALA-PDT than Photofrin-PDT (χ(2) =5.39, p=0.02). Strictures and skin photosensitivity were significantly more common after treatment with Photofrin-PDT than ALA-PDT (33 vs. 9 % and 43 vs. 6 %, respectively, p<0.05). The rate of buried glands with either drug was significantly higher post-PDT (48 % of patients) than pre-PDT (20 %). ALA-PDT has a better risk profile than Photofrin-PDT. In patients with BE length ≤ 6 cm, preliminary results show ALA-PDT is associated with significantly higher CR-HGD. In longer segments of BE, neither PDT drug is sufficiently efficacious to warrant routine use.

Use of an implanted sacral nerve stimulator to restore urine voiding in chronically paraplegic dogs.

BACKGROUND: Loss of urinary control after spinal cord injury increases risk of urinary tract disease and is problematical for owners of affected dogs. OBJECTIVES: To design, implant, and test a sacral nerve stimulating device for controlling urine voiding in paraplegic dogs. ANIMALS: Nine pet dogs with severe thoracolumbar spinal cord injury causing paraplegia, loss of hindquarter sensation, and incontinence for more than 3 months. The procedure was offered prospectively to owners of suitable candidates after the irreversibility of the incontinence had been ascertained. METHODS: Open label clinical study. Surgically implantable electrode "books" were designed for insertion and retention of mixed sacral nerves. Sacral nerves were accessed via laminectomy and stimulated to test their ability to elicit detrusor contraction and then inserted into the electrode book, which was attached to a subcutaneously implanted, externally activated receiver. RESULTS: In 8/9 dogs, S2 nerves elicited the largest increases in intravesicular pressure with minimum stimulation and were placed in electrode books. Voiding efficiency was >90% in 8 of the 9 implanted dogs. No important detrimental effects of the procedure were observed. CONCLUSIONS AND CLINICAL IMPORTANCE: This sacral nerve stimulating implant is a simple and apparently effective neuroprosthetic device that restores urine voiding in paraplegic dogs.

NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the ß-catenin pathway.

Nuclear factor-κB (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB. NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been unclear. Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), primary (n=15) and metastatic melanoma (n=13) lesions showed a statistically significant elevation in NIK expression when compared with benign nevi (n=30). Moreover, when short hairpin RNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model. As expected, when NIK was depleted there was decreased activation of the non-canonical NF-κB pathway, whereas canonical NF-κB activation remained intact. NIK depletion also resulted in reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, and pro-survival factors such as BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-κB pathway. Shown here for the first time is the demonstration that NIK modulates ß-catenin-mediated transcription to promote expression of survivin. NIK-depleted melanoma cells exhibited downregulation of survivin as well as other ß-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate that NIK mediates both ß-catenin and NF-κB regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma.

New methods for innovation: the development of a toolbox for natural orifice translumenal endoscopic surgery (NOTES) procedures.

BACKGROUND: Devices used for flexible intralumenal procedures are inadequate when used for intraperitoneal surgical procedures such as cholecystectomy. OBJECTIVE: To assess/address limitations of flexible endoscopic devices in intraperitoneal surgery. DESIGN: To describe processes used to invent new devices to facilitate this new surgical genre. SETTING: Engineering laboratory. PATIENTS: None. INTERVENTIONS AND INVENTIONS: Reviews of the limitations of flexible endoscopic instruments and instrumentation/invention needs for a "NOTES cholecystectomy" were completed. MAIN OUTCOME MEASURES: The appropriateness of existing methods of device innovation was evaluated against an inventory of new technologies necessary to perform NOTES. The deficiencies in traditional innovation methods led to the creation of a novel process for invention of new medical devices: the "Inventorama." METHODS: Cooperation between clinicians and industry to develop device concepts to enable NOTES. RESULTS: The devices included: (1) steerable flex trocar, (2) rotary access needle, (3) bipolar hemostasis forceps, (4) Maryland dissectors, (5) articulating hook knife, (6) rotating hook knife, (7) articulating graspers, (8) scissors, (9) ligating clip applier, and (10) tissue apposition system. Six of these ten were built and tested as initial crude prototypes in the Inventorama process; two underwent major modifications. Three were invented via alternate methods, including by independent clinicians. CONCLUSIONS: A new method for efficient medical device invention and development was created to address key technology needs for NOTES. The result was a "toolbox" of devices designed to address the key surgical activities necessary for advanced intralumenal and translumenal flexible endoscopic procedures.

Frequency-fluctuation model applied to Stark-Zeeman spectral line shapes in plasmas.

A very fast method for calculating line shapes in the presence of an external magnetic field accounting for charge particle dynamics is proposed. It is based on a reformulation of the frequency fluctuation model, which provides an expression of the dynamic line shape as a functional of the static distribution function of frequencies. In the presence of an external magnetic field, the distribution of intensity and polarization of the emission depends on the angle between the observation line and the magnetic field's direction. Comparisons with numerical simulations and experimental results for various plasma conditions show very good agreement. Results on hydrogen lines in the context of magnetic fusion and the Lyman-α line, accounting for fine structure, emitted by argon in the context of inertial fusion, are also presented.

Light penetration in the human prostate: a whole prostate clinical study at 763 nm.

Photodynamic therapy (PDT) is being investigated as a treatment for localized prostate cancer. Photodynamic therapy uses a photosensitizing drug which is activated by a specific wavelength of light, in the presence of oxygen. The activated drug reacts with tissue oxygen to produce reactive oxygen species which are responsible for localized tissue necrosis. One of the determinants of the PDT effect is the penetration of light in the prostate. This study assesses the penetration depth of 763 nm light throughout the prostate. Eight men undergoing multiple hollow needle insertion for high dose rate brachytherapy were recruited. 763 nm light, produced by a diode laser, was delivered to the prostate using cylindrically diffusing optical fibers within the plastic needles. Light was detected at different distances from the source, using an isotropic detector within nearby needles. Penetration depth was calculated using the Boltzmann approximation to the diffusion equation. Delivery detector fiber separation was measured on computed tomography. The mean penetration depth was 0.57 cm, but there was within patient variation of a mean factor of 4.3. Further work is ongoing to assess the effect of such variability in light penetration, on the PDT effect.

Optical scanning for rapid intraoperative diagnosis of sentinel node metastases in breast cancer.

BACKGROUND: Intraoperative diagnosis of sentinel node metastases enables an immediate decision to proceed to axillary lymph node dissection, avoiding a second operation in node-positive women with breast cancer. METHODS: An optical scanner was developed that interrogated the cut surface of bivalved, but otherwise unprocessed, sentinel lymph nodes with pulses of white light by elastic scattering spectroscopy (ESS). The scattered light underwent spectral analysis, and individual spectra were initially correlated with conventional histology to develop a diagnostic algorithm. This algorithm was used to create false colour-coded maps of scans from an independent set of nodes, and the optimal criteria for discriminating between normal and cancer spectra were defined statistically. RESULTS: The discriminant algorithm was developed from a training set of 2989 spectra obtained from 30 metastatic and 331 normal nodes. Subsequent scans from 129 independent nodes were analysed. The scanner detected macrometastases (larger than 2 mm) with a sensitivity of 76 per cent (69 per cent including micrometastases) and specificity of 96 per cent. CONCLUSION: In this proof-of-principle study, the ESS results were comparable with current intraoperative diagnostic techniques of lymph node assessment.

Image cytometry accurately detects DNA ploidy abnormalities and predicts late relapse to high-grade dysplasia and adenocarcinoma in Barrett's oesophagus following photodynamic therapy.

BACKGROUND AND AIMS: DNA ploidy abnormalities (aneuploidy/tetraploidy) measured by flow cytometry (FC) are strong predictors of future cancer development in untreated Barrett's oesophagus, independent of histology grade. Image cytometric DNA analysis (ICDA) is an optical technique allowing visualisation of abnormal nuclei that may be undertaken on archival tissue. Our aim was to determine the accuracy of ICDA vs FC, and evaluate DNA ploidy as a prognostic biomarker after histologically successful treatment with photodynamic therapy (PDT). METHODS: Nuclei were extracted from 40 mum sections of paraffin-embedded biopsies and processed for ICDA at UCL and FC at UW using standardised protocols. Subsequently, DNA ploidy was evaluated by ICDA on a cohort of 30 patients clear of dysplasia 1 year after aminolaevulinic acid PDT for high-grade dysplasia (HGD). The results were correlated with long-term outcome. RESULTS: In the comparative study, 93% (41 out of 44) of cases were classified identically. Errors occurred in the near-diploid region by ICDA and the tetraploid region by FC. In the cohort study, there were 13 cases of late relapse (7 cancer, 6 HGD) and 17 patients who remained free of dysplasia after a mean follow-up of 44 months. Aneuploidy post-PDT was highly predictive for recurrent HGD or cancer with a hazard ratio of 8.2 (1.8-37.8) (log-rank P=0.001). CONCLUSIONS: ICDA is accurate for the detection of DNA ploidy abnormalities when compared with FC. After histologically successful PDT, patients with residual aneuploidy are significantly more likely to develop HGD or cancer than those who become diploid. DNA ploidy by ICDA is a valuable prognostic biomarker after ablative therapy.

Dynamic Stark broadening as the Dicke narrowing effect.

A very fast method to account for charged particle dynamics effects in calculations of spectral line shape emitted by plasmas is presented. This method is based on a formulation of the frequency fluctuation model (FFM), which provides an expression of the dynamic line shape as a functional of the static distribution of frequencies. Thus, the main numerical work rests on the calculation of the quasistatic Stark profile. This method for taking into account ion dynamics allows a very fast and accurate calculation of Stark broadening of atomic hydrogen high- n series emission lines. It is not limited to hydrogen spectra. Results on helium- beta and Lyman- alpha lines emitted by argon in microballoon implosion experiment conditions compared with experimental data and simulation results are also presented. The present approach reduces the computer time by more than 2 orders of magnitude as compared with the original FFM with an improvement of the calculation precision, and it opens broad possibilities for its application in spectral line-shape codes.

T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension.

RATIONALE: Mounting data suggest that immune cell abnormalities participate in the pathogenesis of pulmonary arterial hypertension (PAH). OBJECTIVE: To determine whether the T lymphocyte subset composition in the systemic circulation and peripheral lung is altered in PAH. METHODS: Flow cytometric analyses were performed to determine the phenotypic profile of peripheral blood lymphocytes in idiopathic PAH (IPAH) patients (n=18) and healthy controls (n=17). Immunocytochemical analyses of lymphocytes and T cell subsets were used to examine lung tissue from PAH patients (n=11) and controls (n=11). MEASUREMENTS AND MAIN RESULTS: IPAH patients have abnormal CD8+ T lymphocyte subsets, with a significant increase in CD45RA+ CCR7- peripheral cytotoxic effector-memory cells (p=0.02) and reduction of CD45RA+ CCR7+ naive CD8+ cells versus controls (p=0.001). Further, IPAH patients have a higher proportion of circulating regulatory T cells (T(reg)) and 4-fold increases in the number of CD3+ and CD8+ cells in the peripheral lung compared with controls (p<0.01). CONCLUSIONS: Alterations in circulating T cell subsets, particularly CD8+ T lymphocytes and CD4+ T(reg), in patients with PAH suggest that a dysfunctional immune system contributes to disease pathogenesis. A preponderance of CD3+ and CD8+ T lymphocytes in the peripheral lung of PAH patients supports this concept.

A novel use of T-tag sutures for the safe creation and closure of the NOTES gastrotomy using a hybrid technique.

Transgastric Natural Orifice Translumenal Endoscopic Surgery (NOTES) procedures are presently limited by the lack of a reliable method for creating and closing the gastrotomy created during the procedure. Furthermore, due to difficulties with the NOTES technique, the majority of NOTES procedures are presently performed in a "hybrid" fashion in which some degree of laparoscopic assistance is used alongside the NOTES approach. We describe a hybrid approach with a minimal laparoscopic component allowing a very controlled gastrotomy creation and closure. This technique would also allow laparoscopic suturing through a single, small cannula.

Stark broadening of hydrogen lines in low-density magnetized plasmas.

Stark broadening of hydrogen lines in the presence of a magnetic field is revisited, with emphasis on the role of the ion component under typical conditions of magnetized fusion devices. An impact theory for ions valid at low density (N_{e} < or approximately 10;{14} cm;{-3}) and taking into account the Zeeman degeneracy removal of the atomic states is developed. It is shown that the Stark widths of the Lorentz triplet components strongly depend on the magnetic field. The model is validated by a computer simulation method. For the lateral sigma components of Lyalpha , we show that the impact approximation still holds for densities as high as N_{e} approximately 10;{15} cm;{-3}. In contrast, for the central pi component as well as for the other lines from low principal quantum number, significant discrepancies between the proposed theory and the simulation results appear at high density. Application to Dalpha in tokamak divertor plasma conditions shows that, in this case, the quasistatic approximation becomes more relevant.