Comparison of 8 weeks standard treatment (rifampicin plus clarithromycin) vs. 4 weeks standard plus amoxicillin/clavulanate treatment [RC8 vs. RCA4] to shorten Buruli ulcer disease therapy (the BLMs4BU trial): study protocol for a randomized controlled multi-centre trial in Benin

Background Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans that affects skin, soft tissues, and bones, causing long-term morbidity, stigma, and disability. The recommended treatment for BU requires 8 weeks of daily rifampicin and clarithromycin together with wound care, physiotherapy, and sometimes tissue grafting and surgery. Recovery can take up to 1 year, and it may pose an unbearable financial burden to the household. Recent in vitro studies demonstrated that beta-lactams combined with rifampicin and clarithromycin are synergistic against M. ulcerans. Consequently, inclusion of amoxicillin/clavulanate in a triple oral therapy may potentially improve and shorten the healing process. The BLMs4BU trial aims to assess whether co-administration of amoxicillin/clavulanate with rifampicin and clarithromycin could reduce BU treatment from 8 to 4 weeks. Methods We propose a randomized, controlled, open-label, parallel-group, non-inferiority phase II, multi-centre trial in Benin with participants stratified according to BU category lesions and randomized to two oral regimens: (i) Standard: rifampicin plus clarithromycin therapy for 8 weeks; and (ii) Investigational: standard plus amoxicillin/clavulanate for 4 weeks. The primary efficacy outcome will be lesion healing without recurrence and without excision surgery 12 months after start of treatment (i.e. cure rate). Seventy clinically diagnosed BU patients will be recruited per arm. Patients will be followed up over 12 months and managed according to standard clinical care procedures. Decision for excision surgery will be delayed to 14 weeks after start of treatment. Two sub-studies will also be performed: a pharmacokinetic and a microbiology study. Discussion If successful, this study will create a new paradigm for BU treatment, which could inform World Health Organization policy and practice. A shortened, highly effective, all-oral regimen will improve care of BU patients and will lead to a decrease in hospitalization-related expenses and indirect and social costs and improve treatment adherence. This trial may also provide information on treatment shortening strategies for other mycobacterial infections (tuberculosis, leprosy, or non-tuberculous mycobacteria infections). Trial registration ClinicalTrials.gov NCT05169554. Registered on 27 December 2021

Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial

Габапентин показав ефективність у лікуванні хронічного нейропатичного або змішаного болю у дорослих. Хоча фахівці з терапії дитячого болю мають великий досвід роботи з габапентином для лікування невропатичного болю, він практично не використовується за призначенням. Його ефективність та безпека в цьому контексті ніколи не були показані. Метою цього випробування є порівняння габапентину з плацебо як доповнення до морфіну для лікування сильного хронічного змішаного або невропатичного болю у дітей. Це випробування є частиною проекту сьомої рамкової програми Європейського Союзу «Габапентин при педіатричному болю» (GAPP) для розробки дозволу на продаж нової суспензії габапентину для дітей.Габапентин показал эффективность в лечении хронической невропатической или смешанной боли у взрослых. Хотя специалисты по детской боли имеют большой опыт применения габапентина для лечения невропатической боли, он практически не используется по назначению. Его эффективность и безопасность в этом контексте никогда не были показаны. Целью данного исследования является сравнение габапентина с плацебо в качестве дополнения к морфину для лечения тяжелой хронической смешанной или невропатической боли у детей. Это исследование является частью проекта Седьмой рамочной программы Европейского союза «Габапентин в детской боли» (GAPP), направленного на разработку разрешения на использование в педиатрии новой суспензии габапентина.Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension.Project Gabapentin in Paediatric Pain (GAPP), Grant Agreement №60204

p53 overexpression is associated with cytoreduction and response to chemotherapy in ovarian cancer

The aim of this study was to assess the association of p53 status with primary cytoreduction, response to chemotherapy and outcome in stage III–IV primary ovarian cancer patients. Immunohistochemical analysis of p53 was performed on formalin-fixed, paraffin-embedded specimens from 168 primary ovarian carcinomas by using the DO-7 monoclonal antibody. p53 nuclear positivity was found in 84 out of 162 (52%) malignant tumours. A higher percentage of p53 nuclear positivity was observed in patients with advanced stage of disease than in stage I–II (57% vs 23% respectively; P = 0.0022) and in poorly differentiated versus well/moderately differentiated tumours (59% vs 32% respectively; P = 0.0038). The multivariate analysis aimed to investigate the association of FIGO stage, grade and p53 status with primary cytoreduction in 136 stage III–IV patients showed that stage IV disease may influence the possibility to perform primary cytoreduction in ovarian cancer patients. p53-positivity also maintained a trend to be associated with poor chance of cytoreduction. In patients who underwent pathologic assessment of response, cases who did not respond to chemotherapy were much more frequently p53-positive than p53-negative (86% vs 14% respectively; P = 0.012). Moreover, patients with stage III disease and < 2-cm residual tumour were more likely to respond to treatment. In multivariate analysis, FIGO stage and p53 expression were independently correlated with pathologic response to chemotherapy. Time to progression and survival rates were shown not to be different in p53-positive versus p53-negative patients. © 1999 Cancer Research Campaig

Landslides caused by the Mw7.8 Kaikōura earthquake and the immediate response

Tens of thousands of landslides were generated over 10, 000 km2 of North Canterbury and Marlborough as a consequence of the 14 November 2016, MW7.8 Kaikōura Earthquake. The most intense landslide damage was concentrated in 3500 km2 around the areas of fault rupture. Given the sparsely populated area affected by landslides, only a few homes were impacted and there were no recorded deaths due to landslides. Landslides caused major disruption with all road and rail links with Kaikōura being severed. The landslides affecting State Highway 1 (the main road link in the South Island of New Zealand) and the South Island main trunk railway extended from Ward in Marlborough all the way to the south of Oaro in North Canterbury. The majority of landslides occurred in two geological and geotechnically distinct materials reflective of the dominant rock types in the affected area. In the Neogene sedimentary rocks (sandstones, limestones and siltstones) of the Hurunui District, North Canterbury and around Cape Campbell in Marlborough, first-time and reactivated rock-slides and rock-block slides were the dominant landslide type. These rocks also tend to have rock material strength values in the range of 5-20 MPa. In the Torlesse 'basement' rocks (greywacke sandstones and argillite) of the Kaikōura Ranges, first-time rock and debris avalanches were the dominant landslide type. These rocks tend to have material strength values in the range of 20-50 MPa. A feature of this earthquake is the large number (more than 200) of valley blocking landslides it generated. This was partly due to the steep and confined slopes in the area and the widely distributed strong ground shaking. The largest landslide dam has an approximate volume of 12(±2) M m3 and the debris from this travelled about 2.7 km2 downslope where it formed a dam blocking the Hapuku River. The long-term stability of cracked slopes and landslide dams from future strong earthquakes and large rainstorms are an ongoing concern to central and local government agencies responsible for rebuilding homes and infrastructure. A particular concern is the potential for debris floods to affect downstream assets and infrastructure should some of the landslide dams breach catastrophically. At least twenty-one faults ruptured to the ground surface or sea floor, with these surface ruptures extending from the Emu Plain in North Canterbury to offshore of Cape Campbell in Marlborough. The mapped landslide distribution reflects the complexity of the earthquake rupture. Landslides are distributed across a broad area of intense ground shaking reflective of the elongate area affected by fault rupture, and are not clustered around the earthquake epicentre. The largest landslides triggered by the earthquake are located either on or adjacent to faults that ruptured to the ground surface. Surface faults may provide a plane of weakness or hydrological discontinuity and adversely oriented surface faults may be indicative of the location of future large landslides. Their location appears to have a strong structural geological control. Initial results from our landslide investigations suggest predictive models relying only on ground-shaking estimates underestimate the number and size of the largest landslides that occurred

Landslides caused by the Mw7.8 Kaikōura earthquake and the immediate response

Tens of thousands of landslides were generated over 10, 000 km2 of North Canterbury and Marlborough as a consequence of the 14 November 2016, MW7.8 Kaikōura Earthquake. The most intense landslide damage was concentrated in 3500 km2 around the areas of fault rupture. Given the sparsely populated area affected by landslides, only a few homes were impacted and there were no recorded deaths due to landslides. Landslides caused major disruption with all road and rail links with Kaikōura being severed. The landslides affecting State Highway 1 (the main road link in the South Island of New Zealand) and the South Island main trunk railway extended from Ward in Marlborough all the way to the south of Oaro in North Canterbury. The majority of landslides occurred in two geological and geotechnically distinct materials reflective of the dominant rock types in the affected area. In the Neogene sedimentary rocks (sandstones, limestones and siltstones) of the Hurunui District, North Canterbury and around Cape Campbell in Marlborough, first-time and reactivated rock-slides and rock-block slides were the dominant landslide type. These rocks also tend to have rock material strength values in the range of 5-20 MPa. In the Torlesse 'basement' rocks (greywacke sandstones and argillite) of the Kaikōura Ranges, first-time rock and debris avalanches were the dominant landslide type. These rocks tend to have material strength values in the range of 20-50 MPa. A feature of this earthquake is the large number (more than 200) of valley blocking landslides it generated. This was partly due to the steep and confined slopes in the area and the widely distributed strong ground shaking. The largest landslide dam has an approximate volume of 12(±2) M m3 and the debris from this travelled about 2.7 km2 downslope where it formed a dam blocking the Hapuku River. The long-term stability of cracked slopes and landslide dams from future strong earthquakes and large rainstorms are an ongoing concern to central and local government agencies responsible for rebuilding homes and infrastructure. A particular concern is the potential for debris floods to affect downstream assets and infrastructure should some of the landslide dams breach catastrophically. At least twenty-one faults ruptured to the ground surface or sea floor, with these surface ruptures extending from the Emu Plain in North Canterbury to offshore of Cape Campbell in Marlborough. The mapped landslide distribution reflects the complexity of the earthquake rupture. Landslides are distributed across a broad area of intense ground shaking reflective of the elongate area affected by fault rupture, and are not clustered around the earthquake epicentre. The largest landslides triggered by the earthquake are located either on or adjacent to faults that ruptured to the ground surface. Surface faults may provide a plane of weakness or hydrological discontinuity and adversely oriented surface faults may be indicative of the location of future large landslides. Their location appears to have a strong structural geological control. Initial results from our landslide investigations suggest predictive models relying only on ground-shaking estimates underestimate the number and size of the largest landslides that occurred

The Origin and Evolution of the Parental Magmas of Frontal Volcanoes in Kamchatka: Evidence from Magmatic Inclusions in Olivine from Zhupanovsky Volcano

The paper presents data on naturally quenched melt inclusions in olivine (Fo 69–84) from Late Pleistocene pyroclastic rocks of Zhupanovsky volcano in the frontal zone of the Eastern Volcanic Belt of Kamchatka. The composition of the melt inclusions provides insight into the latest crystallization stages (~70% crystallization) of the parental melt (~46.4wt%SiO2, ~2.5wt%H2O, ~0.3wt%S), which proceeded at decompression and started at a depth of approximately 10 km from the surface. The crystallization temperature was estimated at 1100 ± 20°C at an oxygen fugacity of ΔFMQ = 0.9–1.7. The melts evolved due to the simultaneous crystallization of olivine, plagioclase, pyroxene, chromite, and magnetite (Ol : Pl : Cpx : (Crt–Mt) ~ 13 : 54 : 24 : 4) along the tholeiite evolutionary trend and became progressively enriched in FeO, SiO2, Na2O, and K2O and depleted in MgO, CaO, and Al2O3. Melt crystallization was associated with the segregation of fluid rich in S-bearing compounds and, to a lesser extent, in H2O and Cl. The primary melt of Zhupanovsky volcano (whose composition was estimated from data on the most primitive melt inclusions) had a composition of low-Si (~45wt%SiO2) picrobasalt (~14wt%MgO), as is typical of parental melts in Kamchatka and other island arcs, and was different from MORB. This primary melt could be derived by ~8% melting of mantle peridotite of composition close to the MORB source, under pressures of 1.5 ± 0.2 GPa and temperatures 20–30°C lower than the solidus temperature of “dry” peridotite (1230–1240°C). Melting was induced by the interaction of the hot peridotite with a hydrous component that was brought to the mantle from the subducted slab and was also responsible for the enrichment of the Zhupanovsky magmas in LREE, LILE, B, Cl, Th, U, and Pb. The hydrous component in the magma source of Zhupanovsky volcano was produced by the partial slab melting under water-saturated conditions at temperatures of 760–810°C and pressures of ~3.5 GPa. As the depth of the subducted slab beneath Kamchatkan volcanoes varies from 100 to 125 km, the composition of the hydrous component drastically changes from relatively low-temperature H2O-rich fluid to higher temperature H2O-bearing melt. The geothermal gradient at the surface of the slab within the depth range of 100–125 km beneath Kamchatka was estimated at 4°C/km

Riluzole and other prognostic factors in ALS: a population-based registry study in Italy

In this prospective population-based registry study on ALS survival, we investigated the role of riluzole treatment, together with other clinical factors, on the prognosis in incident ALS cases in Emilia Romagna Region (ERR), Italy