Impact of multiple substance use on circulating ST2, a biomarker of adverse cardiac remodelling, in women.

CONTEXT: Cardiovascular disease (CVD) and heart failure (HF) are major causes of mortality in low-income populations and differ by sex. Risk assessment that incorporates cardiac biomarkers is common. However, research evaluating the utility of biomarkers rarely includes controlled substances, which may influence biomarker levels and thus influence CVD risk assessment. MATERIALS AND METHODS: We identified the effects of multiple substances on soluble "suppression of tumorigenicity 2" (sST2), a biomarker of adverse cardiac remodelling, in 245 low-income women. Adjusting for CVD risk factors, we examined associations between substance use and sST2 over six monthly visits. RESULTS: Median age was 53 years and 74% of participants were ethnic minority women. An sST2 level > 35 ng/mL (suggesting cardiac remodelling) during ≥1 study visit was observed in 44% of participants. In adjusted analysis, higher sST2 levels were significantly and positively associated with the presence of cocaine (Adjusted Linear Effect [ALE]:1.10; 95% CI:1.03-1.19), alcohol (ALE:1.10; 95% CI:1.04-1.17), heroin (ALE:1.25; 95% CI:1.10-1.43), and the interaction between heroin and fentanyl use. CONCLUSION: Results suggest that the use of multiple substances influences the level of sST2, a biomarker often used to evaluate cardiovascular risk. Incorporating substance use alongside cardiac biomarkers may improve CVD risk assessment in vulnerable women.

Outdoor Activities Associated with Lower Odds of SARS-CoV-2 Acquisition: A Case-Control Study.

Access to recreational physical activities, particularly in outdoor spaces, has been a crucial outlet for physical and mental health during the COVID-19 pandemic. There is a need to understand how conducting these activities modulates the risk of SARS-CoV-2 infection. In this case-control study of unvaccinated individuals conducted in San Francisco, California, the odds of testing positive to SARS-CoV-2 were lower for those who conducted physical activity in outdoor locations (adjusted odds ratio [aOR]: 0.16, 95% confidence interval [CI]: 0.05, 0.40) in the two weeks prior to testing than for those who conducted no activity or indoor physical activity only. Individuals who visited outdoor parks, beaches, or playgrounds also had lower odds of testing positive to SARS-CoV-2 (aOR: 0.28, 95% CI: 0.11, 0.68) as compared with those who did not visit outdoor parks, beaches, or playgrounds. These findings, albeit in an unvaccinated population, offer observational data to support pre-existing ecological studies that suggest that activity in outdoor spaces lowers COVID-19 risk.

Strategy for a globally coordinated response to a priority neglected tropical disease: snakebite envenoming

In one of his final essays, statesman and former United Nations secretary general Kofi Annan said, ‘Snakebite is the most important tropical disease you’ve never heard of’. Mr. Annan firmly believed that victims of snakebite envenoming should be recognised and afforded greater efforts at improved prevention, treatment, and rehabilitation. During the last years of his life, he advocated strongly for the World Health Organisation (WHO) and the global community to give greater priority to this disease of poverty and its victims. Snakebite envenoming (SBE) affects as many as 2.7 million people every year, most of whom live in some of the world’s most remote, poorly developed, and politically marginalised tropical communities. With annual mortality of 81,000 to 138,000 and 400,000 surviving victims suffering permanent physical and psychological disabilities, SBE is a disease in urgent need of attention. Like many diseases of poverty, SBE has failed to attract requisite public health policy inclusion and investment for driving sustainable efforts to reduce the medical and societal burden. This is largely due to the demographics of the affected populations and their lack of political voice.

Strategy for a globally coordinated response to a priority neglected tropical disease: snakebite envenoming

In one of his final essays, statesman and former United Nations secretary general Kofi Annan said, ‘Snakebite is the most important tropical disease you’ve never heard of’. Mr. Annan firmly believed that victims of snakebite envenoming should be recognised and afforded greater efforts at improved prevention, treatment, and rehabilitation. During the last years of his life, he advocated strongly for the World Health Organisation (WHO) and the global community to give greater priority to this disease of poverty and its victims. Snakebite envenoming (SBE) affects as many as 2.7 million people every year, most of whom live in some of the world’s most remote, poorly developed, and politically marginalised tropical communities. With annual mortality of 81,000 to 138,000 and 400,000 surviving victims suffering permanent physical and psychological disabilities, SBE is a disease in urgent need of attention. Like many diseases of poverty, SBE has failed to attract requisite public health policy inclusion and investment for driving sustainable efforts to reduce the medical and societal burden. This is largely due to the demographics of the affected populations and their lack of political voice.

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom.

OBJECTIVE: There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake's bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. METHODS: The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013. RESULTS: 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. CONCLUSIONS: Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom.

Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom.

There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A2 (sPLA2) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA2 inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts.

Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite.

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential prereferral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses, and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA2) inhibitors with brief exploration of other potential drug targets on venom molecules.

Snakebite: An Exploratory Cost-Effectiveness Analysis of Adjunct Treatment Strategies.

The cost-effectiveness of the standard of care for snakebite treatment, antivenom, and supportive care has been established in various settings. In this study, based on data from South Indian private health-care providers, we address an additional question: "For what cost and effectiveness values would adding adjunct-based treatment strategies to the standard of care for venomous snakebites be cost-effective?" We modeled the cost and performance of potential interventions (e.g., pharmacologic or preventive) used adjunctively with antivenom and supportive care for the treatment of snakebite. Because these potential interventions are theoretical, we used a threshold cost-effectiveness approach to explore this forward-looking concept. We examined economic parameters at which these interventions could be cost-effective or even cost saving. A threshold analysis was used to examine the addition of new interventions to the standard of care. Incremental cost-effectiveness ratios were used to compare treatment strategies. One-way, scenario, and probabilistic sensitivity analyses were conducted to analyze parameter uncertainty and define cost and effectiveness thresholds. Our results suggest that even a 3% reduction in severe cases due to an adjunct strategy is likely to reduce the cost of overall treatment and have the greatest impact on cost-effectiveness. In this model, for example, an investment of $10 of intervention that reduces the incidence of severe cases by 3%, even without changing antivenom usage patterns, creates cost savings of $75 per individual. These findings illustrate the striking degree to which an adjunct intervention could improve patient outcomes and be cost-effective or even cost saving.

Parotid swelling after Russell's viper envenomation: an unusual and poor prognostic sign.

Parotid swelling, an unusual and poorly understood sign, is associated with poor prognosis in the setting of Russell's viper envenomation. The large, aggressive Russell's viper is one of the most deadly snakes causing severe hematological and neurological manifestations. Research into this sign should be initiated and understanding could lead to improved outcomes.

1000 cases of tubeless video-assisted thoracic surgery at the Rome Tor Vergata University.

In the early 2000s, the 'Awake Thoracic Surgery Research Group' at Tor Vergata University began a program of thoracic operations in awake nonintubated patients. To our knowledge this was the first program created with this specific purpose. Since then over 1000 tubeless operations have been carried out successfully, making this series one of the widest in the world. Both nononcologic and oncologic conditions were successively approached and major operations for lung cancer are now being performed. Uniportal access was progressively adopted with significant positive outcomes in postoperative recovery, patient acceptance and economical costs. Failure rates due to patient's intolerance and open surgery conversion are progressively reducing. Tubeless thoracic surgery can be accomplished in a safe manner with effective results.

First Evidence of Cardiac Stem Cells From the Left Ventricular Apical Tip in Patients With Left Ventricular Assist Device Implantation.

BACKGROUND: Recent studies have challenged the dogma that the adult heart is a postmitotic organ and raise the possibility of the existence of resident cardiac stem cells (CSCs). Our study aimed to explore if these CSCs are present in the "ventricular tip" obtained during left ventricular assist device (LVAD) implantation from patients with end-stage heart failure (HF) and the relationship with LV dysfunctional area extent. METHODS: Four consecutive patients with ischemic cardiomyopathy and end-stage HF submitted to LVAD implantation were studied. The explanted "ventricular tip" was used as a sample of apical myocardial tissue for the pathological examination. Patients underwent clinical and echocardiographic examination, both standard transthoracic echocardiography (TTE) and speckle tracking echocardiography (STE), before LVAD implantation. RESULTS: All patients presented severe apical dysfunction, with apical akinesis/diskinesis and very low levels of apical longitudinal strain (-3.5 ± 2.9%). Despite this, the presence of CSCs was demonstrated in pathological myocardial samples of "ventricular tip" in all 4 of the patients. It was found to be a mean of 6 c-kit cells in 10 fields magnification 40×. CONCLUSIONS: Cardiac stem cells can be identified in the LV apical segment of patients who have undergone LVAD implantation despite LV apical fibrosis.

An update on myasthenia gravis, challenging disease for the dental profession.

Myasthenia gravis is an autoimmune neuromuscular disorder characterized by fluctuating weakness and skeletal muscle fatigue. Clinical signs and symptoms may vary considerably according to the age at presentation, patterns of autoantibodies and associated thymic abnormalities, so that therapeutic options are highly individualized. Facial and oropharyngeal muscle weakness is common at disease onset, and therefore dentists are often the first health professionals to encounter these patients. Myasthenic patients require special consideration and advice in order to ensure optimal and safe dental treatment. Oral manifestations, treatment timing and modality, the choice and effects of drugs and medications, and prevention of myasthenic crisis are all important aspects with which dentists and oral health care providers should be thoroughly acquainted.

From "awake" to "monitored anesthesia care" thoracic surgery: A 15 year evolution.

Although general anesthesia still represents the standard when performing thoracic surgery, the interest toward alternative methods is increasing. These have evolved from the employ of just local or regional analgesia techniques in completely alert patients (awake thoracic surgery), to more complex protocols entailing conscious sedation and spontaneous ventilation. The main rationale of these methods is to prevent serious complications related to general anesthesia and selective ventilation, such as tracheobronchial injury, acute lung injury, and cardiovascular events. Trends toward shorter hospitalization and reduced overall costs have also been indicated in preliminary reports. Monitored anesthesia care in thoracic surgery can be successfully employed to manage diverse oncologic conditions, such as malignant pleural effusion, peripheral lung nodules, and mediastinal tumors. Main non-oncologic indications include pneumothorax, emphysema, pleural infections, and interstitial lung disease. Furthermore, as the familiarity with this surgical practice has increased, major operations are now being performed this way. Despite the absence of randomized controlled trials, there is preliminary evidence that monitored anesthesia care protocols in thoracic surgery may be beneficial in high-risk patients, with non-inferior efficacy when compared to standard operations under general anesthesia. Monitored anesthesia care in thoracic surgery should enter the armamentarium of modern thoracic surgeons, and adequate training should be scheduled in accredited residency programs.

In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease.

Cyclosporine A (CsA) has been demonstrated to be effective for the treatment of a variety of ophthalmological conditions, including ocular surface disorders such as the dry eye disease (DED). Since CsA is characterised by its low water solubility, the development of a topical ophthalmic formulation represents an interesting pharmaceutical question. In the present study, two different strategies to address this challenge were studied and compared: (i) a water-soluble CsA prodrug formulated within an aqueous solution and (ii) a CsA oil-in-water emulsion (Restasis, Allergan Inc., Irvine, CA). First, the prodrug formulation was shown to have an excellent ocular tolerance as well as no influence on the basal tear production; maintaining the ocular surface properties remained unchanged. Then, in order to allow in vivo investigations, a specific analytical method based on ultra high pressure liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC-MS/MS) was developed and optimised to quantify CsA in ocular tissues and fluids. The CsA ocular kinetics in lachrymal fluid for both formulations were found to be similar between 15 min and 48 h. The CsA ocular distribution study evidenced the ability of the prodrug formulation to penetrate into the eye, achieving therapeutically active CsA levels in tissues of both the anterior and posterior segments. In addition, the detailed analysis of the in vivo data using a bicompartmental model pointed out a higher bioavailability and lower elimination rate for CsA when it is generated from the prodrug than after direct application as an emulsion. The interesting in vivo properties displayed by the prodrug solution make it a safe and suitable option for the treatment of DED.

Randomized comparison of awake nonresectional versus nonawake resectional lung volume reduction surgery.

OBJECTIVE: The study objective was to assess in a randomized controlled study (NCT00566839) the comparative results of awake nonresectional or nonawake resectional lung volume reduction surgery. METHOD: Sixty-three patients were randomly assigned by computer to receive unilateral video-assisted thoracic surgery lung volume reduction surgery by a nonresectional technique performed through epidural anesthesia in 32 awake patients (awake group) or the standard resectional technique performed through general anesthesia in 31 patients (control group). Primary outcomes were hospital stay and changes in forced expiratory volume in 1 second. During follow-up, the need of contralateral treatment because of loss of postoperative benefit was considered a failure event as death. RESULTS: Intergroup comparisons (awake vs control) showed no difference in gender, age, and body mass index. Hospital stay was shorter in the awake group (6 vs 7.5 days, P = .04) with 21 versus 10 patients discharged within 6 days (P = .01). At 6 months, forced expiratory volume in 1 second improved significantly in both study groups (0.28 vs 0.29 L) with no intergroup difference (P = .79). In both groups, forced expiratory volume in 1 second improvements lasted more than 24 months. At 36 months, freedom from contralateral treatment was 55% versus 50% (P = .5) and survival was 81% versus 87% (P = .5). CONCLUSIONS: In this randomized study, awake nonresectional lung volume reduction surgery resulted in significantly shorter hospital stay than the nonawake procedure. There were no differences between study groups in physiologic improvements, freedom from contralateral treatment, and survival. We speculate that compared with the nonawake procedure, awake lung volume reduction surgery can offer similar clinical benefit but a faster postoperative recovery.