The role of sex in the pathophysiology of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin

Mass Vaccine Administration under Supply Uncertainty

The insurgence of COVID-19 requires fast mass vaccination, hampered by scarce availability and uncertain supply of vaccine doses and a tight schedule for boosters. In this paper, we analyze planning strategies for the vaccination campaign to vaccinate as many people as possible while meeting the booster schedule. We compare a conservative strategy and q-days-ahead strategies against the clairvoyant strategy. The conservative strategy achieves the best trade-off between utilization and compliance with the booster schedule. Q-days-ahead strategies with q < 7 provide a larger utilization but run out of stock in over 30% of days

Planning a Mass Vaccination Campaign with Balanced Staff Engagement

The insurgence of the COVID pandemic calls for mass vaccination campaigns worldwide. Pharmaceutical companies struggle to ramp up their production to meet the demand for vaccines but cannot always guarantee a perfectly regular delivery schedule. On the other hand, governments must devise plans to have most of their population vaccinated in the shortest possible time and have the vaccine booster administered after a precise time interval. The combination of delivery uncertainties and those time requirements may make such planning difficult. In this paper, we propose several heuristic strategies to meet those requirements in the face of delivery uncertainties. The outcome of those strategies is a daily vaccination plan that suggests how many initial doses and boosters can be administered each day. We compare the results with the optimal plan obtained through linear programming, which however assumes that we know in advance the whole delivery schedule. As for performance metrics, we consider both the vaccination time (which has to be as low as possible) and the balance between vaccination capacities over time (which has to be as uniform as possible). The strategies achieving the best trade-off between those competing requirements turn out to be the q-days ahead strategies, which put aside doses to guarantee that we do not run out of stock on just the next q days. Increasing the look-ahead period, i.e. q, allows to achieve a lower number of out-of-stock days, though worsening the other performance indicators

Long-term response to immuno-oncology after discontinuation for immuno-related pneumonia in metastatic renal carcinoma: a case report

Immuno-oncology demonstrated substantial efficacy in cancer treatment. Immune-related adverse events (irAEs) can virtually involve every organ, with different incidence depending on the different immune-checkpoint inhibitor. irAEs consequences can range from quality of life worsening and therapy discontinuation to death, if not recognized promptly. However, patients interrupting therapy due to irAEs in absence of progressive disease can benefit from immuno-oncology over time after discontinuation. We present the case of a man affected by metastatic renal cell carcinoma (mRCC) that experienced a long-term response to programmed cell death-1 inhibitor, nivolumab, after interruption due to immune-related pnenumonia. IrAEs can be associated to efficacy and very long-term response in mRCC patients treated with immuno-oncology

A Radial Basis Function Spike Model for Indirect Learning via Integrate-and-Fire Sampling and Reconstruction Techniques

This paper presents a deterministic and adaptive spike model derived from radial basis functions and a leaky integrate-and-fire sampler developed for training spiking neural networks without direct weight manipulation. Several algorithms have been proposed for training spiking neural networks through biologically-plausible learning mechanisms, such as spike-timing-dependent synaptic plasticity and Hebbian plasticity. These algorithms typically rely on the ability to update the synaptic strengths, or weights, directly, through a weight update rule in which the weight increment can be decided and implemented based on the training equations. However, in several potential applications of adaptive spiking neural networks, including neuroprosthetic devices and CMOS/memristor nanoscale neuromorphic chips, the weights cannot be manipulated directly and, instead, tend to change over time by virtue of the pre- and postsynaptic neural activity. This paper presents an indirect learning method that induces changes in the synaptic weights by modulating spike-timing-dependent plasticity by means of controlled input spike trains. In place of the weights, the algorithm manipulates the input spike trains used to stimulate the input neurons by determining a sequence of spike timings that minimize a desired objective function and, indirectly, induce the desired synaptic plasticity in the network

Bone metastases from urothelial carcinoma. The dark side of the moon

Bone metastases are common in genitourinary cancers, but they are underreported and not well researched. Synchronous bone metastases occur in 1.39–5.5% of bladder cancer patients, while 30–40% of cases are metachronous. Bone morphogenetic proteins (BMPs) play a key role in regulating proliferation, migration and invasion of tumor cells in bone microenvironment of bone metastases from metastatic urothelial carcinoma (mUC). Bone metastases represent a poor prognostic factor due to high morbidity and mortality correlated to skeletal-related events (SREs). The incidence rate of SREs in bladder, renal pelvis, and ureteral cancer varies from 39 to 68%. Radiotherapy is the most frequent treatment for SREs. The early use of bone targeted therapies (BTT), zoledronic acid and denosumab, improves SREs incidence and morbidity and it seems to improve overall survival (OS). To date, several new agents (immunotherapy and targeted drugs) demonstrated efficacy in mUC. However, subgroup analysis for bone metastases is often not available, due to difficulties in analysing bone samples, non-RECIST lesions and delay in systemic treatment due to SREs that limit the enrolment of bone mUC patients in clinical trials. Larger solid tumor studies that included UC patients are the main source of data for the management of mUC patients with bone metastases. For these patients, multidisciplinary approach should be preferred, involving orthopaedics, radiotherapists and rehabilitation to improve outcome and quality of life. New prospective trials should characterize clinical and molecular features of patients with bone metastases and the impact of new drugs on this poor prognostic metastatic site

Prevalence of silent coeliac disease in atopics

Background. Coeliac disease sometimes runs a subclinical/silent course and is often associated with immunologic and non-immunologic diseases. Although atopy is described as one of the most frequently associated conditions, the prevalence of coeliac disease in atopics has not yet been established. Aim. To evaluate the frequency of coeliac disease in an Italian series of atopics. Patients and Methods. Sera from 401 consecutive atopics with no clinical evidence of malabsorption were tested for IgA antiendomysial antibodies by indirect immunofluorescence on human umbilical cord and IgA anti tissue transglutaminase by enzyme-linked immunosorbent assay. Results. Four patients (1%) were found to be positive for both autoantibodies. Intestinal biopsy confirmed the diagnosis of active coeliac disease. One of the 4 coeliacs was also affected by Down's syndrome, autoimmune thyroiditis and coeliac hepatitis. In another case, a previously unknown severe iron deficiency was detected. Conclusions. The present study shows, for the first time, that the prevalence of coeliac disease in atopics is 1%, which is significantly higher than that in the general Italian population. Therefore, atopy should be considered a condition at risk and atopic patients routinely screened by means of specific autoantibody testing