Tag: 10/2/23

Categories : HospitalsTags : Leave a comment

Charlotte Maxeke Repairs Make Progress, but Doubts Remain

On By ModernMedia
A fire broke out on 16 April 2021 at Charlotte Maxeke Hospital in Johannesburg. Credit: Gauteng Health

By Ufrieda Ho for Spotlight

2023 is the crunch year to complete the restoration of the fire-damaged sections of Charlotte Maxeke Johannesburg Academic Hospital, but one month in, it has not been plain sailing.

There are doubts over timeframes, the quality of workmanship, compliance, and effective project management. Added to this are deepening concerns that theft and suspected sabotage continue and that HR red tape and inefficiencies are standing in the way of getting the right people into 774 vacant posts that need to be filled to meet the high demand for healthcare services.

According to Gauteng Department of Health’s head of communication, Motalatale Modiba, the province is on track to meet its December 2023 deadline to complete repair work. There is a separate deadline for 2026 to complete fire safety compliance throughout the hospital.

Scramble for parking persists

January kicked off with what should have been the reopening of parking bays on the hospital campus. The parking levels were among the worst affected areas in the fire that broke out on 16 April 2021. Delays in getting parking areas reopened have had dire knock-on effects on the efficient running of the hospital. Staff and visitors have had to scramble to find parking on the streets around the hospital. This adds to traffic congestion and jammed-up appointment schedules even as the hospital is trying to play catch-up after healthcare services were disrupted by COVID and the fire. Added to this, there have been reports of theft from motor vehicles as well as muggings and assaults of doctors and nurses having to make their way to and from their cars.

Before the fire, the hospital had 1700 parking bays. Since the fire, only 229 have been accessible on the hospital campus and another 400 in sites around the hospital – it’s a shortfall of about 1000 parking bays.

Modiba told Spotlight at the beginning of February, “The construction of the temporary access ramp to level P3 is 100% complete. The only outstanding thing is the enrolment of the traffic management system to ensure a greater flow of vehicles into the parking, manage different parking zones, and vehicle access. The P3 parking bays will be available for usage soon.”

‘Criminal syndicates’

But DA spokesperson for health in the province, Jack Bloom says after his own site visit in January that continued delays to reopen this section is “gross incompetence that is causing misery as staff and patients hunt for parking every day and some sick people have to walk a long way from where they’ve found parking”.

“It’s not a great start for the year,” says Bloom. He says delays are being made worse by the higher stages of rolling blackouts that have hit the country, even though the hospital campus is exempt from loadshedding.

“Another issue is that we still haven’t been able to crack down on criminal syndicates operating at our hospitals. I believe what we’re seeing in the media now is only skimming the surface of widespread corruption in the system,” he says.

Insiders at Charlotte Maxeke have again raised alarms over ongoing theft that they say smacks of sabotage. According to them, the current situation is that cables and piping that run in-between hospital floors have been stolen or destroyed, resulting in disrupted oxygen flow that is fed to wards in Block 5 of the hospital. Block 5, houses, among others, the transplant unit.

Last year, the National Department of Health confirmed to Spotlight that vandalism and theft were rife. Investigations resulted in three officials in the Department of Infrastructure and Development being arrested in connection with these crimes.

Modiba did not respond to follow-up questions on how theft, vandalism, and sabotage are being dealt with by the provincial health department.

Repair work “on track”

Still, Modiba insists that the province is on track to meet both its 2023 and 2026 deadlines. Modiba however, also didn’t respond to a follow-up question on what compliance protocols will be followed in the three-year gap till fire safety compliance is expected to be completed.

It was fire safety compliance being flouted (including non-functioning fire doors, hose couplings that were stolen or broken, and no floor plan available for firefighters when they arrived on site) that led to the April 21 fire spreading and causing the extensive damage it did.

The repair bill now carries a price tag of R1.16 billion. According to Modiba, just over a billion of this will come from National Treasury, with around R146 million from donors making up the remainder.

The restoration work plan has also had to be adjusted in the past few months. An initial approach to work on fire compliance in multiple hospital blocks at a time was rejected by clinicians because it would be too disruptive for patient care.

“Decanting will now happen on a block-by-block basis with compliance work estimated to be between six to eight months per block. Services will keep rotating within the facility while contractors work from one area to another,” Modiba says.

He also tells Spotlight that the emergency unit which only reopened in May last year – and at the time only for referral patients – is now fully functioning. “All specialities are now present at the facility; there are no longer services that are being remotely rendered at other facilities,” he adds.

Modiba says that the hospital currently runs 1024 beds compared to the pre-fire status of 1138 beds. This comprises 1068 public beds and 70 Folateng beds. Folateng is the private ward within the hospital. There are 108 ICU and high-care beds and between 60 000 and 70 000 outpatients per month.

Meeting demands amid HR issues

Professor Adam Mahomed, head of the Department of Internal Medicine at the hospital, says meeting these massive demands when whole units and blocks have been out of commission has been a feat of adapting by doctors and nurses who have optimised ward space and found ways to repurpose parts of the hospital.

“Wards that used to fit 20 to 24 beds, we now have turned into wards that fit 32 beds,” he says.

Mahomed says it’s not optimal and amounts to trying to function in an overburdened state, especially with gross staff shortages. He says they expect the healthcare need to increase from the current numbers to having to run 1 400 beds in the hospital.

“We are seeing more people and sicker people coming through the doors because, during the COVID years, many people were not coming for healthcare or taking their chronic meds. We are also still playing catch up in oncology and surgery.”

Mahomed singles out inefficiencies in the hospital’s human resources department as the biggest stumbling block. He is calling for an independent audit and investigation into how human resources at Charlotte Maxeke is being run.

According to him, there are mounting questions around irregularities of why positions are not being filled timeously, or seemingly deliberately delayed and not just as a tactic to wait for budgets to refresh with the new financial year in April.

Some examples of “silly paperwork”, he says, are sessional doctors who have worked in the public sector previously being asked to produce matric certificates from 40 years ago. Other doctors have been asked to produce police clearance certificates, while others are asked to have proof of citizenship issued by the Department of Home Affairs.

According to Modiba, Charlotte Maxeke Hospital has 5334 approved posts and 774 vacancies currently. Of the 774 vacant positions, 253 vacancies are in administration and support, 40 for allied workers, 124 in medical, and 357 in nursing.

Mahomed says, “We need to have staff that will be able to accommodate 1400 beds and we need to have increased resources allocated for a hospital that is already over-burdened. We need to get HR to stop with the red tape, silly paperwork, and bureaucracies. “Bureaucracy is hampering us from getting actual resources to the people – HR bureaucracy is killing people. Politicians and management are still running healthcare when they should be taking input from those who are on the ground.”

Republished from Spotlight under a Creative Commons 4.0 Licence.

Source: Spotlight

Categories : GeneticsTags : Leave a comment

DNA Analysis can Cut Adverse Drug Reactions by 30%

On By ModernMedia
Genetics
Image source: Pixabay

Patients can experience 30% fewer serious adverse reactions if their drugs are tailored to their genes, reports a study published in The Lancet. A European collaboration involving researchers from Karolinska Institutet suggests that a genetic analysis prior to drug therapy could significantly reduce suffering and healthcare costs.

 A significant proportion of patients experience adverse reactions to their medication. Since we each carry a unique set of genes, we react differently to the same drugs. For example, some people break them down faster, meaning that they require a higher dose to obtain the desired effect.  

DNA pass that fits in the wallet

To overcome this problem, researchers from Leiden University Medical Center in the Netherlands, Karolinska Institutet and other collaborating institutions have developed the principle for a “DNA pass” that has been clinically validated in the recently published study.

“It’s basically a credit card-sized card with a magnetic strip containing all the important genetic data on a particular patient,” explains one of the study’s co-authors Magnus Ingelman-Sundberg, professor of molecular toxicology at the Department of Physiology and Pharmacology at Karolinska Institutet. 

“When a patient’s card is scanned, doctors and pharmacists can work out the optimal dose of a drug for that particular individual.”

The study included almost 7 000 patients from seven European countries between March 2017 and June 2020 all of whom were genotyped with respect to variations in twelve specific genes of significance to drug metabolism, transport and side-effects. All participants then received their drugs either conventionally or with a genotype-based modification.

Twelve weeks after their drug regimen began, the patients were contacted by a specialist nurse about any adverse reactions, such as diarrhoea, pain or loss of taste. The study concluded that such adverse reactions to drugs can be greatly reduced by analysing the genes that code for enzymes that metabolise them.

“The patients who’d received genotype-driven treatment had, on average, 30 per cent fewer adverse reactions than the controls,” says Professor Ingelman-Sundberg.  

Now sufficiently compelling data

Professor Ingelman-Sundberg, a long-standing expert at the European Medical Agency on the development of this method, believes that there is now sufficiently compelling data to warrant the widespread use of the DNA pass.

“I think we’ve come to the point where a genetic pass like this will be useful,” he says. 

Globally, the problem of adverse reactions is considerable. In the EU, they cause up to 128 000 fatalities a year and up to 9% of all hospital admissions, a figure that more than doubles to 20% in over 70s.

“Our results strongly suggest that an initial genotyping of the patients will deliver significant savings to society,” says Professor Ingelman-Sundberg. “The genotyping itself need only be done once per patient at a maximum cost of 6,000 SEK. The general introduction of this predictive system could therefore go a long way towards reducing public healthcare costs.”

Source: Karolinska Institutet

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ChatGPT can Now (Almost) Pass the US Medical Licensing Exam

On By ModernMedia
Photo by Maximalfocus on Unsplash

ChatGPT can score at or around the approximately 60% pass mark for the United States Medical Licensing Exam (USMLE), with responses that make coherent, internal sense and contain frequent insights, according to a study published in PLOS Digital Health by Tiffany Kung, Victor Tseng, and colleagues at AnsibleHealth.

ChatGPT is a new artificial intelligence (AI) system, known as a large language model (LLM), designed to generate human-like writing by predicting upcoming word sequences. Unlike most chatbots, ChatGPT cannot search the internet. Instead, it generates text using word relationships predicted by its internal processes.

Kung and colleagues tested ChatGPT’s performance on the USMLE, a highly standardised and regulated series of three exams (Steps 1, 2CK, and 3) required for medical licensure in the United States. Taken by medical students and physicians-in-training, the USMLE assesses knowledge spanning most medical disciplines, ranging from biochemistry, to diagnostic reasoning, to bioethics.

After screening to remove image-based questions, the authors tested the software on 350 of the 376 public questions available from the June 2022 USMLE release. 

After indeterminate responses were removed, ChatGPT scored between 52.4% and 75.0% across the three USMLE exams. The passing threshold each year is approximately 60%. ChatGPT also demonstrated 94.6% concordance across all its responses and produced at least one significant insight (something that was new, non-obvious, and clinically valid) for 88.9% of its responses. Notably, ChatGPT exceeded the performance of PubMedGPT, a counterpart model trained exclusively on biomedical domain literature, which scored 50.8% on an older dataset of USMLE-style questions.

While the relatively small input size restricted the depth and range of analyses, the authors note their findings provide a glimpse of ChatGPT’s potential to enhance medical education, and eventually, clinical practice. For example, they add, clinicians at AnsibleHealth already use ChatGPT to rewrite jargon-heavy reports for easier patient comprehension.

“Reaching the passing score for this notoriously difficult expert exam, and doing so without any human reinforcement, marks a notable milestone in clinical AI maturation,” say the authors.

Author Dr Tiffany Kung added that ChatGPT’s role in this research went beyond being the study subject: “ChatGPT contributed substantially to the writing of [our] manuscript… We interacted with ChatGPT much like a colleague, asking it to synthesise, simplify, and offer counterpoints to drafts in progress…All of the co-authors valued ChatGPT’s input.”

Source: EurekAlert!

Categories : Cancer VaccinesTags : Leave a comment

Transforming the Way Cancer Vaccines are Designed and Made

On By ModernMedia
Photo by Louise Reed on Unsplash

A new way to significantly increase the potency of almost any vaccine has been developed by researchers from the International Institute for Nanotechnology (IIN) at Northwestern University, which they describe in Nature.

The scientists used chemistry and nanotechnology to change the structural location of adjuvants and antigens on and within a nanoscale vaccine, greatly increasing vaccine performance. The antigen targets the immune system, and the adjuvant is a stimulator that increases the effectiveness of the antigen. 

“The work shows that vaccine structure and not just the components is a critical factor in determining vaccine efficacy,” said lead investigator Chad A. Mirkin, director of the IIN. “Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognises and processes it.”

This new heightened emphasis on structure has the potential to improve the effectiveness of conventional cancer vaccines, which historically have not worked well, Mirkin said. 

Mirkin’s team has studied the effect of vaccine structure in the context of seven different types of cancer to date, including triple-negative breast cancer, papillomavirus-induced cervical cancer, melanoma, colon cancer and prostate cancer to determine the most effective architecture to treat each disease.   

Conventional vaccines take a blender approach   

With most conventional vaccines, the antigen and the adjuvant are simply blended and injected into a patient, giving no control over the vaccine structure, and, consequently, limited control over trafficking and processing of the vaccine components. Thus, there is no control over how well the vaccine works.  

“A challenge with conventional vaccines is that out of that blended mish mosh, an immune cell might pick up 50 antigens and one adjuvant or one antigen and 50 adjuvants,” said study author and former Northwestern postdoctoral associate Michelle Teplensky, who is now an assistant professor at Boston University. “But there must be an optimum ratio of each that would maximise the vaccine’s effectiveness.” 

Enter SNAs (spherical nucleic acids), which are the structural platform, invented and developed by Mirkin, used in this new class of modular vaccines. SNAs allow scientists to pinpoint exactly how many antigens and adjuvants are being delivered to cells. SNAs also enable scientists to tailor how these vaccine components are presented, and the rate at which they are processed. Such structural considerations, which greatly impact vaccine effectiveness, are largely ignored in conventional approaches.  

Vaccines developed through ‘rational vaccinology’ offer precise dosing for maximum effectiveness

Mirkin came up with this approach to systematically control antigen and adjuvant locations within modular vaccine architectures, and called it ‘rational vaccinology’. It is based on the concept that the structural presentation of vaccine components matters as much as the components themselves in driving efficacy.   

“Vaccines developed through rational vaccinology deliver the precise dose of antigen and adjuvant to every immune cell, so they are all equally primed to attack cancer cells,” said Mirkin. “If your immune cells are soldiers, a traditional vaccine leaves some unarmed; our vaccine arms them all with a powerful weapon with which to kill cancer. Which immune cell ‘soldiers’ do you want to attack your cancer cells?”

Building an (even) better vaccine  

The team developed a cancer vaccine that reduced tumour growth by more than four times compared to checkpoint inhibitor monotherapy, and led to a 40% extension in median survival.  

By reconfiguring the architecture of a vaccine containing multiple targets, the SNA enables the immune system to find tumour cells. The team investigated differences in how well two antigens were recognised by the immune system depending on their placement, on the core or perimeter, of the SNA structure. For an SNA with optimum placement, they could increase the immune response and how quickly the nanovaccine triggered cytokine (an immune cell protein) production to boost T cells attacking the cancer cells. The scientists also studied how the different placements affected the immune system’s ability to remember the invader, and whether the memory was long-term.  

“Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognises and processes it,” Mirkin said. 

The most powerful structure throws two punches to outsmart the tumour  

The study data show that attaching two different antigens to an SNA comprising a shell of adjuvant was the most potent approach for a cancer vaccine structure. These engineered SNA nanostructures stalled tumour growth in multiple animal models.   

“It is remarkable,” Mirkin said. “When altering the placement of antigens in two vaccines that are nearly identical from a compositional standpoint, the treatment benefit against tumours is dramatically changed. One vaccine is potent and useful, while the other is much less effective.”  

Many current cancer vaccines are designed to primarily activate cytotoxic T cells, only one defence against a cancer cell. Because tumour cells are always mutating, they can easily escape this immune cell surveillance, quickly rendering the vaccine ineffective. The odds are higher that the T cell will recognise a mutating cancer cell if it has more antigens to recognise it.   

“You need more than one type of T cell activated, so you can more easily attack a tumour cell,” Teplensky said. “The more types of cells the immune system has to go after tumours, the better. Vaccines consisting of multiple antigens targeting multiple immune cell types are necessary to induce enhanced and long-lasting tumour remission.”  

Another advantage of the rational vaccinology approach, especially when used with a nanostructure like an SNA, is that it’s easy to alter the structure of a vaccine to go after a different type of disease. Mirkin said they simply switch out a peptide, a snippet of a cancer protein with a chemical handle that “clips” onto the structure, not unlike adding a new charm to a bracelet.   

Towards the most effective vaccine for any cancer type 

“The collective importance of this work is that it lays the foundation for developing the most effective forms of vaccine for almost any type of cancer,” Teplensky said. “It is about redefining how we develop vaccines across the board, including ones for infectious diseases.” 

In a previously published paper, Mirkin, Teplensky and colleagues demonstrated the importance of vaccine structure for SARS-CoV-2 by creating vaccines that exhibited protective immunity in 100% of animals against a lethal viral infection.  

“Small changes in antigen placement on a vaccine significantly elevate cell-to-cell communication, cross-talk and cell synergy,” Mirkin said. “The developments made in this work provide a path forward to rethinking the design of vaccines for cancer and other diseases as a whole.”   

Source: Northwestern University

Categories : Diseases, Syndromes and ConditionsTags : Leave a comment

Strep A Toxin Serves as Both Weapon and Shield

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Streptococcus pyrogenese bound to human neutrophil
Streptococcus pyogenese bound to a human neutrophil. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Griffith University researchers have unlocked one of the secrets as to why some forms of Streptococcus Group A (Strep A) are associated with severe invasive infection. The results, published in mBio, suggest that a toxin it secretes not only damages cells but helps Strep A resist host defence.

Around the world, invasive Strep A diseases are responsible for more than 163 000 deaths annually and a recent increase in cases of invasive Strep A disease has been observed internationally.

For the past 10 years, Institute for Glycomics Associate Professor Manisha Pandey and Professor Michael Good have been researching the pathways in which Strep A can spread through the body.

“The findings from this study will have far-reaching implications as Strep A is responsible for a significant number of invasive and non-invasive infections which cause significant morbidity and mortality globally,” Associate Professor Pandey said.

“The reason for this is that invasive organisms express significantly more of the toxin, streptolysin O (SLO), which was the main focus of this study.

“SLO exerts potent cell and tissue destructive activity and promotes Strep A resistance to clearance by white cells in the body which is the critical first element of host defence against invasive Strep A infection.”

Professor Good said: “We found SLO alters interactions with host cell populations and increases Strep A viability at sites in the body such as the blood and spleen, and that its absence results in significantly less virulence.”

“Essentially, the less SLO present, the less severe the case of Strep A.”

SLO is secreted by nearly all Strep A isolates, but those that secrete the most SLO are the most virulent.

This work underscores the importance of SLO in Strep A virulence while highlighting the complex nature of Strep A pathogenesis.

This improved insight into host-pathogen interactions will enable a better understanding of host immune evasion mechanisms and inform streptococcal vaccine development programs.

Dr Pandey said a key finding was the presence of SLO in invasive organisms did not impair the ability of the Strep A vaccine candidate developed by Griffith University’s Institute for Glycomics and which is now in a clinical trial.

The Strep A virulence study was part of a PhD project undertaken by Dr Emma Langshaw.

Source: Griffith University

Categories : GeneticsTags : Leave a comment

Genetic Variations Influence Drug Metabolism in Patients of African Descent

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Photo by Agung Pandit Wiguna

Investigators have identified new genetic variations that affect gene expression in the liver cells of patients of African ancestry, findings that provide insight into how drugs are metabolised differently in different populations, according to a study published in The American Journal of Human Genetics.

Expression quantitative locus (eQTL) studies use an individual’s genomic and transcriptomic data to uncover unique genetic variants that regulate gene expression. However, people of African descent have not been well represented in these databases.

Having this comprehensive, multiomic data is key to uncovering the mechanisms that regulate an individual’s genome and understanding how different groups of people respond to drugs differently, which can improve treatment strategies, according to Minoli Perera, PharmD, PhD, associate professor of Pharmacology and senior author of the study.

“We don’t have data from any historically excluded populations to run these analyses, so a big motivation of my lab is to create data in African ancestry populations so that they are represented in multiomics,” said Perera.

In the current study, the investigators treated hepatocytes from liver tissue samples from African American patients with six FDA approved drugs: Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital and Omeprazole.

The investigators then performed whole-genome genotyping and RNA sequencing on primary hepatocytes treated both with and without the drugs. They also mapped eQTLs, or single-nucleotide polymorphisms (SNPs) affecting gene expression, in the liver cells.

From this comprehensive analysis, they uncovered varying transcriptional changes in the cell lines across the different drug treatments and identified NRF2 as a potential gene transcription regulator.

“NRF2 has been already identified as a very important transcription factor for drug metabolism, but this is a much more comprehensive way to look at it,” Perera said.

The investigators also discovered nearly 3000 genetic variants that affect how well hepatocytes respond to external stimuli, including drugs, which the investigators called drug response eQTLs, or reQTLs. Notably, they discovered reQTLs for drug-metabolising genes such as CYP3A5.

Most individuals of European ancestry carry a specific genetic variant in CYP3A5 which results in no/low CYP3A5 enzyme, whereas individuals of African ancestry carry that variant at a lower frequency. According to Perera, this is a problem because most participants that are recruited for clinical trials are of European ancestry, and the findings from these trials directly inform how often and how much of a drug should be prescribed to all patients, regardless of their ancestry.

“When you test drugs in a group of people with limited diversity, and then say this is the dose, this is how fast it’s metabolised, this is how often you dose the drug and then you give this medication to the entire U.S. population, we don’t know for sure how accurate those measures are, and that’s just with one variant. Other variants that may influence how much or how little we up-regulate these important enzymes,” Perera said.

Perera said her team is now expanding their work by increasing the number of hepatocytes from African American participants they’re studying and incorporating other types of omics techniques, such as epigenetic profiling.

“Almost exclusively we’ve done epigenetic screenings in European populations, so what can we find in the epigenome that’s important for African Americans. Also, because there’s more genetic variation in individuals of African descent, would that change the epigenome in ways that we aren’t able to see in Europeans,” Perera said. “We hope that what we’re doing can help annotate new studies coming along for African ancestry populations.”

Source: Northwestern University