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A review of the current literature and future directions.

Long-Acting Anti-MRSA Agents: One Dose to Cure?

Along with a 1 reported case in Massachusetts, the

New Hampshire Department of Health and Human Services (DHHS) has confirmed a person infected with eastern equine encephalitis (EEE) has died. The public health agency said the person was hospitalized due to severe central nervous system disease. The last reported human EEEV infection in New Hampshire was in 2014, when DHHS identified 3 human infections, including 2 fatalities. In the same statement, DHHS mentions there has been 1 confirmed case in Vermont this summer.

On August 16, the Massachusetts Department of Public Health (MDPH) released a statement discussing the confirmation of the first human case of EEE in the state this year. The confirmed case was discovered in an 80 year old man who was exposed to the vector borne disease in Worcester County. As a result, the risk level in the local communities of Douglas, Oxford, Sutton, and Webster has been raised to critical, and in Dudley, Northbridge, and Uxbridge the risk is increased to high.

Additionally, the neighboring communities of Auburn, Charlton, Grafton, Leicester, Mendon, Millbury, Millville, Southbridge, and Upton are now considered at moderate risk according to MDPH.

“This is the first time we have seen a person infected with EEE in Massachusetts since 2020,” Public Health Commissioner Robbie Goldstein, MD, PhD, said in a statement. “EEE is a rare but serious disease and a public health concern. We want to remind residents of the need to protect themselves from mosquito bites, especially in areas of the state where we are seeing EEE activity.

Though very rare, EEE is serious and a potentially fatal disease that can affect people of all ages. EEE is generally spread to humans through the bite of an infected mosquito. There were 12 human cases of EEE in Massachusetts in 2019 with 6 deaths, and 5 human cases with 1 death in 2020. There were no human cases of EEE in Massachusetts in 2021, 2022, or 2023.

EEE has a fatality rate of 33% to 70%, with most deaths occurring 2–10 days after the onset of symptoms.

In addition to a high mortality rate, long-term physical and mental complications, including permanent neurological deficits have been identified in many people who survive EEE.

Plymouth is approximately 40 miles south of Boston along the coast, and Worcester County is in the middle of the state, so the 2 areas are not in close proximity, but due to the elevated risk locally, the town of Plymouth decided to take action in response to outdoor parks. As of last Friday, all town public parks and fields are close daily from dusk until dawn.

“As Mass DPH has now elevated Plymouth’s EEE risk status to high, it is important to take extra precautions when outdoors and follow state and local health guidelines to avoid unnecessary risk to exposure to EEE. The health and safety of our community, residents, and visitors remain our priority,” Plymouth’s Commissioner of Health and Human Services, Michelle Bratti, said in a statement.

According to the Centers for Disease Control and Prevention (CDC) most people who are infected with the virus do not develop symptoms; however, for those that do, the date from the bite to the onset of the illness is 4 to 10 days. EEE can also result in fever or neurologic disease. The type of illness will depend on the age of the person and other factors. Those who are infected can develop meningitis.

There are no FDA-approved treatments for EEE and for patients who develop severe cases, they can be hospitalized to receive supportive treatment.

Over the weekend, MDPH detailed plans of spraying for mosquitos including aerially in areas of Plymouth County, and truck-mounted spraying in parts of Worcester County. As of Saturday, 10 communities in Massachusetts were raised to high or critical risk for EEE virus.

“The risk from EEE is high in parts of Plymouth County and critical in parts of Worcester County,” State Epidemiologist Catherine M. Brown, DVM, said in a statement. “In addition to recommending that people use mosquito repellent with an EPA-registered active ingredient and clothing to reduce exposed skin, we also recommend that evening outdoor events be rescheduled to avoid the hours between dusk and dawn. The mosquitoes most likely to spread EEE are most active during the dusk to dawn hours.”

There are preventative strategies to avoid EEE, and the MDPH has listed such measures 

For those who live in Massachusetts and want more information on EEE, it can be found 

 or by calling the DPH Division of Epidemiology at 617-983-6800.

1.NH DHHS Identifies Person Infected with Eastern Equine Encephalitis Virus in New Hampshire.The New Hampshire Department of Health and Human Services. August 27, 2024. Accessed August 28, 2024.
https://www.dhhs.nh.gov/news-and-media/nh-dhhs-identifies-person-infected-eastern-equine-encephalitis-virus-new-hampshire
2. State health officials announce season’s first human case of Eastern Equine Encephalitis in Massachusetts. MDPH. August 16, 2024. Accessed August 27, 2024.
https://www.mass.gov/news/state-health-officials-announce-seasons-first-human-case-of-eastern-equine-encephalitis-in-massachusetts
3.Plymouth to Close all Public Parks and Fields from Dusk to Dawn. Town of Plymouth. August 23, 2024. Accessed August 27, 2024. PDF.
4. Eastern Equine Encephalitis: Symptoms, Diagnosis, and Treatment. CDC. May 15, 2024. Accessed August 27, 2024.
https://www.cdc.gov/eastern-equine-encephalitis/symptoms-diagnosis-treatment/index.html
5. State officials announce plans to spray for mosquitoes in sections of Worcester and Plymouth counties due to EEE. MDPH. August 24, 2024. Accessed August 27, 2024. 
https://www.mass.gov/news/state-officials-announce-plans-to-spray-for-mosquitoes-in-sections-of-worcester-and-plymouth-counties-due-to-eee



The town of Plymouth decided to prohibit people from using the parks from dusk to dawn due to concerns over eastern equine encephalitis after a man contracted the rare disease in the state.

Concerns Over Mosquito-Borne Illness Causes Massachusetts Town to Create Curfew for Parks, Spraying in Counties

With melting ice and the release of ancient pathogens, there are concerns around the emergence of potentially unknown infectious diseases

Will the Melting Permafrost Uncover Vector Borne and Zoonotic Pathogens and Release Ancient Infectious Diseases? 

For years, increased temperatures have been leading to climate change and concerns around rising ocean temperatures and glaciers melting and creating sea rise. Another less discussed climate concern has been the melting permafrost on land and the potential release of zoonotic and vector borne pathogens into the environment.

There are unique discoveries of extinct animals and other organisms from thousands of years ago being made today in the Arctic. In 2020, for example, investigators in Siberia stumbled upon a saber tooth cub, which they estimated to be 32,000 years old, was uncovered and it remained intact.

Additionally, in Siberia, researchers uncovered what has been referred to as “zombie viruses.” 

“We report the preliminary characterizations of 13 new viruses isolated from 7 different ancient Siberian permafrost samples, 1 from the Lena river and 1 from Kamchatka cryosol. As expected from the host specificity imposed by our protocol, these viruses belong to 5 different clades infecting 

. but not previously revived from permafrost: Pandoravirus, Cedratvirus, Megavirus, and Pacmanvirus, in addition to a new Pithovirus strain, which are characterized as viruses that have inactive for thousands of years,” investigators reported.

“There's certainly been a lot of interest in recent times, and a lot of publicity around things like zombie viruses. So there's no easy answer to that. I think to start with, there are people giving this quite a lot of attention right now, certainly in the scientific world, also in the risk assessment world, and that includes things like national security,” said Emily Jenkins PhD, DVM, BScHon, professor and graduate chair, Department of Veterinary Microbiology, and head of the Zoonotic Parasite Research Unit at the Western College of Veterinary Medicine at the University of Saskatchewan, Saskatoon, Canada. “What we can say is that there's not a whole lot of evidence of spontaneous reemergence from the tundra right now.”

She does say the potential jump of these ancient viruses into humans and animals is still a very difficult transmission, especially as these pathogens may not survive.

“There was a nematode resuscitated from permafrost and was alive, a 40,000 year old roundworm. One thing to think about is that free living organisms are designed to survive more in the environment than pathogens,” Jenkins said. “Like the roundworms, are those so called zombie viruses. They're actually not pathogens of people or even animals.They're either free living or the viruses in particular, were actually viruses of amoeba. So it is quite a big stretch to jump from those things surviving to pathogens. The risk is not zero, but it's low probability.”

Polar Bears: The Proverbial Canary in the Coal Mine?

Jenkins has been studying organisms and animals in the melting permafrost and says there is evidence that can be gleaned from work with polar bears.

“We had this treasure trove of archived polar bear serum that stretched from the 80s, 90s, to the 2010s," Jenkins said. “We were able to take that set of sera and test it for exposure to a whole range of pathogens, including toxoplasma. We showed that over those decades, the amount of polar bears getting exposed was higher and higher—probably as a result of them losing sea ice, spending more time on land, and being more exposed to terrestrial pathogens.”

However, although nothing of concern has arisen from this in terms of older pathogens, she points to climate change issues affecting the Arctic, and the emergence of the modern-day vector borne viruses that could be a greater concern. 

“One of the groups of pathogens we know are going to change with climate change is vectors and vector borne diseases. Some of the work that we did on those polar bear blood samples showed that they were increasingly exposed to these vector borne or mosquito borne diseases as they spent more time on land,” Jenkins said. “And interestingly, the female polar bears, when they're pregnant, they spend 8 months on land, vs the males, who only spend 3 months on land. So the females were way more exposed to these vector borne viruses. And when we started looking across the North American Arctic, from Alaska to Greenland, sure enough, these particular vector borne viruses, which people don't think of the Arctic as this hotbed of vector borne disease, but they were present in mosquitoes all the way from Alaska to Greenland. So that's another significant potential outcome of climate change: increased numbers of vectors that develop and more rapid development of both the vectors and the viruses.”

Jenkins spoke at the recent IDWeek on this topic and says the environment is the biggest driver of changes and influences humans, animals, and pathogens.

"So recognizing that the drivers are much bigger than us and our animals and wildlife is, I think, the message of One Health—which is that we're all in this together. Environment is driving massive changes, and we have some tools in our toolkit that we didn't used to have, in terms of surveillance and interventions. So I'm hopeful that One Health offers not the magic solution, but a solution to some of these really increasingly pressing challenges, especially as we see the climate change crisis and human health and socioeconomic crises all coming together globally.

1.Black R. The world’s first saber-toothed cat mummy has been found in Siberia. 

 November 19, 2024. Accessed November 28, 2024.
https://www.nationalgeographic.com/science/article/sabertooth-cat-mummy-first-cub.
2.Alempic JM, et al. An update on eukaryotic viruses revived from ancient permafrost. Biorxiv. February 2, 2023. Accessed November 28, 2024.
https://www.biorxiv.org/content/10.1101/2022.11.10.515937v2
3.Jenkins E.A One Health understanding of shifting zoonoses in the Arctic. Presented at IDWeek 2024. October 16-19, 2024. Los Angeles, CA.

With melting ice and the release of ancient viruses, there are concerns around the emergence of potentially unknown infectious diseases. Emily Jenkins PhD, DVM, BScHon, offers insights on “zombie viruses” and says polar bears might hold the key to understanding what lies ahead, and how a One Health approach may help in surveillance and prevention.

Bruce Jones, PharmD, FIDSA, BCPS offered clinical considerations for the concerns around infective endocarditis and when choosing empiric therapy.

Treatment Considerations for Empiric Therapy

 bacteremia remains a serious infection that can lead to infective endocarditis, and a higher mortality rate. With this in mind, what do you want to consider in treatment options?

, I think of a pathogen with metastatic tendencies; it often spreads to distant sites and tends to form abscesses. For us, we used to assume MRSA until proven otherwise if 

 was in our differential. Around 2015, things changed with the introduction of multiplex PCR—specifically Biofire at our institution—which was a game-changer for managing bacteremia. This tool allows us to quickly identify MRSA versus MSSA, and even detect 

 itself very early on, which helps guide treatment decisions upfront.

Another key point I emphasize is beginning with the end in mind, particularly regarding OPAT. Many of these patients will need 4 to 6 weeks of treatment, so from a discharge and OPAT perspective, it's crucial to make these decisions early, ideally well before discharge. Often, we tend to wait until the last moment, but it’s better to evaluate these factors early in the admission.

What are your clinical considerations when choosing an empiric therapy for these patients?

 Clinical stability is our top priority. For a very sick patient in the ICU on multiple pressors, we approach aggressively upfront, as 

 infections carry a high mortality rate. Our goal is to get the infection under control as quickly as possible.

We also consider the suspected source of the infection. For example, when MRSA is suspected, if it's a respiratory source, we might avoid using daptomycin. Comorbidities play a big role as well; renal function is one of the first things we assess, especially when considering vancomycin in patients with acute kidney injury or chronic kidney disease.

Once we know whether it's MSSA or MRSA—thanks to rapid diagnostics—we tailor treatment accordingly. For MSSA, cefazolin or an antistaphylococcal penicillin is our go-to. For MRSA, we often consider vancomycin or daptomycin, though we've used less vancomycin in the past year or two and more daptomycin instead. While our use of linezolid has been slower to increase, it's still an option. We're also starting to see some off-label use of ceftaroline, and with the release of septiviprol, we’ll soon have another tool in our toolkit.

The conversation was edited for grammar and clarity.

Combining over 1,000 human antibodies, GIGA-2339 aims to achieve viral clearance and activate the immune system, offering a potential solution where current therapies fall short of providing a cure.

GigaGen Doses First Patient in Phase 1 Trial of GIGA-2339, a Potential Functional Cure for Chronic Hepatitis B

GigaGen Inc has announced the dosing of its first patient in a Phase 1 clinical trial investigating GIGA-2339, a recombinant polyclonal antibody for the treatment of chronic 

 B virus (HBV) infection. The trial will assess the safety and tolerability of the drug, which holds a potential functional cure for chronic HBV.

Current treatments for chronic HBV can suppress viral replication but do not offer a cure. It remains a global health threat, affecting over 296 million people worldwide and causing more than 800,000 deaths each year. GIGA-2339 is designed to target the Hepatitis B surface antigen (HBsAg), a key protein that facilitates viral replication, potentially allowing for viral clearance and long-term immune system activation.

Developed using GigaGen’s innovative recombinant polyclonal antibody platform, GIGA-2339 combines over 1,000 fully human antibodies targeting HBV, providing a highly potent and diverse treatment option. The drug is over 2,000 times more potent than existing therapies and aims to tackle a broad range of circulating HBV variants, including potential escape mutations.

In an exclusive interview, Carter Keller, senior vice president at Grifols and Head of GigaGen, shared his excitement about the trial's launch and the drug’s potential to address the challenges of chronic HBV.

“We’re really excited. We just announced that we’ve dosed our first patient in our Hepatitis B trial,” Keller said. “The Hepatitis B trial is for a product called GIGA-2339. This is a mixture of thousands of different antibodies made recombinantly. They’re human antibodies, all targeted towards the Hepatitis B surface antigen, and it really represents a new way to treat the disease. We’re really excited to see how it performs in the clinic.”

GIGA-2339 is unique in that it uses a polyclonal approach, meaning it includes multiple antibodies that target different parts of the virus. Keller explained how this could offer advantages over existing therapies.

“We have a unique platform that allows us to take the best human immune systems, extract the genetic components of those immune systems, and recombinantly reproduce them,” he said. “We can then select the antibodies that are directed towards the virus or viral target we’re interested in. This is a very unique way to treat disease, nobody’s ever done it like this before.”

The approach allows for a diverse and multifaceted immune response. “The fact that we have thousands of different antibodies against Hepatitis B antigens means we can target multiple epitopes of the HBV. By coating the surface of the virus and viral particles, we can mount a highly efficient immune response to clear the virus,” Keller added.

Moreover, this diversity of antibodies allows GIGA-2339 to target all HBV genotypes and tackle potential escape mutations that can arise during treatment. “Having thousands of antibodies against different epitopes allows us to target all genotypes of the virus. This means we won't miss patients with different or diverse genotypes. It also helps us address any potential escape mutations that might arise during treatment.”

Focus on Safety and Efficacy in Phase 1 Trial

The Phase 1 clinical trial is primarily focused on determining the safety and tolerability of GIGA-2339 in individuals with chronic HBV who have not responded to previous nucleoside analog therapy. Keller explained that this study differs from typical Phase 1 trials, which are often conducted in healthy volunteers.

“We’re definitely interested in determining what dose is safe and tolerable for different patients. But many safety and tolerability studies are conducted in healthy volunteers. In contrast, this Phase 1 study is being done in individuals with chronic HBV. This gives us an opportunity to find a safe dose that also optimally depletes the Hepatitis B surface antigen in these patients,” Keller noted.

The goal of the trial is to find the optimal dose that can effectively reduce the levels of HBsAg, which could lead to better outcomes in later trials. “Finding the dose that optimally depletes the surface antigen will allow us to move into Phase Two clinical trials, where we can expand the patient population at that dose and better assess the drug’s efficacy in a statistically significant way,” he said.

The Path Toward a Functional Cure for HBV

A key objective for GigaGen is to explore the possibility of a functional cure for HBV. Keller explained that GIGA-2339 could offer something beyond just viral suppression.

“We have a hypothesis that if we can downregulate the Hepatitis B surface antigen, an antigen that’s known to suppress the immune system, we might be able to not only clear the virus but also reactivate the immune system,” Keller explained. “This could potentially lead to what we call a functional cure. We’re very interested to see how this plays out in our clinical trial.”

By reducing HBsAg levels, the drug could help restore the body's natural immune response to the virus, which may lead to a sustained immune-mediated clearance of the infection. Keller referred to this as a “virtuous cycle”: “There’s this kind of 'virtuous cycle' where we efficiently deplete the virus, reactivate the immune system, and then the immune system helps to clear the virus.”

Keller highlighted the importance of this innovation in the context of HBV treatment and beyond. “Our platform allows us to create these incredibly diverse therapies. It’s the only platform that can do this at scale while maintaining manufacturing consistency. This gives us the ability to treat as many patients as needed,” Keller said.

As GigaGen’s clinical trials progress, the company remains hopeful that GIGA-2339 will offer a novel solution to the millions living with chronic HBV. With its unique combination of potent, broad-acting antibodies and a potential to reactivate the immune system, GIGA-2339 could play a key role in advancing the treatment landscape for chronic hepatitis B.

“We’re really excited to see where this takes us. If we’re successful in targeting the surface antigen and reactivating the immune system, we could see significant improvements for people living with chronic HBV,” Keller concluded.

Watch our previous interview with Keller to gain additional background and insights into the developments that led to this milestone: 

HBV Antibody GIGA-2339 Cleared for Clinical Trials to Address Hepatitis B Cure Gap

GigaGen Doses First Patient in Phase 1 Trial of Recombinant Polyclonal Drug Candidate, GIGA-2339, for Hepatitis B Virus. 

 November 19, 2024. Accessed November 25, 2024. 

https://www.globenewswire.com/news-release/2024/11/19/2983574/0/en/GigaGen-Doses-First-Patient-in-Phase-1-Trial-of-Recombinant-Polyclonal-Drug-Candidate-GIGA-2339-for-Hepatitis-B-Virus.html

Daniel B. Chastain, PharmD, BCIDP, AAHIVP, FIDSA, reviews the data of this class of therapies and how it may be clinically beneficial.  

Considering a Beta Lactam as Adjunctive Therapy for Staphylococcus aureus Early in Treatment 

It has been documented that the incidence rates for 

 bacteremia (SAB) ranges from 20 to 50 cases/100,000 population per year, and the mortality rates are between 10% and 30%.

According to one study, this accounts for a greater number of deaths than for several other infectious diseases including AIDS, tuberculosis, and viral hepatitis combined.

This infection can be particularly challenging on seniors as age is the largest factor for mortality with older patients more than twice as likely to expire from SAB.

“One of the things that I've always heard and always been taught is respect 

 bacteremia, in that it's always challenging, and it's certainly a difficult process [treating it], said Daniel B. Chastain, PharmD, BCIDP, AAHIVP, FIDSA clinical associate professor University of Georgia College of Pharmacy.

 can also be heterogenous in presentation and lead to patient management issues. 

Chastain reviewed the literature looking at the use of beta-lactams as adjunctive therapy for 

, and presented his findings at IDWeek last month.

One of the novel approaches is to consider prescribing combination therapy earlier in the treatment cycle.

“Given the presentation, given the severity of the illness, why not add combination therapy up front? Once you have a blood culture that has staphylococcus species before you know that it's MSSA or MRSA, there are certainly some older data that supports a beta-lactams from start to finish, having improved outcomes compared to deescalating from vancomycin to a beta-lactam,” Chastain said. “So if we could start with vancomycin, adaptomycin, in addition to either a cefazolin or an antistaphylococci penicillin, perhaps we're able to better impact that patient's care up front and maybe decrease the risk of complicated 

He sees another potential benefit in risk stratification looking at patient presentation, which may help identify who would be a better candidate for combination therapy. Chastain notes there does not appear to be a reduction in mortality in the literature. “Most of them don't result in mortality benefit, which is really interesting, despite improvements in time to blood culture sterilization or decreased risk of recurrence or persistent 

“I think the lack of mortality benefit is largely from the fact that most of our clinical trials that we have now include a wide variety of patients with diverse sources. So some may have catheter-related infections; whereas others may have bone or joint involvement. Some may have endovascular [infections], so if we're able to better risk stratify, perhaps upfront, through biomarkers or certain sub phenotypes, then perhaps, maybe we can better affect their care overall, and actually figure out who could benefit from that combination therapy.”

He does believe in exercising caution when considering adjunctive therapy.

“I think that of the data that we have, early combination therapy for patients that are at high risk for poor outcomes, so high risk for complicated 

bacteremia or high risk for mortality, will hopefully certainly improve patient outcomes,” Chastain said. “And then the only thing I would add is that there are some door framework and radar analysis that have been done to suggest that perhaps patients don't always have the greatest experience with combination therapy. So, I think it's important that we balance being a little bit more aggressive with treatment as well as what the patient experiences, and taking that whole entire process into account as we try to treat these patients.”

1.van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. 

. 2012;25(2):362-386. doi:10.1128/CMR.05022-11
2. Chastain D. Beta-Lactam Adjunctive Therapy for Difficult 

 Infections. Presented at IDWeek 2024. October 16-19, 2024. Los Angeles, CA.

This bacteremia can present heterogeneously and be difficult to contain, especially in an older patient population. Daniel B. Chastain, PharmD, BCIDP, AAHIVP, FIDSA, reviews the data of this class of therapies and how it may be clinically beneficial in combination with other antimicrobials.

The Centers for Disease Control and Prevention’s (CDC) issued a Health Alert Network (HAN) Health Advisory to information the public that a case of clade I mpox was confirmed by the California Department of Public Health (CDPH) on November 15. This is the first case in the United States. The person had traveled to areas where clade I transmission has been ongoing.

In terms of the person’s condition, the individual is receiving care in the US and is isolating from others. The patient, who has no underlying health conditions, has not had any severe manifestations of disease, and symptoms are improving, according to the CDC’s statement. The federal agency said it is working closely with the local and state health authorities to investigate the circumstances surrounding this case and to prevent spread of the virus. As of November 18, no additional clade I mpox cases have been reported in the country.1

Distinguishing Between Clade I and Clade II


According to the CDC, mpox has 2 distinct genetic clades: clade I (with subclades Ia and Ib), which has been endemic to some countries in Central Africa, and clade II (with subclades IIa and IIb) is historically endemic to some countries in West Africa.

Clade I mpox has previously been observed to be more transmissible and to cause a higher proportion of severe infections than clade II MPXV.

 Carlos del Rio, MD, FIDSA, executive associate dean, Emory School of Medicine & Grady Health System, distinguished professor, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, discussed the differences between the 2 clades. 

"The current mpox clade I outbreak in the DRC has already infected over 14,000 persons (mostly women and children under 15) and has caused over 500 deaths. The outbreak has now spread to other countries in Africa and there is the possibility of spread beyond the continent," said del Rio. "Clade I is more virulent and has a higher mortality than clade II (which caused the 2022 outbreak mostly among MSM [men who have sex with men]). The available 

 is effective in the prevention of mpox clade I but the challenge is not having enough vaccine available in countries that need it most."

There have been outbreaks of clade II in the US, as previously reported by 

From January 1 through November 15, 2024, about 

2,000 confirmed cases of clade I mpox and at least 47 deaths have been reported in Central and Eastern African countries. These countries include Burundi, Central African Republic, Democratic Republic of the Congo, Republic of the Congo, Rwanda, and Uganda. Data from affected countries indicate that a large proportion of clade I mpox cases among adults were associated with heterosexual contact. Transmission to close contacts within households, including to children, also has been reported.

Back in August, the Africa Centers for Disease Control and Prevention (Africa CDC) has officially declared the ongoing mpox outbreak a Public Health Emergency of Continental Security (PHECS)—the first such declaration by the agency since its inception in 2017.

The person had recently traveled to areas experiencing clade I mpox virus  transmission and sought medical care for mpox symptoms in the United States.  

MICHAEL KENT, PHARMD

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