Category: 8. Health

Introductions

Nephrolithiasis, or kidney stone disease, is a serious condition that affects approximately 12% of the global population, impacting health-care systems worldwide.^1–3 Symptomatic kidney stone management requires a comprehensive approach that includes both medical and surgical interventions.⁴ Unlike surgical interventions, extracorporeal shock wave lithotripsy (ESWL) is a noninvasive modality and has become the preferred treatment for uncomplicated renal and ureteral calculi, typically less than 20 mm, due to its effectiveness, low morbidity, and high patient preference.^5,6 Nevertheless, stone-free rates (SFRs) after ESWL range from 46% to 91%.⁷ Therefore, obtaining crucial patient information for preoperative surgical planning should be a mandatory step in determining the probability of procedural success and the necessity of ancillary procedures.

Various scoring systems for classifying the complexity of renal stones and nomograms that predict outcomes after renal stone surgery have been developed and externally validated.⁸ However, limitations exist. The Clinical Research Office of the Endourological Society (CROES) nomogram is complex and requires extensive preoperative data, while the S.T.O.N.E. (stone size, tract length, obstruction, number of involved calices, and essence/ stone density) was validated in a small cohort, potentially limiting its generalizability. For ESWL, Tran et al⁹ devised the Triple D scoring system, which is based on CT imaging and takes into account three parameters: stone density, stone volume, and skin-to-stone distance (SSD). Any scoring system must be simple, fast, and accurate to be widely used in daily practice.

The modified Seoul National University Renal Stone Complexity (S-ReSC-R) scoring system is a modified version of the original Seoul National University Renal Stone Complexity system that includes one additional point when the stone located lower calyx is proven to be a precise and rapid assessment in the predictive model for both percutaneous nephrolithotomy and flexible ureteroscopy.^10,11 We hypothesize that the S-ReSC-R is an accurate tool for predicting stone-free rates after ESWL.

We aimed to evaluate the predictive value of the S-ReSC-R scoring system for determining treatment outcomes following ESWL, using stone-free status as the primary endpoint.

Materials and Methods

This was a retrospective observational study approved by the Ethics Committee of Ranong Hospital (no. COA_PHRN013/2564) and conducted in accordance with the principles outlined in the Declaration of Helsinki. Consent for chart review was not required because of the retrospective nature of the study. All data were encrypted and remained confidential.

A total of 332 patients undergoing ESWL for kidney stones at a tertiary hospital between January 2019 and November 2021 were reviewed for inclusion in the study. The inclusion criteria were an age of 18 years or older, previously untreated renal stones greater than 4 mm in size, and available preoperative CT imaging. The exclusion criteria were a stone in a solitary kidney, uncorrectable bleeding disorders, active urinary tract infection, urinary tract obstruction or abnormalities, and pregnancy. Twenty-eight patients were excluded because of insufficient imaging, and seven were excluded due to incomplete clinical data. Thus, 297 patients were included in the analysis.

The data collected included medical history, physical examination, complete blood count, serum biochemical profile, urinalysis, and coagulation profile. Non-contrast CT was used preoperatively to determine the stone characteristics. The largest dimension of a stone visualized on a soft tissue window in a coronal view represented the stone’s size. Stone Hounsfield units (HU) were calculated by taking the mean attenuation of three consistent, nonoverlapping regions of interest chosen from stones in bone windows. SSD measurements were performed using axial CT as the average distance from the skin to the surface of the targeted stone at 0°, 45°, and 90° angles.

S-ReSC-R scores were calculated using the method described by Jung et al.⁹ The S-ReSC-R score is calculated by summing the points assigned to specific stone locations: renal pelvis (#1); superior and inferior major calyceal groups (#2–#3); and anterior and posterior minor calyceal groups of the superior (#4–#5), middle (#6–#7), and inferior calyx (#8–#9). If a stone is situated in inferior locations (#3, #8–#9), one extra point is added for each site. Thus, the total S-ReSC-R score ranges from 1 to 12 points. A higher score indicates greater stone complexity and may be associated with less favorable procedural outcomes. Based on these scores, the patients were divided into a low score (1–2 points) group, an intermediate score (3–4 points) group, and a high score (5–12 points) group.

Triple D scores were calculated based on the formula devised by Tran et al.⁸ Values were calculated for each of the three stone parameters (stone volume, stone density, and SSD). One point was assigned for any parameter that was below the cutoff value (150 μ L for stone volume, 600 HU for stone density, and 12 cm for SSD). Thus, the Triple D score ranged from 0 (worst) to 3 (best).

Before ESWL, urine examinations and cultures were evaluated. If the results indicated urinary tract infection, an antibiotic was prescribed, and the procedure was postponed. Following the standard protocol, all patients underwent ESWL as outpatients in the supine position without anesthesia or sedation. A Siemens Modularis Vario Lithostar electromagnetic lithotripter was used in the procedures. Stone localization and real-time tracking during the procedure were performed using both ultrasound and fluoroscopy. The frequency applied was 60–90 shock waves/min. The total number of shock waves applied in one session ranged from 3000 to 5000, or the session was stopped when significant stone fragmentation was detected. The patients were advised to increase fluid intake and to take analgesics consistently after the procedure. A follow-up X-ray KUB and ultrasonography examination was scheduled four to six weeks later to assess residual fragments. Treatment success was defined as complete stone clearance without any residual fragments.

Statistical Analysis

Statistical analysis was performed using IBM SPSS Statistics for MacOS, version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive variables were represented as numbers and percentages. Associations between continuous variables, such as stone size, HU, SSD, and BMI, were assessed using the Student’s t-test. Categorical variables, such as gender, stone laterality, and stone location, were compared using the chi-square test. Values of p < 0.05 were considered statistically significant. Univariate and multivariate logistic regression analyses were used to identify significant predictors of stone-free status. Receiver operator characteristic (ROC) curves were drawn to assess the predictive ability of the S-ReSC-R and Triple D scoring systems.

Results

Among the 297 patients, 156 were male, and 141 were female. The procedure was successful in 62.3% (185/297) of the patients and unsuccessful in 37.7% (112/297). In the univariate analysis, there were no significant differences between the two groups in terms of age, gender, stone laterality, stone density, or SSD. Conversely, statistically significant differences were observed in stone size, presence of a lower pole stone, and mean S-ReSC-R score (all p < 0.001; Table 1).

Table 1 Baseline Demographic and Clinical Characteristics of the Study Cohort

The SFRs were significantly lower with higher S-ReSC-R scores (p < 0.001). The low score (1–2) group had an SFR of 72.4% (165/228), the intermediate score (3–4) group had an SFR of 36.0% (18/50), while the high score (5–12) group had an SFR of 10.5% (2/19). The SFRs determined by the individual S-ReSC-R scores differed significantly (p < 0.001) from those obtained using the three-tier S-ReSC-R classification (Table 2).

Table 2 Stone-Free Rates Following ESWL by Individual S-ReSC-R Scores and Low, Intermediate, and High Score Groups

As shown in Table 3, multivariate logistic stepwise regression revealed significant inverse associations between the SFR and both the S-ReSC-R score (p < 0.001) and the Triple D score (p < 0.001). The ROC curves drawn to assess the accuracies of the S-ReSC-R and Triple D scoring systems in predicting stone-free status are shown in Figures 1 and 2, respectively. While both scoring systems exhibited high predictive accuracy, the S-ReSC-R system had a higher area under the curve (AUC) than the Triple D system (0.767 vs 0.694).

Table 3 Multivariate Analysis of Stone-Free Status Predictors

Figure 1 ROC curve of the S-ReSC-R score. Abbreviations: ROC, receiver operator characteristic; S-ReSC-R, modified Seoul National University Renal Stone Complexity.

Figure 2 ROC curve of the Triple D score. Abbreviation: ROC, receiver operator characteristic.

Discussion

The use of ESWL in the management of urolithiasis marks a significant milestone in urology. Since its introduction in 1980, it has been established as the primary modality for renal calculus management.¹² However, SFRs after ESWL vary widely, depending on several factors. To obtain the best results, ensure safety, and reduce re-treatment rates, a combination of technological advancements, improved procedural techniques, and proper patient selection is essential. Advanced lithotripters equipped with expanded focal zones and automatic image-based renal stone tracking mechanisms enhance the accuracy of shock wave delivery to the target while reducing potential harm to adjacent renal parenchymal tissue.^13,14 Notably, lowering the shock wave rate has proven beneficial for fragmenting stones, especially those exceeding 1 cm in size.¹⁵ Li et al¹⁶ showed that ESWL at a rate of 60–90 shock waves/min outperformed a rate of 120 shock waves/min in terms of fragmentation. A gradual increase in the device’s energy voltage, termed “ramping”, not only reduces the risk of tissue injury but also augments stone fragmentation.¹⁷

Proper patient selection is also crucial for the success of ESWL. The key selection factors are stone size, stone location, SSD, and Hounsfield units. A larger stone size is associated with a higher risk of ESWL failure. In a study of 2954 patients with single or multiple radiopaque renal stones undergoing ESWL monotherapy, Abdel-Khalek et al¹⁸ reported success rates of 89.7% for stones of <15 mm and 78% for stones of >15 mm (p < 0.001). Similarly, in a study of 427 patients with renal stones, Al-Ansari et al¹⁹ reported success rates of 90% for stones of ≤10 mm and 70% for stones of >10 mm (p < 0.05). Our multivariate analysis confirms that stone size is an independent predictor of ESWL success.

The location of kidney stones, particularly those situated in the lower pole, also plays a crucial role in the success of ESWL. Lower pole stones present a distinct challenge due to their relatively low clearance rates, which range from 47% to 75%.²⁰ Tarawneh et al²¹ reported an ESWL success rate for lower calyceal stones of only 47%, which was significantly lower than that for stones in other locations (79%; p = 0.012). Similarly, Samir et al²² found that a lower calyceal location was an independent predictor of ESWL success (p = 0.017). In line with these results, a statistically significant difference in SFRs between lower pole and non–lower pole stones was observed in our study (p < 0.001), confirming the significant influence of a lower pole location on ESWL outcomes. We believe that scoring systems in which stone location plays an important role, such as the S-ReSC-R system, are suitable for predicting tone-free status after ESWL.

ESWL failure has also been associated with a greater SSD, especially in Western populations. Pareek et al²³ found that an SSD of up to 10 cm was a powerful predictor of stone-free status. This is because with greater SSDs, shock waves travel longer distances, which results in shock wave attenuation. However, studies involving Asian populations have reported contradictory results. Because Asian populations have thinner bodies than Western populations, it has been argued that SSD cannot be applied to Asian patients.²⁴ Our results are in line with those of other studies, without significant differences in both groups. Thus, the SSD may not be universally applicable as a predictor of stone-free status following ESWL.

Stone fragility is determined by the stone’s composition and mineral content. Several studies have examined the relationship between stone density on radiological imaging and stone composition, suggesting that stone density can predict stone characteristics.^25,26 In our study, the mean stone density did not differ significantly between the successful and unsuccessful ESWL groups. However, 71.1% of the patients with a stone density below 500 HU had favorable treatment outcomes, compared to only 47.4% of those with a stone density above 500 HU. Different studies have proposed varying stone density thresholds. Gupta et al²⁷ reported optimal ESWL outcomes with a mean stone density of ≤750 HU. Similarly, a prospective study of 50 patients with urinary stones reported that a threshold of 970 HU had high specificity and sensitivity in predicting ESWL success.²⁸

Cutting-edge technologies such as artificial intelligence and virtual reality are increasingly becoming integral to a range of surgical procedures and assist in predictive analyses of various interventions.^29–31 Despite these advancements, numerous regions around the world still lack internet access, highlighting disparities in access to technology. Traditional tools, such as scoring systems and nomograms, have been developed using multiple clinical variables to assess procedural complexity and predict outcomes. However, nomograms have not been widely adopted in clinical practice due to their complexity and lack of practicality. Clinical scoring systems are generally easy to use and require minimal training and no specialized software, which has made them more popular in routine practice. Tran et al⁹ introduced the Triple D scoring system, a straightforward system based on CT imaging that evaluates three stone-related parameters. However, it does not fully account for stone location, particularly a lower pole location, an important variable considered in other scoring systems, such as the S-ReSC-R system.

In our cohort of 297 patients undergoing ESWL, we found that the S-ReSC-R score was significantly associated with stone-free status in both univariate and multivariate logistic regression analyses (p < 0.001). The score demonstrated better discriminative performance than the Triple D score, with an AUC of 0.767 compared to 0.694. This finding supports the clinical utility of incorporating stone location, as accounted for in the S-ReSC-R system, when predicting ESWL outcomes. As a practical and efficient tool, the S-ReSC-R scoring system has been applied to various surgical treatments, including flexible ureteroscopy and percutaneous nephrolithotomy. Therefore, its application to ESWL is reasonable.

Our research has certain limitations. First, the sample size was small. Moreover, because of the study’s retrospective nature, patients with missing CT scans were excluded, as without CT images, stone attenuation and SSD could not be measured. Second, although metabolic evaluation is an important parameter for assessing stone disease outcomes, such data were not included in this study. However, to the best of our knowledge, this is the first study to validate the S-ReSC-R score for the ESWL procedure. We believe that our findings provide a strong foundation for future research on the clinical applications of this system.

Conclusion

Our study demonstrates that the S-ReSC-R score is a reliable predictor of ESWL outcomes. Thus, the S-ReSC-R scoring system is a valuable tool for clinical planning in patients undergoing ESWL, offering both simplicity in calculation and proven effectiveness.

Acknowledgments

We would like to thank everyone involved in this study, as well as the Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, for its support in the statistical analysis.

Disclosure

The authors declare that they have no competing interests in this work.

References

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Europe is experiencing increasing prevalence of arbovirus diseases — those transmitted by arthropod vectors such as mosquitoes, ticks, or sand flies. These diseases, including dengue, chikungunya, and Zika, have traditionally been endemic to the tropical and subtropical regions of South America, the Caribbean, Africa, and Asia. Their frequency and scale have increased globally in the past two decades, and the geographic range of transmission has expanded into areas previously unaffected, including non-endemic regions in Europe.

While most cases are imported, mosquito species and ticks are establishing themselves further northwards and westwards in Europe. According to the European Centre for Disease Prevention and Control (ECDC), between 2021 and 2024, the number of autochthonous (locally acquired) dengue outbreaks and cases increased considerably, and chikungunya and Zika infections have also now been reported in Mediterranean regions.

Arbovirus Diseases Becoming More Common

Tamás Bakonyi, ECDC principal expert on vector-borne and zoonotic diseases, told Medscape Medical News that arbovirus diseases have become more common in Europe due to a combination of environmental, biological, and societal factors.

Climate conditions can change the environment in which infectious diseases thrive, contributing to their increase and impact, he said. Rising temperatures, milder winters, more frequent extreme weather events, and changing rainfall patterns may create more favorable conditions for the transmission of several vector-, food-, and waterborne diseases.

“Vector-borne diseases like dengue, chikungunya virus disease, West Nile virus infections, Lyme borreliosis, and tick-borne encephalitis are particularly sensitive to changes in temperature, humidity, and rainfall,” he explained. Warmer temperatures increase mosquito and tick survival and shorten pathogen incubation times, which in turn accelerates disease transmission cycles.

Most Cases Imported

International travel has led to the importation of arboviruses from endemic regions to Europe, Bakonyi said. This underlies most reported arbovirus infections in Europe but may spark local outbreaks. The ECDC collects data on imported cases on an annual basis. Its latest interactive surveillance atlas, for the year 2023, showed across the EU:

• Dengue: 5027 travel-associated cases vs 129 locally acquired cases.
• Chikungunya: 320 imported cases including in Spain (191), Germany (44), and France (39), with no reported locally acquired cases.
• Zika virus infection: 79 travel-associated cases with none locally acquired.

In addition, the ECDC collects seasonal data over the summer on locally acquired cases of various arboviral diseases. Its latest communicable disease threats surveillance for the week ending August 01, 2025, showed:

• Locally acquired dengue in three European countries in 2025 so far: France (6, including 2 new cases since the previous week), Italy (3), and Portugal (2 in Madeira).
• Locally acquired chikungunya in France (49) and Italy (2) so far during 2025.
• Up to 30 July, Crimean-Congo hemorrhagic fever cases were reported in Greece (2) and Spain (2).
• Up to 30 July, human cases of West Nile virus infection were reported in Bulgaria, France, Greece, Italy, and Romania.

Be Alert for Symptoms

Clinicians across Europe this summer should be on the alert for symptoms of arbovirus infections, both mosquito-borne and tick-borne diseases, Bakonyi advised.

Dengue — Most cases are imported by travelers returning to the EU from endemic areas, but these may generate local, mosquito-borne transmission in areas with competent vectors and supportive climatic/weather conditions. Transmission is primarily by Aedes aegypti globally and Aedes albopictus in Europe, where the species is increasingly frequent. Symptoms include an acute, high fever, occasionally progressing to hemorrhagic fever, with headache, myalgia, arthralgia, and a maculopapular rash. Up to 5% of cases can be severe, with increased vascular permeability that can lead to life-threatening hypovolemic shock.

Chikungunya — A notifiable disease at the EU level. Around a third of cases are asymptomatic; the remainder are characterized by sudden onset fever, chills, headache, myalgia, nausea, photophobia, incapacitating joint pain, and petechial or maculopapular rash. Recovery may take months but typically occurs within 10 days and gives lifelong immunity.

Zika — Generally asymptomatic, but may cause mild fever, arthralgia, and fatigue, with a maculopapular rash, conjunctivitis, myalgia, and headache. It is usually short (2-7 days) and self-limiting, but infection during pregnancy may lead to congenital central nervous system malformations such as microcephaly, with a raised risk for fetal loss.

West Nile fever — About 80% of infections are asymptomatic but may cause fever, headache, malaise, myalgia, fatigue, and eye pain, sometimes with a rash. Some 1%-10% of cases may be severe, especially among older people. Most cases in humans occur between July and September, when mosquitoes are active.

Diagnosis More Difficult

Diagnosis should be on the basis of clinical presentation and epidemiologic context, as well as laboratory tests, which vary by disease, Bakonyi said. Testing has become more difficult recently due to the global expansion of arboviruses, leading to antibodies that cross-react on serological assays.

As for treatment, Bakonyi recommended referring to the World Health Organization (WHO), which issued its first global arbovirus guidelines in July. These also point to the difficulty in distinguishing between arboviral infections because early symptoms often overlap.

Treatment Largely Symptomatic

Treatment is largely symptomatic in mild infections. With suspected or confirmed nonsevere dengue, chikungunya, Zika, or yellow fever, the WHO recommends oral rehydration, with paracetamol or dipyrone for managing pain and fever. Corticosteroids are not recommended in nonsevere infections, and nonsteroidal anti-inflammatory drugs should be avoided in all cases.

For hospitalized patients with suspected or confirmed severe arboviral disease, the WHO recommends:

• Prefer crystalloid fluids over colloids for intravenous (IV) rehydration.
• Use capillary refill time and serum lactate levels to guide decisions on IV fluid management, with a passive leg raise test for patients in shock.
• Avoid systemic corticosteroids and immunoglobulins.
• Avoid prophylactic platelet transfusions in patients with platelet counts < 50,000/μL unless there is active bleeding.

Sheena Meredith is an established medical writer, editor, and consultant in healthcare communications, with extensive experience writing for medical professionals and the general public. She is qualified in medicine and in law and medical ethics.

Researchers using patient-derived stem cells reveal a rare ALS mutation triggers a chronic stress response in motor neurons, blocking it reverses damage in lab models, paving the way for new treatment strategies

A breakthrough study using patient-derived stem cells has identified how a rare ALS-causing mutation disrupts cellular communication, activating a chronic protective mechanism that ultimately damages motor neurons. Crucially, researchers were able to reverse this damage in the lab by inhibiting the stress response, suggesting a promising new therapeutic pathway for ALS treatment. This discovery opens up a new horizon of hope for potential ALS treatments.

The findings are detailed in the peer-reviewed journal EMBO Molecular Medicine.

Providing vital clues for treating ALS

A new study by Case Western Reserve University researchers used stem cells created from ALS patients to target a specific gene as a kind of shut-off valve for a stress that affects nerve cells, and this was successful. This success provides a solid foundation for further research and potential treatments.

Whilst the research involved a rare type of ALS, the scientists are hopeful the results could provide insight into potentially treating the condition more widely. This potential for broader ALS therapies is a promising step forward in the field of ALS research.

“This work could help lay the foundation for genetically informed clinical trials,” said lead researcher Helen Cristina Miranda, an associate professor of genetics and genome sciences at Case Western Reserve’s School of Medicine.

Blocking the stress response reversed damage

The researchers studied an inherited type of ALS caused by a mutation in a gene (vesicle-associated membrane protein B, or VAPB). The VAPB gene provides instructions for making a protein that helps link different parts of the cell so they can communicate and respond to stress.

“This is especially important in nerve cells,” Miranda said. “When they break down, the neurons become more vulnerable to degeneration.”

iPSCs, or induced pluripotent stem cells, are special cells created in the lab from a person’s skin or blood that can be turned into almost any cell type in the body. In this study, the researchers used iPSCs from ALS patients to grow their motor neurons in a dish, allowing them to study the disease using real human cells.

The researchers found a mutation in the VAPB gene that disrupted communication between key parts of the cell, specifically between the endoplasmic reticulum (ER) and mitochondria. The ER acts like a quality control centre and helps produce and fold proteins, ensuring everything within the cells runs smoothly. Mitochondria generate the energy that cells, especially nerve cells, need to stay alive.  This disruption leads to chronic activation of a mechanism called the Integrated Stress Response (ISR).

Although it was helpful, sustained ISR activation reduces protein production and impairs cell survival, leading to damaged motor neurons and contributing to this rare form of ALS. The researchers were able to identify the ISR as a potential therapeutic target.

“We also showed that blocking this stress response can reverse damage in the lab, a promising step toward future treatments,” she said. “That’s a promising proof-of-concept for future therapeutic strategies.”

The team’s study focused on a particular rare type of ALS, but they hope to expand the research to test whether the target might work on other forms of the disorder.

“It’s very rare, more prevalent in Brazil, but studying it gives us a window into how ALS motor neurons respond to stress,” Miranda said. “We are now testing ISR inhibitors in more complex neuromuscular models and exploring how this approach might benefit other ALS subtypes.”

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A new study led by Liverpool School of Tropical Medicine shows that mosquitoes are killed when they feed on blood and then land on a surface sprayed with nitisinone, a drug currently used to treat a rare genetic condition in humans.

The research shows that this is true even when the mosquitoes are highly resistant to existing insecticides, which opens a promising new avenue for formulating nitisinone for indoor spraying or bed nets at a time when resistance poses a significant threat to vector control programs worldwide.

Nitisinone is lethal to mosquitoes as it blocks an enzyme that they need to safely process the protein and amino acids they get from blood. 

The new paper, published in Parasites & Vectors, follows on from a study earlier this year that showed that nitisinone is deadly to mosquitoes when they drink the blood from someone on nitisinone therapy. The drug is safe and already approved for widespread human use and is currently the only treatment for the rare genetic disorders tyrosinemia type 1 and alkaptonuria.

In this new study, nitisinone was shown to be mosquitocidal to several mosquito species (Anopheles, Aedes and Culex), including those that transmit malaria, reemerging infections such as dengue and Zika, and emerging viral threats like Oropouche and Usutu viruses.

The research also proved that nitisinone killed mosquitoes regardless of whether exposure occurred before or after a blood meal, tapping into mosquito resting behaviour before or after feeding.  Because nitisinone works by disrupting the mosquito’s bloodmeal digestion (tyrosine metabolism), which is not a pathway targeted by any of our current insecticides, it could help public health campaigns eliminate mosquitoes where insecticide resistance has made other products fail.

Dr Lee Haines, senior author and Honorary Research Fellow at LSTM said: “Our conclusions are exciting.  Working with a drug like nitisinone, and its versatility, bodes well for creating new products to combat mosquitoes.  The fact that it effectively kills insecticide-resistant mosquitoes could be a game-changer in areas where resistance to current insecticides is causing public health interventions to fail.

“This project proved how important it is to think outside the box.  We don’t know yet why nitisinone is absorbed through the mosquito’s feet, and why the other similar compounds are not.  But it is going to be exciting to solve this mystery!”

Zachary Stavrou-Dowd, Research Assistant and PhD student at LSTM, and lead author on the new paper, said: “Nitisinone acts to clog up the mosquito digestive system. When a mosquito gorges on your arm, that blood contains a massive protein load. What we have shown here is that we can turn that key trait against them. The mosquito can’t digest the blood; it becomes overloaded by its own meal; it dies.”

The research was part funded by the Jean Clayton Fund for early career researchers at LSTM.

Zachary Stavrou-Dowd said: “Receiving the Jean Clayton Early Career Researcher Award at LSTM was a pivotal moment, it not only helped fund part of this study but also strengthened our application for a Rosetrees Seedcorn Grant. It’s a great example of how internal support can catalyse external funding opportunities and boost visibility for early career researchers like me.”

Reference: Stavrou-Dowd ZT, Parsons G, Rose C, et al. The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake. Parasites Vectors. 2025;18(1):316. doi: 10.1186/s13071-025-06939-0

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Researchers from the University of the Sunshine Coast’s Thompson Institute believe lifestyle risk factors may be leaving chemical warning signs of decline in your brain – long before any symptoms of dementia play out.

Forty-five percent of dementia cases are potentially preventable, and simple lifestyle choices including exercise, diet and social connection all contribute to your risk score.

But what if these risk factors were leaving chemical warning signs of decline in your brain – long before any symptoms of dementia played out?

Researchers from the University of the Sunshine Coast’s Thompson Institute believe they’ve found just that. 

It not only opens new avenues for early detection in dementia research – it could also help our understanding of how the brain deteriorates to increase risk of earlier dementia.

The study, published today in Cerebral Cortex, used Magnetic Resonance Imaging and MR-spectroscopy to measure the brain chemical levels of 79 healthy older adults.

All participants had normal memory, thinking skills and cognitive function. What varied was their modifiable-dementia risk score – calculated from health and lifestyle factors such as physical activity, sleep, social engagement, and diet. 

Lead author Dr Jacob Levenstein said the research team discovered specific patterns in individuals’ brain chemistry relating to that risk score. 

“We examined the concentration levels of Gamma-aminobutyric acid (GABA) – which you can think of as the brain’s ‘brake system,” he said. 

“GABA is a neurochemical messenger that helps calm down brain activity and keep neural networks balanced. These results suggest ‘riskier’ lifestyle choices could hinder the brain’s ability to properly regulate itself.

“We found that with higher modifiable dementia risk scores, individuals had lower GABA concentrations in movement and sensory brain regions.   

“In the prefrontal cortex – a brain region that handles complex thinking and decision-making – we also found that with higher modifiable dementia risk, individuals had lower concentrations of total N-acetylaspartate (tNAA) and total choline (tCho).

“These two neurochemicals play important roles in brain tissue health and cell-to-cell communication. 

“Lower levels of these neurochemicals in the brain’s ‘command centre’ may suggest deterioration occurs long before noticeable changes in behaviour or memory.” 

The findings not only open the door for new early detection and intervention research, they also shed light on how the brain might deteriorate before dementia sets in.

“Crucially, these three neurochemical markers were identified in healthy older adults, meaning they could play a role in the detection of dementia years before behavioural symptoms appear, giving a head-start on prevention and mitigation” Dr Levenstein said.

As co-author of the research and Lead of the Thompson Institute’s Healthy Brain Ageing Program Dr Sophie Andrews points out, there is additional good news in these findings too.

“These are modifiable factors. You can make simple everyday choices that will improve your brain’s health trajectory,” she said.

“We’ve shown that simple things like improving physical activity levels and sleep quality, looking after your mental health, and moving toward a Mediterranean-style diet, can significantly improve your outlook.”  

Reference: Levenstein JM, Treacy C, Andrews SC. Neurophysiological correlates of modifiable dementia risk factors in cognitively unimpaired older adults. Cereb Cortex. 2025;35(8):bhaf179. doi: 10.1093/cercor/bhaf179

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The obesity rate has more than doubled in the last 30 years, affecting more than one billion people worldwide. This prevalent condition is also linked to other metabolic disorders, including type 2 diabetes, cardiovascular diseases, chronic kidney disease, and cancers. Current treatment options include lifestyle interventions, bariatric surgery, and GLP-1 drugs like Ozempic or Wegovy, but many patients struggle to access or complete these treatments or to maintain their weight loss afterwards.

Salk Institute scientists are looking for a new treatment strategy in microproteins, an understudied class of molecules found throughout the body that play roles in both health and disease. In a new study, the researchers screened thousands of fat cell genes using CRISPR gene editing to find dozens of genes that likely code for microproteins—one of which they confirmed—that regulate either fat cell proliferation or lipid accumulation.

The findings, published in Proceedings of the National Academy of Sciences on August 07, 2025, identify new microproteins that could potentially serve as drug targets to treat obesity and other metabolic disorders. The study also showcases the value of CRISPR screening in future microprotein discovery.

“CRISPR screening is extremely effective at finding important factors in obesity and metabolism that could become therapeutic targets,” says senior author Alan Saghatelian, a professor and holder of the Dr. Frederik Paulsen Chair at Salk. “These new screening technologies are allowing us to reveal a whole new level of biological regulation driven by microproteins. The more we screen, the more disease-associated microproteins we find, and the more potential targets we have for future drug development.”

Current obesity and metabolic disorder therapeutics

When our energy consumption exceeds our energy expenditure, fat cells can grow in both size and number. Fat cells store the excess energy in the form of fatty molecules called lipids. But while some excess storage is manageable, too much can cause fat deposits to accumulate around the body—leading to whole-body inflammation and organ dysfunction.

Many factors regulate this complex energy storage system. The problem is, how do we find them all, and how do we filter for factors that may make good therapeutic candidates?

This has been a longstanding question for Salk scientists. In fact, Salk Professor Ronald Evans has been working on it for decades. Evans is an expert on PPAR gamma, a key regulator of fat cell development and a potent target for treating diabetes. Several drugs have been developed to target PPAR gamma to treat obesity, but they resulted in side effects like weight gain and bone loss. An ideal PPAR gamma-based obesity therapeutic has yet to hit the market.

When PPAR gamma drugs fell short, GLP-1 drugs entered the scene. GLP-1 is a peptide small enough to be considered a microprotein, and it serves as a blood sugar and appetite regulator. But, like PPAR gamma, GLP-1 drugs have their own shortcomings, such as muscle loss and nausea. Nonetheless, the popularity of GLP-1 drugs demonstrates a promising future for microprotein drugs in the obesity therapeutic space.

Saghatelian’s team is now searching for the next microprotein therapeutic with new genetic tools that bring microproteins out of the “dark.” For many years, long stretches of the genome have been considered “junk” and thus left unexplored. But recent technological advances have allowed scientists to look at these dark sections and find a hidden world of microproteins—in turn, expanding protein libraries by 10 to 30 percent.

In particular, the Salk team is using innovative CRISPR screening to scour the “dark” for possible microproteins. This approach is enabling the simultaneous discovery of thousands of potential microproteins involved in lipid storage and fat cell biology, accelerating the search for the next PPAR gamma or GLP-1 drug.

How CRISPR screening accelerates the search for microproteins

CRISPR screens work by cutting out genes of interest in cells and observing whether the cell thrives or dies without them. From these results, scientists can determine the importance and function of specific genes. In this case, the Salk team was interested in genes that may code for microproteins involved in fat cell differentiation or proliferation.

“We wanted to know if there was anything we had been missing in all these years of research into the body’s metabolic processes,” says first author Victor Pai, a postdoctoral researcher in Saghatelian’s lab. “And CRISPR allows us to pick out interesting and functional genes that specifically impact lipid accumulation and fat cell development.”

This latest research follows up on a prior study from Saghatelian’s lab. The previous study identified thousands of potential microproteins by analyzing microprotein-coding RNA strands derived from mouse fat tissues. These microprotein-coding RNA strands were filed away to await investigation into their functions.

The new study first expanded this collection to include additional microproteins identified from a pre-fat cell model. Notably, this new model captures the differentiation process from pre-fat cell to a fully mature fat cell. Next, the researchers screened the cell model with CRISPR to determine how many of these potential microproteins were involved in fat cell differentiation or proliferation.

“We’re not the first to screen for microproteins with CRISPR,” adds Pai, “but we’re the first to look for microproteins involved in fat cell proliferation. This is a huge step for metabolism and obesity research.”

Microproteins of interest and next steps

Using their mouse model and CRISPR screening approach, the team identified microproteins that may be involved in fat cell biology. They then narrowed the pool even further with another experiment to create a shortlist of 38 potential microproteins involved in lipid droplet formation—which indicates increasing fat storage—during fat cell differentiation.

At this point, the shortlisted microproteins were all still “potential” microproteins. This is because the genetic screening finds genes that may code for microproteins, rather than finding the microproteins themselves. While this approach is a helpful workaround to finding microproteins that are otherwise so small they elude capture, it also means that the screened microproteins require further testing to confirm whether they are functional.

And that’s what the Salk team did next. They picked several of the shortlisted microproteins to test and were able to verify one. Pai hypothesizes this new microprotein, called Adipocyte-smORF-1183, influences lipid droplet formation in fat cells (also known as adipocytes).

Verification of Adipocyte-smORF-1183 is an exciting step toward identifying more microproteins involved in lipid accumulation and fat cell regulation in obesity. It also verifies that CRISPR is an effective tool for finding microproteins involved in fat cell biology, obesity, and metabolism.

“That’s the goal of research, right?” says Saghatelian. “You keep going. It’s a constant process of improvement as we establish better technology and better workflows to enhance discovery and, eventually, therapeutic outcomes down the line.”

Next, the researchers will repeat the study with human fat cells. They also hope their success inspires others to use CRISPR screenings to continue bringing microproteins out from the dark—like Adipocyte-smORF-1183, which until now, was considered an unimportant bit of “junk” DNA.

Further validation or screening of new cell libraries will expand the list of potential drug candidates, setting the stage for the new-and-improved obesity and metabolic disorder therapeutics of the future.

Reference: Pai VJ, Shan H, Donaldson CJ, et al. CRISPR–Cas9 screening reveals microproteins regulating adipocyte proliferation and lipid metabolism. PNAS. 2025;122(32):e2506534122. doi: 10.1073/pnas.2506534122

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Some reassuring news for patients taking GLP-1 receptor agonists: Concerns that the drugs may cause retinopathy may be overblown.

A new analysis of nearly 160,000 people with diabetes taking four different GLP-1 medications for at least a year has found no increased risk for diabetic retinopathy associated with the drugs.

“We found no difference in the risk of sight-threatening retinopathy between GLP-1 agents among adults with type 2 diabetes and moderate cardiovascular risk, and this supports choosing the most appropriate agent for patients without consideration of potential difference in diabetic retinopathy complications,” Andrew J. Barkmeier, MD, a retina specialist at Mayo Clinic in Rochester, Minnesota, reported at the American Society of Retina Specialists (ASRS) 2025 Annual Meeting in Long Beach, California.

Barkmeier presented data from a retrospective analysis of patients in a commercial and Medicare database from 2014 through 2021 who were taking semaglutide, dulaglutide, liraglutide, or exenatide.

Previous Red Flag

The 2016 SUSTAIN-6 trial, which evaluated cardiovascular outcomes in people taking semaglutide for diabetes, reported participants had a 76% greater risk for retinopathy complications. Since then, Barkmeier said, clinicians have been concerned about the potential for eye damage in patients taking GLP-1 agents, and more specifically, semaglutide. A 2023 meta-analysis found that specific GLP-1s, along with patient demographic and clinical characteristics, may also influence the risk for diabetic retinopathy.

But Barkmeier told Medscape Medical News the new study “reassures the physicians prescribing these medications and the patients taking these medications that they can choose the most appropriate GLP-1 medication for them without having to consider potential differences in diabetic retinopathy risk.”

He and his colleagues performed a three-way comparison of patients initially treated with exenatide, dulaglutide, or liraglutide, along with a two-way comparison of semaglutide and dulaglutide over the latter years of the study, “when both of those medications were prominently prescribed,” Barkmeier told attendees at the meeting. Neither comparison found any differences in the primary composite outcome, which was treatment for diabetic macular edema or proliferative retinopathy, between the drugs.

In the three-way comparison, the rate of probability of requiring retina treatment for patients was 0.4% for all three GLP-1 agents at 2 years and 0.6%-0.7% at 3 years. In the two-way comparison, the probability of treating for retinopathy outcomes for dulaglutide and semaglutide was 0.5% and 0.4% at 2 years and 0.8% and 0.7% at 3 years, respectively.

The three-way comparison was noteworthy, Barkmeier said, because the median follow-up time was around 2.5 years, and more than 12,000 patients have at least 5 years of follow-up.

“The systemic benefits of these medications are so large, and the risks of reducing cardiovascular events are so clear that any continued research related to eye complications has to be weighed in the context of all the benefits,” Barkmeier told Medscape Medical News.

‘Stay in Lane’

Geoffrey G. Emerson, MD, PhD, a retina specialist with Retina Consultants of Minnesota and president-elect of ASRS, said Barkmeier’s research answers questions about GLP-1 drugs and retinopathy raised in previous research.

“His large cohort gives us confidence that GLP-1 agents are similar in terms of their effect on diabetic retinopathy, with generally beneficial effects,” Emerson told Medscape Medical News.

Studies have found GLP-1 medications may exacerbate diabetic macular edema early in the treatment, “but usually this is short-term and manageable,” Emerson said. “We still caution that any treatment that rapidly lowers hyperglycemia can temporarily worsen diabetic macular edema.”

The study suggests that retina specialists “should stay in our lane” and take care of retinopathy in patients taking GLP-1 agents, Emerson added.

“This story is far from over,” he said. “These obesity and diabetes treatments impact the eye in various ways, including perhaps worsening macular degeneration and probably reducing the risk of retinal vein occlusion, retinal artery occlusion, and late-stage diabetic retinopathy. Overall, we think the ocular effects are mostly beneficial, but stay tuned; this is a hot topic.”

The study was independently supported. Barkmeier reported having no relevant financial relationships. Emerson reported having relationships with Roche, Eli Lilly & Company, Regeneron Pharmaceuticals, and Novartis.

Richard Mark Kirkner is a medical journalist based in Philadelphia.