Zika Virus and Blood Transfusions

 Zika and Blood Transfusions: The Current Landscape

Scanning Electron Microscope image of Zika

Zika virus, initially identified in the Zika forest of Uganda in 1947, emerged as a significant global health concern during the outbreak that began in Brazil in 2015. Transmitted primarily through the bite of an infected Aedes species mosquito, Zika garnered international attention due to its association with microcephaly in newborns and other severe birth defects. Additionally, concerns were raised about the potential for Zika virus transmission through blood transfusions, creating an urgency in the blood banking community to implement safety measures.

Zika Transmission through Blood Transfusions

While the majority of Zika virus cases result from mosquito bites, several instances of transmission through blood transfusions were reported during the major outbreaks. The virus can survive and remain infectious in blood products, making the transfusion of contaminated blood a possible transmission route. Furthermore, a significant number of infected individuals are asymptomatic, which makes it harder to identify and defer potentially infectious donors based solely on clinical symptoms.

Blood Screening for Zika

Given the potential risks associated with Zika virus transmission through transfusions, many countries, particularly those with reported Zika cases, initiated blood screening procedures to ensure the safety of the blood supply.

In the United States, the Food and Drug Administration (FDA) issued guidance in 2016 recommending universal testing of all donated Whole Blood and blood components for Zika virus in the states and territories with active transmission. By 2018, this guidance expanded to include universal testing across all states and territories, regardless of the presence of active Zika cases. This approach utilized nucleic acid testing (NAT) to detect the presence of the virus in donated blood.

Current Testing Guidelines

Over time, as the number of Zika cases declined and a better understanding of the virus and its transmission patterns emerged, the FDA updated its guidelines. In 2019, the FDA revised its recommendations, allowing blood centers to test pooled samples rather than individual donations. This shift was based on risk-assessment models showing a significant decrease in the prevalence of Zika virus infection among blood donors in the U.S.

Internationally, blood screening protocols vary based on the prevalence of the virus, available resources, and the assessed risk of transfusion-transmitted Zika virus. Many countries with no reported cases or those that have never experienced local transmission might not routinely screen blood donations for Zika.

Implications for Blood Safety

The introduction and continuous update of Zika screening protocols signify the nimbleness required in transfusion medicine. In the face of emerging infectious threats, the blood banking community must be prepared to quickly assess risks and implement appropriate safety measures.

Zika's emergence reinforced the importance of proactive measures, research, and international collaboration to ensure the safety of the blood supply. While the immediate crisis associated with the Zika virus has subsided, the lessons learned continue to shape policies and preparedness strategies for future threats.

The Effects of Zika Virus

While many people infected with Zika virus remain asymptomatic or experience only mild symptoms, the real concern lies in the complications linked to the virus:

1. Birth Defects: One of the most alarming complications associated with Zika is its ability to cause congenital disabilities when pregnant women contract the virus. Microcephaly, where a baby's head is much smaller than expected, is the most recognized of these birth defects. Infants with microcephaly often have underdeveloped brains, leading to long-term developmental challenges and sometimes even death.

2. Guillain-Barré Syndrome (GBS): Zika has been associated with GBS, a rare neurological disorder where a person's immune system attacks their nerves. GBS can result in muscle weakness and, in severe cases, paralysis. Though most people recover from GBS, some might experience long-term effects, and in rare cases, it can be fatal.

3. Other Neurological Complications: Apart from GBS, Zika has been linked to other neurological conditions such as meningoencephalitis and myelitis.

Therapeutic Phlebotomy

Therapeutic Phlebotomy: Controlled Blood Removal as Treatment

Therapeutic phlebotomy, often simply termed as "bloodletting," has been practiced for centuries, dating back to ancient civilizations like the Egyptians and Greeks. They believed that removing blood from the body could rid it of evil spirits or balance out the four humors: blood, phlegm, black bile, and yellow bile. While modern medicine has debunked these ancient theories, controlled blood removal remains a medically approved treatment for specific conditions. One such condition is polycythemia vera, but there are several others where therapeutic phlebotomy has proven beneficial.

 Therapeutic Phlebotomy Procedure

Undergoing therapeutic phlebotomy is similar to giving blood at a blood donation center. The patient is comfortably seated, and a large needle is inserted into a vein, typically in the arm. Blood is then drawn into a bag. The entire process can last anywhere from 30 minutes to an hour, depending on the volume of blood being removed.

It's essential to drink plenty of fluids before and after the procedure to help replace the lost volume and prevent feelings of dizziness or lightheadedness.

Patient Experiences

Patients undergoing therapeutic phlebotomy often report a range of experiences. Some feel revitalized, while others might feel tired immediately after the procedure. Temporary dizziness or lightheadedness is not uncommon. For those with conditions like hemochromatosis, they often report feeling 'lighter' and less fatigued as excess iron is removed from their system. Over time, with regular phlebotomies, symptoms related to their underlying condition, such as joint pain in hemochromatosis or itching in polycythemia vera, often diminish.

Risks and Side Effects of Therapeutic Phlebotomy

As with any medical procedure, there are potential risks involved. These can include:

• Bruising at the needle site
• Infection, although this is rare if proper aseptic techniques are used
• Feeling faint or dizzy
• Hematoma (a collection of blood outside of blood vessels)

It's also worth noting that over time, veins can become scarred or harder to access. In such cases, a phlebotomist or healthcare provider might choose a different site or vein for blood removal.

Polycythemia Vera (PV)

Polycythemia vera is a rare type of blood cancer where the bone marrow produces too many red blood cells. This overproduction thickens the blood, slowing its flow and increasing the risk of clots. These clots can lead to severe complications such as heart attacks or strokes. By regularly removing a specific volume of blood, therapeutic phlebotomy reduces the number of circulating red blood cells. This procedure brings the hematocrit closer to normal levels, reducing the associated risks. Patients might require frequent phlebotomies initially, with the frequency tapering off as the condition stabilizes.

Hemochromatosis

Hemochromatosis is a genetic disorder causing the body to absorb too much iron from food. Over time, this excess iron accumulates in organs, particularly the liver, heart, and pancreas, leading to complications such as liver disease, heart problems, or diabetes. Through therapeutic phlebotomy, blood is removed regularly to decrease the body's iron levels. Blood may be removed weekly until iron levels normalize, and maintenance sessions might follow every 2-4 months.

Porphyria Cutanea Tarda (PCT)

PCT, the most common type of porphyria, arises from a deficiency of the enzyme uroporphyrinogen decarboxylase. Patients exhibit symptoms like blisters on sun-exposed skin, excessive hair growth, and liver abnormalities. Elevated liver iron stores often accompany PCT, and iron plays a role in its manifestation. Therapeutic phlebotomy serves to reduce these iron stores, subsequently decreasing porphyrin levels in the liver and mitigating symptoms.

Secondary Polycythemia

Beyond the primary polycythemia vera, there's secondary polycythemia, where red blood cell overproduction results from external factors, such as chronic hypoxia or tumors secreting erythropoietin. Therapeutic phlebotomy can address the excessive red blood cells, offering symptomatic relief and reducing potential complications.

Patient Monitoring and Individualized Care

For those undergoing therapeutic phlebotomy, regular monitoring is crucial. It ensures that optimal hematocrit or iron levels are maintained and complications are avoided. Factors like the patient's age, overall health, and the underlying condition dictate the frequency and volume of blood removal. Regular blood tests and clinical assessments guide adjustments in the phlebotomy regimen, ensuring each patient receives care tailored to their unique needs.

Polycythemia Vera

 

What is Polycythemia Vera?

Definition and Characteristics: Polycythemia Vera (PV) is a rare type of blood cancer classified as a myeloproliferative neoplasm, which is characterized by the bone marrow's abnormal and uncontrolled cell growth. This results in an excessive production of blood cells, notably red blood cells (erythrocytes), but also white blood cells (leukocytes) and platelets (thrombocytes). A key feature of PV, distinguishing it from most other blood cancers, is the significant increase in red blood cells, a condition known as erythrocytosis or "many cells in the blood."

Prevalence and Demographics:

• PV is more commonly diagnosed in men than in women.
• It is rare in individuals under 40 years old and becomes more prevalent with age.
• Annually, 1 in 36,000 men and 1 in 77,000 women are diagnosed with PV.
• About 1 in 4,500 people are affected by PV at any given time.

Genetics and Mutation:

• PV is generally not inherited and originates from a somatic genetic mutation post-conception.
• Most patients with PV have a mutation in the Janus Kinase 2 (JAK2) gene, crucial for cell signaling and regulation within the bone marrow. This mutation leads to uncontrolled cell production.

Primary vs. Secondary Polycythemia:

• Primary Polycythemia (Polycythemia Vera): A malignant overproduction of cells in the bone marrow due to a cancerous process.
• Secondary Polycythemia: Caused by increased red blood cell production due to factors outside the bone marrow, such as low oxygen conditions or hormonal triggers, and not related to a cancerous process.

Non-Cancerous Causes: Conditions like sleep apnea, COPD, smoking, alcohol use, and the use of diuretics can lead to non-cancerous forms of polycythemia or erythrocytosis by stimulating the production of erythropoietin, a hormone that signals the bone marrow to produce more red blood cells.

Polycythemia Vera is a complex condition with specific genetic underpinnings and significant implications for blood cell production. Its diagnosis and treatment require careful differentiation from other forms of polycythemia, with a focus on managing the uncontrolled production of blood cells and the factors contributing to secondary forms of the condition.

Signs and Symptoms

Detecting Polycythemia Vera: Understanding Blood Work Indicators

Identification Challenges:

• Many individuals with Polycythemia Vera (PV) may be unaware of their condition due to its gradual onset.
• PV often comes to light during routine blood tests, like a Complete Blood Count (CBC), which can reveal anomalies hinting at the disease.

Key CBC Findings in PV:

• Increased Red Blood Cell (RBC) Count: A significant indicator of PV, reflecting the overproduction of RBCs.
• Elevated Hemoglobin Levels: Hemoglobin, the major protein in RBCs responsible for oxygen transport, also increases as RBC count rises.
• Higher Hematocrit Percentage: Indicates a higher proportion of RBCs in blood volume. Hematocrit is the percentage of blood volume occupied by RBCs, with the remainder mostly being plasma.
• Possible Increase in White Blood Cells and Platelets: Some individuals may also experience a slight, typically non-malignant, increase in these cell counts.

Normal Blood Count Ranges:

• RBC Count: Approximately 4.5 to 6.0×10^12/L for men and 4.0 to 5×10^12/L for women.
• Hemoglobin Levels: Typically 14 to 17 grams per deciliter (dL) for men and 12 to 15 g/dL for women.
• Hematocrit Range: Between 40-50% for men and 35-45% for women.
• It's important to note that normal ranges can slightly vary by location due to differences in lab equipment and population.

Clinical Implications:

• Values above these normal ranges, along with other symptoms, may prompt a healthcare provider to suspect PV.
• Such findings necessitate further investigation to confirm the diagnosis and understand the extent of the condition.

Normal Blood Counts per MayoClinic laboratories

Polycythemia vera is dangerous however, because with an increase of Red Blood Cells beyond what is normal, the blood starts to become thicker and less viscous. This makes circulating the blood throughout the body much more difficult and can lead to dangerous situations such as blood clots and strokes. The situation in which the thickening, or an increase of viscosity of the blood, is called hyperviscosity syndrome. It is not specific to PV, and patient's with other hematologic malignancies such as Waldenstroms macroglobulinemia, leukemias, Multiple Myeloma, etc. Patient's with PV that start to experience hyperviscosity syndrome can expect to see most non-specific symptoms such as 

• Headache
• Nausea
• Vision Changes and retinopathy
• Dizziness/Vertigo
• Seizures and potentially even coma. 
• Dyspnea (Shortness of breath)
• Fatigue/Weakness
• Stroke
• Night Sweats
• Bruising / Extended Bleeding
• Weight Loss

Circulatory Clots:

• About 20% of PV patients experience clots within their circulatory system, significantly increasing the risk of strokes and Transient Ischemic Attacks (TIAs).
• The increased blood viscosity associated with PV leads to decreased blood flow and higher risk of thrombotic events, potentially causing organ damage and heart attacks.

Symptoms Overview:

• Erythromelalgia: Characterized by blotchy, discolored, red skin, often warm to the touch and accompanied by a burning pain. This is due to increased red blood cells and slower circulation, causing periodic blockage in extremities.

• Itchy Skin: Experienced by nearly half of all PV patients, often triggered after warm baths/showers. It may be an early symptom, believed to be caused by abnormal histamine and cytokine release.

• Gout: A form of painful arthritis from uric acid buildup, commonly affecting the big toe. In PV, high RBC turnover and possible organ damage contribute to excessive uric acid production.

• Splenomegaly: The spleen enlarges as it filters an excessive number of red blood cells, leading to discomfort or pain in the affected area.

• Myelofibrosis: Severe scarring of the bone marrow seen in PV progression, leading to a broad decrease in cell production (anemia, reduced white cells, and platelets). Up to 10% of PV patients may develop myelofibrosis, further increasing gout risk.

Deeper Insights:

• PV's impact on blood viscosity and cell proliferation poses significant risks, from increased clotting to organ strain.
• Distinct symptoms like erythromelalgia and itchy skin after exposure to warmth highlight the body's stressed state due to excessive cell counts.
• Conditions like gout and myelofibrosis underscore the systemic effects of PV, affecting everything from joint health to bone marrow function.
• Understanding these symptoms and complications is crucial for managing PV and mitigating its impacts on patient health.

Recognizing and Diagnosing Polycythemia Vera (PV)

Early Detection Challenges:

• Patients with Polycythemia Vera may not realize they have the disease due to intermittent or vague symptoms such as headaches, fever, itchy skin, or dizziness. Some may notice an abdominal bulge from splenomegaly.

Diagnostic Process:

• A Complete Blood Count (CBC) is crucial for diagnosing PV, revealing increased Red Blood Cell (RBC) mass—a key indicator of the condition.
  • For Men: A hemoglobin concentration above 16.5 g/dL, hematocrit over 50%, and an increased RBC count suggest PV.
  • For Women: Hemoglobin around 16g/dL and hematocrit about 48% could signal the disease.
• Ruling out secondary causes (e.g., dehydration) for increased blood counts is essential for a closer PV diagnosis. Abnormally high numbers, especially with symptoms, support the diagnosis, while borderline numbers require further investigation.

Advanced Testing for Confirmation:

• JAK2 Mutation Testing: Testing for mutations in the Janus Kinase 2 (JAK2) gene is a critical step. The common mutation "JAK2(V617F)" is found in most PV patients. Laboratories can also search for other mutations if JAK2(V617F) is not present.

• Erythropoietin (EPO) Levels: PV patients usually have very low EPO levels due to a feedback mechanism; abundant RBCs and oxygenation negate the need for more EPO production. High RBC/Hgb/Hct counts from other causes don't show this drastic EPO reduction. Testing EPO levels in conjunction with JAK2 mutations can confirm PV.

• Bone Marrow Biopsy: A definitive diagnosis may require a bone marrow biopsy or aspirate, often taken from the iliac crest. This procedure examines the marrow directly, typically revealing excessive RBC production.

Key Points:

• Initial symptoms of PV can be easily overlooked or misattributed, highlighting the importance of thorough medical evaluations for accurate diagnosis.
• The CBC plays a foundational role in signaling potential PV, with further tests like JAK2 mutation analysis and EPO level measurement providing critical confirmation.
• A bone marrow biopsy offers a direct look at marrow activity, confirming the excessive production of blood cells characteristic of PV.

Treatment of Polycythemia Vera

Understanding the Disease and Risks:

• Polycythemia Vera is an incurable blood cancer with treatments available to manage symptoms and improve outcomes.
• Life expectancy is generally optimistic, with many living over 20 years post-diagnosis, provided they adhere to their treatment plan.
• The primary risk for PV patients is clotting, with disease progression to conditions like myelofibrosis, Acute Myelogenous Leukemia (AML), or Myelodysplastic Syndrome (MDS) as secondary concerns.

Risk-Based Treatment Approach:

• Treatment varies based on factors like age, health, disease severity, and clotting history.
• Patients under 60 without clotting issues are considered lower risk compared to older patients or those with previous clotting events.

Key Treatment Methods:

• Therapeutic Phlebotomy:

  • Involves removing up to 500mL of blood to reduce blood viscosity and alleviate symptoms.
  • Frequency is initially high until hematocrit normalizes, then reduces based on individual needs.

• Aspirin Therapy:

  • Low-dose aspirin may be prescribed to lower clotting risk by inhibiting platelet function, suitable for low-risk patients without bleeding issues.

• Antihistamines:

  • Helps manage increased itchiness, especially following exposure to warm water.

• Hydroxyurea (HU):

  • A myelosuppressive drug for higher-risk patients, inhibiting DNA production in cells to reduce RBC and platelet counts.
  • While concerns exist regarding its link to leukemia progression, evidence suggests minimal risk.

• Ruxolitinib (Jakafi or Jakavi):

  • A JAK1 and JAK2 enzyme inhibitor, particularly useful for patients with JAK2 mutations leading to uncontrolled cell production.
  • Prescribed when Hydroxyurea is ineffective or unsuitable.

• Ropeginterferon Alfa-2b-njft (BESREMi):

  • An FDA-approved treatment since 2021, BESREMi modulates cell signaling to have anti-proliferative, immune-modulating, and pro-apoptotic effects.

CAR-T Therapy

CAR-T Therapy: From Concept to Clinical Application

The Genesis of CAR-T 

CAR-T, which stands for Chimeric Antigen Receptor T-cell therapy, represents a groundbreaking evolution in cancer treatment. Rooted in immunotherapy principles, CAR-T pivots on the idea of harnessing the body's immune system, specifically the T-cells, and re-engineering them to become adept fighters against cancer cells.

A Closer Look at T-cells and CAR 

T-cells are white blood cells and stalwarts of the adaptive immune system. Their primary function is to identify foreign threats and mount an immune response. However, cancer cells, due to their genetic similarity to normal cells, often manage to evade this detection.

The Chimeric Antigen Receptor (CAR) is a synthetic, bioengineered receptor. When introduced into T-cells, CAR provides them the ability to recognize specific antigens, predominantly present on the surface of cancer cells. This equips the T-cells with a targeting system, enabling them to locate and destroy cancer cells with heightened precision.

Apheresis: Harvesting the Fighters 

The journey of CAR-T therapy begins with the extraction of the patient's T-cells, a process known as apheresis:

• Mechanics of Apheresis: This procedure, while resembling standard blood donation, is more intricate. Blood is extracted and passed through a machine where white blood cells, specifically T-cells, are separated. The rest of the blood is then infused back into the patient.

• Duration and Output: Depending on the patient's health, T-cell count, and specific therapeutic protocol, apheresis can span several hours. The objective is to secure an optimal number of T-cells for the subsequent genetic modification.

Transition to Specialized Laboratories 

Post-apheresis, the extracted T-cells are primed for their transformative journey:

• Transport Dynamics: The viability of T-cells during transportation is paramount. Rigorous temperature controls, along with quick transportation methods, are employed to ensure the cells remain functional upon arrival at the labs.

• T-cell Modification: Within these state-of-the-art labs, the T-cells undergo genetic engineering. Using viral vectors or other methodologies, the CAR is integrated into the T-cells, enabling them to target specific cancer antigens.

• Culturing and Expansion: After successful genetic modification, these T-cells are cultured in specialized environments, promoting their growth and multiplication. This ensures a robust army of CAR-T cells for reinfusion into the patient.

Reintroduction and the Fight Within 

The genetically modified T-cells, now termed CAR-T cells, are ready for reintroduction:

• Preparing the Battlefield: Patients might undergo a 'lymphodepleting' chemotherapy regimen before CAR-T cell infusion. This creates a more favorable internal environment, enhancing the efficacy and proliferation of infused CAR-T cells.

• Reinfusion Dynamics: Administering the CAR-T cells is similar to a blood transfusion. Once inside, these engineered cells commence their mission, detecting, and decimating targeted cancer cells.

Navigating Challenges 

Despite its transformative potential, CAR-T therapy presents challenges:

• Safety and Side Effects: The introduction of engineered cells and their aggressive action can lead to severe reactions. Cytokine release syndrome (CRS), characterized by a sudden surge in inflammatory cytokines, can be life-threatening in certain cases. Neurological side effects are also documented.

• Complexity and Cost: The intricate multi-step process, from apheresis to genetic engineering in specialized labs, renders CAR-T therapy expensive. The complexity also demands an intricate logistical orchestration, from T-cell extraction to their reinfusion.

The Future of CAR-T 

 As CAR-T therapy garners more clinical experience, research aims to enhance its safety profile, expand its applicability, and optimize its cost structure. There's ongoing exploration into targeting solid tumors, minimizing side effects, and introducing modulatory mechanisms to control CAR-T cell activity.

Moreover, advancements in biotechnology, genetic engineering, and immunology promise to refine the CAR-T process further, presenting hope for a broader range of malignancies and more accessible therapeutic options for patients globally.

By intertwining the principles of immunology, the precision of genetic engineering, and the clinical rigor of processes like apheresis, CAR-T therapy epitomizes the vanguard of personalized medicine in oncology.

Can I Get an Infection From A Blood Transfusion?

In the realm of medical treatments, blood transfusions stand out as both indispensable and miraculous. They rejuvenate lives, ensuring that surgeries proceed, that trauma victims survive, and that patients with blood disorders thrive. Yet, with this life-saving potential comes the inherent question: Is there a risk of infection?

Historical Context of Transfusions

The landscape of blood transfusions, particularly in the early days, had its pitfalls. In earlier decades, before robust testing mechanisms were implemented, blood recipients faced higher risks. HIV, for example, was transmitted via transfusions in the early days of the AIDS epidemic. However, over time, the blood donation and transfusion field underwent transformative changes to drastically minimize these risks.

Initial Defenses: The Blood Donor Selection Process

Long before blood is drawn from a donor's arm, the process of ensuring its safety begins. Every donor undergoes a detailed interview and is required to answer a comprehensive questionnaire. This is meticulously designed to weed out potential risks based on travel history, medical background, and certain behavioral factors. This rigorous interview, while time-consuming, establishes the first line of defense against bloodborne pathogens.

Blood Testing: The Scientific Vanguard against Infections

The post-donation phase sees each unit of blood subjected to an exhaustive battery of tests:

HIV: Sensitive assays detect both the virus's antibodies and its RNA, ensuring that even recent infections don't slip through.

Hepatitis B & C: Both antibody and nucleic acid tests are deployed, offering dual layers of detection.

Syphilis: Regarded as an age-old enemy, modern treponemal tests detect this infection with impressive accuracy.

Other Threats: Whether it's West Nile virus, HTLV, or emerging concerns like Zika, blood banks remain vigilant, incorporating new tests as threats evolve.

Window Periods: A Persistent Challenge

Infections have a 'window period'—a timeframe post-infection when tests might not detect the pathogen. As testing becomes more advanced, these windows shrink, but they still pose a challenge that blood banks grapple with. The emphasis is on reducing this window as much as possible.

From Microbes to Prions: Broadening the Horizon

While viruses and bacteria are primary concerns, other potential threats, like prions (which cause conditions like Creutzfeldt-Jakob Disease), demand attention. The insidious nature of prions, their resistance to conventional sterilization techniques, and their long incubation period pose unique challenges, prompting continued research and surveillance.

Safety in Numbers: Quantifying the Risk

Statistics offer a clearer perspective:

• For HIV, the risk stands at roughly 1 in 1.5 million.
• Hepatitis B: About 1 in 280,000.
• Hepatitis C: Approximately 1 in 1 million.

It's crucial to understand that these figures, as low as they are, represent a worst-case scenario. Real-world risks are often even lower, thanks to multiple overlapping safety measures.

Global Collaboration: A United Front

Blood safety isn't an isolated endeavor. Blood banks, researchers, and policymakers worldwide collaborate, sharing data, strategies, and insights. This global network ensures that emerging threats are rapidly identified, and best practices are universally adopted.

Continuous Training: The Human Element

Behind every machine and every test are dedicated professionals. Their training isn't static. As technology evolves and new threats emerge, continuous education ensures that these professionals remain at the forefront of safety.

Ethical Considerations and Transparency

Blood banks prioritize not just physical safety but also ethical considerations. Donors are informed about the tests their blood undergoes and any resultant findings. This transparency fortifies the bond of trust between donors and blood banks.

Blood Products and Derivatives: Extended Safety

Beyond whole blood, various blood products (plasma, platelets, cryoprecipitate) are used in medicine. Each has its unique processing and testing protocols, but the emphasis on safety remains paramount across all products.

The Relentless Pursuit of Safety

In the vast medical tapestry, blood transfusions remain a beacon of both hope and safety. The multi-tiered safety nets, combined with unwavering dedication from professionals in the field, ensure that risks are minimized. While perfection might remain an aspirational goal, the blood transfusion community relentlessly marches towards it, ensuring that each unit transfused not only saves a life but also stands as a testament to rigorous safety and quality.