Comorbidities in aging patients with sickle cell disease.

Sickle cell disease (SCD) in general and sickle cell anemia in particular is a highly complex disorder both at the molecular and clinical levels. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Moreover, despite the fact that SCD is a chronic malady, its manifestations are both acute and chronic. The former include, among other things, the recurrent vaso-occlusive crises (its hallmark) and acute chest syndrome. The chronic complications include most commonly avascular necrosis and leg ulcers. Currently, survival of patients with SCD has improved dramatically thanks to newborn screening, antibiotic prophylaxis, better vaccine, safer blood transfusion and the use of hydroxyurea. It is the advent of these therapies that improved the survival. This improvement, however, introduced a third dimension of the disease: comorbidities that occur in aging people in the general population. There is concern that the gain in survival may be offset by the comorbidities. Thus it is the purpose of this review to identify the comorbidities in the elderly with SCD and differentiate them from the basis disease to implement proper therapies so that better survival could be maintained

The Evolving Pharmacotherapeutic Landscape for the Treatment of Sickle Cell Disease.

Sickle cell disease (SCD) is an extremely heterogeneous disease that has been associated with global morbidity and early mortality. More effective and inexpensive therapies are needed. During the last five years, the landscape of the pharmacotherapy of SCD has changed dramatically. Currently, 54 drugs have been used or under consideration to use for the treatment of SCD. These fall into 3 categories: the first category includes the four drugs (Hydroxyurea, L-Glutamine, Crizanlizumab tmca and Voxelotor) that have been approved by the United States Food and Drug Administration (FDA) based on successful clinical trials. The second category includes 22 drugs that failed, discontinued or terminated for now and the third category includes 28 drugs that are actively being considered for the treatment of SCD. Crizanlizumab and Voxelotor are included in the first and third categories because they have been used in more than one trial. New therapies targeting multiple pathways in the complex pathophysiology of SCD have been achieved or are under continued investigation. The emerging trend seems to be the use of multimodal drugs (i.e. drugs that have different mechanisms of action) to treat SCD similar to the use of multiple chemotherapeutic agents to treat cancer

Finite Volume Properly Convex Deformations of the Figure-eight Knot

In this paper we show that some open set of the representations of the fundamental group of figure-eight knot complement found in \cite{Ballas12a} are the holonomies of a family of finite volume properly convex projective structures on the figure-eight knot complement.Comment: 21 pages, 7 figure. Incorporated additional referee comments, fixed typos. Simplified the proof of Lemma 3.3. To appear in Geometriae Dedicat

Of pools, oceans, and the Dead Sea.

In a comprehensive study in this issue of Blood, Carden and colleagues describe the importance of the tonicity of IV fluids used in the treatment of patients with sickle cell disease (SCD) during vaso-occlusive crises (VOCs). Hypertonic fluids decreased sickle red blood cell (sRBC) deformability, increased occlusion, and increased sRBC adhesion in microfluidic human microvasculature models. Hypotonic fluids decreased sRBC adhesion but prolonged sRBC transit time. Fluids with intermediate tonicities resulted in optimal changes that reduced the risk of vaso-occlusion. © 2017 by The American Society of Hematology

Deformations of Non-Compact, Projective Manifolds

In this paper, we demonstrate that the complete hyperbolic structure of various two-bridge knots and links cannot be deformed to an inequivalent strictly convex projective structure. We also prove a complementary result showing that under certain rigidity hypotheses, branched covers of amphicheiral knots admit non-trivial, strictly convex deformations near their complete hyperbolic structure.Comment: 28 pages, 1 figure corrected typos, added references, incorporated referee suggestions, strengthened conclusion of main result and fixed small gap in its proo

Drugs for preventing red blood cell dehydration in people with sickle cell disease.

BACKGROUND: Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs. This is an updated version of a previously published review. OBJECTIVES: To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group\u27s Haemoglobinopathies Trials Register. We also searched online trials registries for any ongoing trials (01 July 2018).Last search of the Group\u27s Haemoglobinopathies Trials Register: 08 October 2018. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data. MAIN RESULTS: Of the 51 studies identified, three met the inclusion criteria, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups (low-quality evidence). A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. AUTHORS\u27 CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red blood cell survival (depending on dose), this did not lead to fewer painful crises.Given this is no longer an active area of research, this review will no longer be regularly updated

Drugs for preventing red blood cell dehydration in people with sickle cell disease.

BACKGROUND: Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs. This is an updated version of a previously published review. OBJECTIVES: To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group\u27s Haemoglobinopathies Trials Register.Last search of the Group\u27s Trials Register: 28 November 2015. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data. MAIN RESULTS: Of the 51 studies identified, three met the inclusion criteria. The first study tested the effectiveness of zinc sulphate to prevent sickle cell-related crises in a total of 145 participants and showed a significant reduction in painful crises over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15). However, analysis was restricted due to limited statistical data. Changes to red cell parameters and blood counts were inconsistent. No serious adverse events were noted in the study.The second study was a Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo. Compared to the placebo group the high dose senicapoc showed significant improvement in change in hemoglobin level, number and proportion of dense red blood cells, red blood cell count and indices and hematocrit. The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups. A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. AUTHORS\u27 CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red cell survival (depending on dose), this did not lead to fewer painful crises.We will continue to run searches to identify any potentially relevant trials; however, we do not plan to update other sections of the review until new trials are published