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Abstract The formation of water ice clouds or hazes on Mars imposes substantial limitations on the vertical transport of water into the middle-upper atmosphere, impacting the planet’s hydrogen loss. Recent observations made by the Mars Environmental Dynamics Analyzer instrument onboard Mars 2020 Perseverance rover have shown a marked decline in water ice abundance within the mesosphere (above 35-40 km) when Mars is near its aphelion (near the northern summer solstice), notably occurring during solar longitudes (Ls) between Ls 70∘ and 80∘. Orbital observations around the same latitudes indicate that temperatures between ~ 30-40 km reach a minimum during the same period. Using cloud microphysics simulations, we demonstrate that this decrease in temperature effectively increases the amount of water cold-trapped at those altitudes, confining water ice condensation to lower altitudes. Similarly, the reinforcement of the cold trap induced by the lower temperatures results in significant reductions in the water vapor mixing ratio above 35–40 km, explaining the confinement of water vapor observed around aphelion from orbiters.

Introduction Colonocyte oxidation of bacterial-derived butyrate has been reported to maintain synergistic obligate anaerobe populations by reducing colonocyte oxygen levels; however, it is not known whether this process is disrupted during the progression of type 2 diabetes. Our aim was to determine whether diabetes influences colonocyte oxygen levels in the University of California Davis type 2 diabetes mellitus (UCD-T2DM) rat model.Research design and methods Age-matched male UCD-T2DM rats (174±4 days) prior to the onset of diabetes (PD, n=15), within 1 month post-onset (RD, n=12), and 3 months post-onset (D3M, n=12) were included in this study. Rats were administered an intraperitoneal injection of pimonidazole (60 mg/kg body weight) 1 hour prior to euthanasia and tissue collection to estimate colonic oxygen levels. Colon tissue was fixed in 10% formalin, embedded in paraffin, and processed for immunohistochemical detection of pimonidazole. The colonic microbiome was assessed by 16S gene rRNA amplicon sequencing and content of short-chain fatty acids was measured by liquid chromatography-mass spectrometry.Results HbA1c % increased linearly across the PD (5.9±0.1), RD (7.6±0.4), and D3M (11.5±0.6) groups, confirming the progression of diabetes in this cohort. D3M rats had a 2.5% increase in known facultative anaerobes, Escherichia–Shigella, and Streptococcus (false discovery rate

Abstract Background Clostridioides difficile infections have become more frequently diagnosed and associated with greater disease severity, which has resulted in an increase burden on the healthcare system. These increases are attributed to the increased prevalence of hypervirulent strains encompassing select ribotypes. These epidemic ribotypes were characterized as hypervirulent due to higher in vitro spore and toxin production, as well as increased incidence, severity and mortality within patients. However, it is unclear whether epidemic ribotypes are truly more virulent than non-epidemic ribotypes in vivo. Furthermore, there is conflicting evidence about the ability of a strain’s in vitro phenotype to be predictive of their in vivo virulence. The goals of the current studies were to determine if epidemic ribotypes are more virulent than other ribotypes in animal models, and whether the in vitro virulence phenotype of an isolate or ribotype predict in vivo virulence. Results To determine if epidemic strains were truly more virulent than other non-epidemic strains, the in vivo virulence of 13 C. difficile isolates (7 non-epidemic and 6 epidemic ribotype isolates) were determined in murine and hamster models of CDI. The isolates of epidemic ribotype of C. difficile were found to be more virulent in both the murine and hamster models than non-epidemic isolates. In particular, the group of epidemic ribotypes of C. difficile had lower LD50 values in hamsters. The increased severity of disease was associated with higher levels of Toxin A and Toxin B production found in fecal samples, but not numbers of organisms recovered. The isolates were further characterized for their in vitro virulence phenotypes, e.g. toxin production, growth rates, spore formation and adherence of spores to intestinal epithelial cell lines. Although there were higher levels of toxins produced and greater adherence for the group of epidemic ribotypes, the in vitro profiles of individual isolates were not always predictive of their in vivo virulence. Conclusions Overall, the group of epidemic ribotypes of C. difficile were more virulent in vivo despite individual isolates having similar phenotypes to the non-epidemic isolates in vitro.

Native Hawaiians are proud and resilient people who have endured significant impacts from colonization. Despite being in a time of vibrant cultural revitalization, Native Hawaiians have a shorter life expectancy than other racial and ethnic groups in Hawai‘i. The primary aim of this paper was to share data from the first year of a 5-year study with Native Hawaiian kūpuna (elders) on their experiences with healthcare, along with barriers to accessing healthcare. Ten kūpuna living in rural areas of Hawai‘i participated in three interviews each, which were held in an informal, talk-story style. The first interview focused on establishing rapport. The second interview focused on the kūpuna's strengths, resiliencies, and what they would like to pass to the next generation. The third interview focused on the elders' experiences with healthcare, which is the focus of this paper. All ten kūpuna reported growing up with limited access to Western healthcare; rather, their families successfully treated many illnesses and injuries with lā‘au lapa‘au (Hawaiian herbal medicine) and other traditional healing practices, as they had done for generations. As Western medicine became more prevalent and accessible, they used both, but many preferred holistic treatments such as prayer, a return to the traditional diet, and lā‘au lapa‘au. As a group, the kūpuna rated their health as fair to good; two had diabetes, two had cardiovascular disease, four had neuropathies, and five were cancer survivors. The kūpuna reported high turnover among providers in rural communities. Limited access to specialists often required them to travel to Honolulu for care, which was costly and especially difficult during coronavirus disease 2019 (COVID-19). Regardless of provider ethnicity, the kūpuna appreciated those who took the time to get to know them as people and respected Hawaiian cultural practices. They advised that Western providers speak honestly and directly, have compassion, and build connections to patients and their communities.

In the first 600 sols of the Mars2020 mission, L _S 5.6 ^o – 316.8 ^o , 46 cloud movies and 145 cloud surveys were collected to observe clouds at Jezero Crater, the landing site of the Perseverance Rover. Cloud movies were processed using the Mean-Frame Subtraction (MFS) method for revealing cloud structures, which were subsequently analyzed using digital-image processing. Two-dimensional Fast Fourier Transforms (2D-FFT) were used to compute cloud structure sizes ranging from 2.90 to 15.25 km for clouds between 30 and 50 km altitude, based on coincident Mars Climate Sounder vertical profiles of atmospheric water-ice. Same-value thresholding was used to detect the cloud structures in MFS-processed and projected cloud movies. The resolution dependence that was needed to resolve these structures over various thresholds was examined to find multifractal scaling of Mars clouds for resolutions between 0.1 and 1.6 km. We characterize the multiscaling observed in the images and its implications for the design of cloud-tracking cameras from the surface as well as for cloud-resolving models.

La sociedad civil organizada cumple un rol cada vez más relevante en el mundo y Chile no es la excepción: discusiones públicas y reformas en distintos ámbitos han sido protagonizadas por movimientos y organizaciones cívicas. Sin embargo, la intersección entre las comunicaciones y la sociedad civil es un campo aún poco explorado en el país. Este artículo presenta los resultados de un estudio exploratorio sobre los desafíos que enfrentan quienes desempeñan labores de comunicaciones en organizaciones del tercer sector. Para esto, se realizaron dos grupos focales, en los cuales, 15 directores y profesionales de comunicaciones de distintas organizaciones de la sociedad civil en Chile describieron la situación actual y los desafíos que visualizan en el ejercicio de sus labores. Varios de los hallazgos coinciden con los descritos en la literatura internacional, pero surgen tres elementos distintivos de la experiencia nacional: la dependencia de los medios tradicionales, la falta de herramientas y recursos para afrontar los impactos de la transformación digital de las comunicaciones y la escasa valoración del aporte de los comunicadores a sus organizaciones.

Le poème épique de William Blake, Milton, commence par une diatribe contre les mercenaires, ce qui, dans le contexte miltonien, fait immédiatement penser aux Considerations Touching the Likeliest Means to Remove Hirelings out of the Church. Ces deux textes font référence aux discours bibliques sur le travail, plus particulièrement aux notions chrétiennes de vocation et de travail et à la distinction qu’établit Jésus entre le bon berger et le mercenaire dans la parabole du berger (Jean 10.1-21). Pour Milton et Blake, ce discours sur le travail eut une influence directe sur leur conception de ce qu’est l’artiste, le public et de leurs responsabilités et rôles mutuels. Dans son poème, Blake prend comme point de départ la distinction biblique de Milton entre le vrai travailleur et le mercenaire, et fait de cette distinction le fondement de l’énigmatique Chant du Barde qui déclenche l’action du poème. Le Chant du Barde est, entre autres, une parabole concernant le travail qui rejoint la plupart des préoccupations exprimées dans la Bible ou développées par Milton. En fait, la forme et le contenu paraboliques du Chant du Barde deviennent des moyens essentiels pour, à la fois, accomplir et décrire le genre de travail que Blake considérait comme la mission du vrai travailleur et du vrai poète-prophète.

As with most health care provider education programs, physical therapy programs seek ways to develop professional behaviors of students. This study describes the integration of a one-week service-learning experience into an existing clinical internship. Quantitative and qualitative data were analyzed between groups of students who participated in the experience, expressed a desire to participate but were unable to, and those who did not wish to participate. Results suggest that engaging in, as well as the desire to engage in, a service-learning project for under-served members of our community is associated with professional behavior development from students’ and clinical preceptors’ perspectives.

The molecular determinants of the immune response to Mycobacterium tuberculosis HN878 infection in a rabbit model of pulmonary cavitary tuberculosis were studied. Aerosol infection of rabbits resulted in a highly differentially expressed global transcriptome in the lungs at 2 weeks, which dropped at 4 weeks and then gradually increased. While IFNγ was progressively upregulated throughout the infection, several other genes in the IFNγ network were not. T-cell activation network genes were gradually upregulated and maximally induced at 12 weeks. Similarly, the IL4 and B-cell activation networks were progressively upregulated, many reaching high levels between 12 and 16 weeks. Delayed peak expression of genes associated with macrophage activation and Th1 type immunity was noted. Although spleen CD4+ and CD8+ T cells showed maximal tuberculosis antigen-specific activation by 8 weeks, macrophage activation in lungs, lymph nodes and spleen did not peak until 12 weeks. In the lungs, infecting bacilli grew exponentially up to 4 weeks, followed by a steady-state high bacillary load to 12 weeks that moderately increased during cavitation at 16 weeks. Thus, the outcome of HN878 infection of rabbits was determined early during infection by a suboptimal activation of innate immunity and delayed T-cell activation.

Mycoplasma lipoproteins are recognized by Toll-like receptors (TLR), but TLRs' role in responses to infection are unknown. Mycoplasma pulmonis is a naturally occurring respiratory pathogen in mice. In the current study, we used TLR-transfected HEK cells and TLR2(-/-) bone marrow-derived dendritic cells to demonstrate TLR2-mediated events are important in the initial host-mycoplasma interactions promoting cytokine responses. As we found alveolar macrophages expressed TLR1, TLR2 and TLR6 mRNAs, a role for TLR2 in innate immune clearance in lungs was examined. Three days post-infection, TLR2(-/-) mice had higher M. pulmonis numbers in lungs, but not in nasal passages. However, TLR2(-/-) mice had higher lung cytokine levels, indicating TLR2-independent mechanisms are also involved in host responses. Thus, TLR2 plays a critical role in the ability of innate immunity to determine M. pulmonis numbers in the lung, and it is likely that early after respiratory infection that TLR2 recognition of M. pulmonis triggers initial cytokine responses of host cells.

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria., (© 2021 GA²LEN. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown., Aim: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19., Materials and Methods: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences., Results: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19., Conclusions: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: To describe how clinicians conceptualised equipoise in the PART (Partial prostate Ablation vs Radical prosTatectomy in intermediate-risk unilateral clinically localised prostate cancer) feasibility study and how this affected recruitment., Subjects and Methods: PART included a QuinteT Recruitment Intervention (QRI) to optimise recruitment. Phase I aimed to understand recruitment, and included: scrutinising recruitment data, interviewing the trial management group and recruiters (n = 13), and audio-recording recruitment consultations (n = 64). Data were analysed using qualitative content and thematic analysis methods. In Phase II, strategies to improve recruitment were developed and delivered., Results: Initially many recruiters found it difficult to maintain a position of equipoise and held preconceptions about which treatment was best for particular patients. They did not feel comfortable about approaching all eligible patients, and when the study was discussed, biases were conveyed through the use of terminology, poorly balanced information, and direct treatment recommendations. Individual and group feedback led to presentations to patients becoming clearer and enabled recruiters to reconsider their sense of equipoise. Although the precise impact of the QRI alone cannot be determined, recruitment increased (from a mean [range] of 1.4 [0-4] to 4.5 [0-12] patients/month) and the feasibility study reached its recruitment target., Conclusion: Although clinicians find it challenging to recruit patients to a trial comparing different contemporary treatments for prostate cancer, training and support can enable recruiters to become more comfortable with conveying equipoise and providing clearer information to patients., (© 2018 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Prostate cancer (PCa) is the most common cancer in men in the UK. Patients with intermediate-risk, clinically localised disease are offered radical treatments such as surgery or radiotherapy, which can result in severe side effects. A number of alternative partial ablation (PA) technologies that may reduce treatment burden are available; however the comparative effectiveness of these techniques has never been evaluated in a randomised controlled trial (RCT)., Objectives: To assess the feasibility of a RCT of PA using high-intensity focused ultrasound (HIFU) versus radical prostatectomy (RP) for intermediate-risk PCa and to test and optimise methods of data capture., Design: We carried out a prospective, multicentre, open-label feasibility study to inform the design and conduct of a future RCT, involving a QuinteT Recruitment Intervention (QRI) to understand barriers to participation., Setting: Five NHS hospitals in England., Participants: Men with unilateral, intermediate-risk, clinically localised PCa., Interventions: Radical prostatectomy compared with HIFU., Primary Outcome Measure: The randomisation of 80 men., Secondary Outcome Measures: Findings of the QRI and assessment of data capture methods., Results: Eighty-seven patients consented to participate by 31 March 2017 and 82 men were randomised by 4 May 2017 (41 men to the RP arm and 41 to the HIFU arm). The QRI was conducted in two iterative phases: phase I identified a number of barriers to recruitment, including organisational challenges, lack of recruiter equipoise and difficulties communicating with patients about the study, and phase II comprised the development and delivery of tailored strategies to optimise recruitment, including group training, individual feedback and 'tips' documents. At the time of data extraction, on 10 October 2017, treatment data were available for 71 patients. Patient characteristics were similar at baseline and the rate of return of all clinical case report forms (CRFs) was 95%; the return rate of the patient-reported outcome measures (PROMs) questionnaire pack was 90.5%. Centres with specific long-standing expertise in offering HIFU as a routine NHS treatment option had lower recruitment rates (Basingstoke and Southampton) - with University College Hospital failing to enrol any participants - than centres offering HIFU in the trial context only., Conclusions: Randomisation of men to a RCT comparing PA with radical treatments of the prostate is feasible. The QRI provided insights into the complexities of recruiting to this surgical trial and has highlighted a number of key lessons that are likely to be important if the study progresses to a main trial. A full RCT comparing clinical effectiveness, cost-effectiveness and quality-of-life outcomes between radical treatments and PA is now warranted., Future Work: Men recruited to the feasibility study will be followed up for 36 months in accordance with the protocol. We will design a full RCT, taking into account the lessons learnt from this study. CRFs will be streamlined, and the length and frequency of PROMs and resource use diaries will be reviewed to reduce the burden on patients and research nurses and to optimise data completeness., Trial Registration: Current Controlled Trials ISRCTN99760303., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 52. See the NIHR Journals Library website for further project information., Competing Interests: Ray Fitzpatrick is a member of the Health Technology Assessment Priority Research Advisory Methods Group. Richard Hindley has received payments for lecturing and proctoring for SonaCare Medical (Charlotte, NC, USA; high-intensity focused ultrasound treatment). Hashim U Ahmed reports grants and personal fees from SonaCare Medical and grants from Trod Medical (Heverlee, Belgium) and Sophiris Bio Inc. (La Jolla, CA, USA) outside the submitted work.

Background: The term prurigo has been used for many decades in dermatology without clear definition, and currently used terminology of prurigo is inconsistent and confusing. Especially, itch-related prurigo remains unexplored regarding the epidemiology, clinical profile, natural course, underlying causes, available treatments and economic burden, although burdensome and difficult to treat., Objective: To address these issues, the multicentre European Prurigo Project (EPP) was designed to increase knowledge on chronic prurigo (CPG). In the first step, European experts of the EADV Task Force Pruritus (TFP) aimed to achieve a consensus on the definition, classification and terminology of CPG. Additionally, procedures of the cross-sectional EPP were discussed and agreed upon., Methods: Discussions and surveys between members of the TFP served as basis for a consensus conference. Using the Delphi method, consensus was defined as an agreement ≥75% among the present members., Results: Twenty-four members of the TFP participated in the consensus conference. Experts consented that CPG should be used as an umbrella term for the range of clinical manifestations (e.g. papular, nodular, plaque or umbilicated types). CPG is considered a distinct disease defined by the presence of chronic pruritus for ≥6 weeks, history and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions (whitish or pink papules, nodules and/or plaques). CPG occurs due to a neuronal sensitization to itch and the development of an itch-scratch cycle., Conclusion: This new definition and terminology of CPG should be implemented in dermatology to harmonize communication in the clinical routine, clinical trials and scientific literature. Acute/subacute forms of prurigo are separated entities, which need to be differentiated from CPG and will be discussed in a next step. In the near future, the cross-sectional EPP will provide relevant clinical data on various aspects of CPG leading to new directions in the scientific investigation of CGP., (© 2017 European Academy of Dermatology and Venereology.)

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Itch is a common symptom in the elderly population over 65 years old, and is often a chronic condition lasting more than 6 weeks. As in all age groups, but especially in the elderly, there can be a significant effect on the general health status and quality of life, with impaired daily activities and lack of sleep, which can also lead in some cases to depression or anxiety. The cause of chronic itch in the elderly is often multifactorial due to physiological changes in the aging skin, including impaired skin barrier function, and also due to decline in immunological (immunosenescence), neurological, and psychological changes associated with age. Common causes of chronic pruritus in the aging skin include xerosis (dry skin), dermatological disorders (eczema, psoriasis, lichen planus), and systemic (renal, hepatic, endocrine), neurodegenerative, and psychological diseases. Comorbidities in the elderly population lead to polypharmacy, increasing the potential risk of drug side effects, which can result in causing or exacerbating itch in the elderly patient. It is essential to obtain a detailed history, including drugs, as well as a thorough clinical examination with appropriate subsequent investigations. Management of the elderly patient with chronic pruritus should include treatment with topical therapies such as emollients as well as other agents for symptomatic relief. Systemic therapies should be directed at any underlying cutaneous or systemic diseases. Often the cause of itch in the elderly cannot be found and some systemic treatments can be used for symptomatic control of the itch, including antihistamines, gabapentin, and selective antidepressants. A holistic approach needs to be taken on an individual basis to relieve chronic pruritus, as the management of itch in the elderly can be a challenge., (© 2016 S. Karger AG, Basel.)

Itch is a common distressing symptom which may be caused by multifactorial aetiologies including inflammatory skin diseases, systemic diseases, neuropathic conditions and psychogenic disorders. Itch is a term used synonymously with pruritus and is defined as acute if it lasts less than 6 weeks or chronic if it persists for more than 6 weeks. It can have the same impact on the quality of life as chronic pain and shares many of the same pathophysiological pathways. Depending on the aetiology of the itch, different pathogenic mechanisms have been postulated with a number of mediators identified. These include histamine, leukotrienes, proteases, neuropeptides, cytokines and opioids, which may activate peripheral itch-mediating C-fibres via receptors on the nerve terminals and central neuronal pathways. Therefore, there is no single universally effective anti-itch treatment available. First-line treatments for itch include topical therapies, such as emollients, mild cleansers (low pH), topical anaesthetics, steroids, calcineurin inhibitors and coolants (menthol). Treatment with systemic therapies can vary according to the aetiology of the chronic itch. Non-sedating antihistamines are helpful in conditions such as urticaria where the itch is primarily histamine mediated. Although the itch of eczema is not mediated by histamine, sedating antihistamines at night are helpful to break the itch-scratch cycle. Chronic itch may also be treated with other systemic therapies, such as anticonvulsants, antidepressants as well as mu-opioid antagonists, kappa-opioid agonists and phototherapy, depending on the cause of the itch. This article summarises the topical and systemic therapies available with our current understanding of the pathophysiology of itch.

Unlabelled: Study Type--Therapy (case series) Level of Evidence What's known on the subject? and What does the study add? Renal cancer is increasingly diagnosed when tumours are small and asymptomatic, during routine abdominal imaging. Whilst surgery is an effective and potentially curative option, it carries a significant risk of complications. Recent work suggests that thermally ablative therapies (RFA, cryotherapy, HIFU) may be suitable minimally invasive treatment options in selected patients. The success of extracorporeal HIFU has been limited by the abdominal wall and rib-cage limiting energy delivery. For this study, a purpose-built laparoscopic HIFU probe was designed to allow direct application of the transducer to the tumour surface, thus facilitating tumour destruction. Successful and accurate tumour destruction was demonstrated, paving the way for further clinical trials, subject to device modifications., Objective: • To test and establish clinical proof of concept for a laparoscopic high-intensity focused ultrasound (HIFU) device that facilitates delivery of ultrasound by direct application of a probe to the tumour surface., Patients and Methods: •   Twelve patients with renal tumours were treated with laparoscopic HIFU using a newly designed probe inserted via an 18-mm laparoscopic port. • HIFU treatment was targeted at a pre-defined proportion of the tumour and immediate laparoscopic partial or radical nephrectomy was then performed., Results: • No tumour ablation was seen in the first five patients which made modifications in the treatment protocol necessary. After this, definite histological evidence of ablation was seen in the remaining seven patients. • The ablated zones were within the targeted area in all patients and no intra-lesional skipping was seen. • Subcapsular skipping was seen at the probe-tumour interface in two patients with viable tumour cells seen at microscopy. • One patient did not undergo surgical extirpation; subsequent biopsy revealed no viable tumour cells. • There were no intraoperative or postoperative complications directly related to HIFU therapy and patients have reached a mean (range) follow-up of 15 (8-24) months with no evidence of metastatic disease or late complications., Conclusions: • Tumour ablation with laparoscopic HIFU is feasible. • Homogenous ablation can be achieved with no vital tissue within the targeted zone. • The technique is associated with low morbidity and may have a role in the definitive management of small tumours.

The aim of this study was to investigate the use of time to maximum enhancement (t(max)) for each voxel in contrast-enhanced MRI (CE-MRI) as a non-invasive tool to determine areas of necrosis following treatment of liver tumours with high-intensity focused ultrasound (HIFU) and, having established the utility of t(max) maps, to develop a three-dimensional (3-D) representation to display this information concisely. 3-D T(1) weighted fast spoiled gradient echo images of the liver were acquired before and after administration of contrast agent. The CE-MR images were aligned to the pre-contrast volume and an estimate of t(max) was obtained for each voxel. Such pre- and post-contrast image sets were acquired before and after ablation. The t(max) maps before and after HIFU treatment were correlated with the procedure notes, radiological reports and gross histological specimen. Finally, 3-D t(max) maps of the whole liver were reconstructed to show all areas of abnormal tissue perfusion. Normal, healthy liver tissue uniformly enhances maximally after approximately 1 min. The computed t(max) maps accurately delineated areas of abnormal contrast agent uptake, corresponding to tumour deposits. Changes in t(max) and non-enhancing voxels after treatment correlate well with volumes targeted during ablation and the necrotic regions seen on gross histological specimens. Alignment of the contrast-enhanced images with the pre-contrast volume greatly improved the conspicuity of the t(max) maps. We conclude that t(max) maps and their 3-D views can be used as a non-invasive tool to assess and potentially to quantify the success of HIFU ablation, and concisely represent the large number of CE-MRI data.