J Int Med Res. 2024 Jan;52(1):3000605231220867. doi: 10.1177/03000605231220867.

ABSTRACT

Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition caused by pancreatic neuroendocrine tumors (p-NETs). The severe hypercortisolemia that characterizes EAS is associated with a poor prognosis and survival. Mitotane is the only adrenolytic drug approved by the Food and Drug Administration and is often used to treat adrenocortical carcinoma. Combination therapy with mitotane and other adrenal steroidogenesis inhibitors is common for patients with Cushing's syndrome (CS). Here, we describe three patients who developed EAS secondary to the liver metastasis of p-NETs. All three rapidly developed hypercortisolemia but no typical features of CS. They underwent anti-tumor and mitotane therapy, which rapidly reduced their blood cortisol concentrations and ameliorated their symptoms. Their hypercortisolemia was controlled long term using a low dose of mitotane. The principal adverse effects were a slight loss of appetite and occasional dizziness, and there were no severe adverse effects. Importantly, even when the tumor progressed, the patients' circulating cortisol concentrations remained within the normal range. In summary, the present case series suggests that mitotane could be used to treat hypercortisolemia in patients with EAS caused by advanced p-NETs, in the absence of significant adverse effects.

PMID:38190848 | PMC:PMC10775748 | DOI:10.1177/03000605231220867

Home Healthc Now. 2024 Jan-Feb 01;42(1):6-12. doi: 10.1097/NHH.0000000000001223.

ABSTRACT

The prevalence of type 2 diabetes and obesity is increasing. Research has demonstrated the use of GLP-1 RA and SGLT-2i medications to be safe and effective for the long-term management of T2DM and obesity. As continued research supports the use of GLP-1 RA and SGLT-2i medications for additional indications, home care clinicians will increasingly care for patients on these medications. It is imperative that home care clinicians are aware of patient indications, adverse effects, and potential safety considerations related to these drugs to ensure patient goals are met.

PMID:38190158 | DOI:10.1097/NHH.0000000000001223

Cochrane Database Syst Rev. 2024 Jan 8;1:CD001552. doi: 10.1002/14651858.CD001552.pub3.

ABSTRACT

BACKGROUND: Carpal tunnel syndrome (CTS) is a compression neuropathy of the median nerve at the wrist. Surgery is considered when symptoms persist despite the use of non-surgical treatments. It is unclear whether surgery produces a better outcome than non-surgical therapy. This is an update of a Cochrane review published in 2008.

OBJECTIVES: To assess the evidence regarding the benefits and harms of carpal tunnel release compared with non-surgical treatment in the short (< 3 months) and long (> 3 months) term.

SEARCH METHODS: In this update, we included studies from the previous version of this review and searched the Cochrane Neuromuscular Specialised Register, CENTRAL, Embase, MEDLINE, ClinicalTrials.gov and WHO ICTRP until 18 November 2022. We also checked the reference lists of included studies and relevant systematic reviews for studies.

SELECTION CRITERIA: We included randomised controlled trials comparing any surgical technique with any non-surgical therapies for CTS.

DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane.

MAIN RESULTS: The 14 included studies randomised 1231 participants (1293 wrists). Eighty-four per cent of participants were women. The mean age ranged from 32 to 53 years, and the mean duration of symptoms from 31 weeks to 3.5 years. Trial sizes varied from 22 to 176 participants. The studies compared surgery with: splinting, corticosteroid injection, splinting and corticosteroid injection, platelet-rich plasma injection, manual therapy, multimodal non-operative treatment, unspecified medical treatment and hand support, and surgery and corticosteroid injection with corticosteroid injection alone. Since surgery is generally used for its long-term effects, this abstract presents only long-term results for surgery versus splinting and surgery versus corticosteroid injection. 1) Surgery compared to splinting in the long term (> 3 months) Surgery probably results in a higher rate of clinical improvement (risk ratio (RR) 2.10, 95% confidence interval (CI) 1.04 to 4.24; 3 studies, 210 participants; moderate-certainty evidence). Surgery probably does not provide clinically important benefit in symptoms or hand function compared with splinting (moderate-certainty evidence). The mean Boston Carpal Tunnel Questionnaire (BCTQ) Symptom Severity Scale (scale 1 to 5; higher is worse; minimal clinically important difference (MCID) = 1) was 1.54 with splint and 0.26 points better with surgery (95% CI 0.52 better to 0.01 worse; 2 studies, 195 participants). The mean BCTQ Functional Status Scale (scale 1 to 5; higher is worse; MCID 0.7) was 1.75 with splint and 0.36 points better with surgery (95% CI 0.62 better to 0.09 better; 2 studies, 195 participants). None of the studies reported pain. Surgery may not provide better health-related quality of life compared with splinting (low-certainty evidence). The mean EQ-5D index (scale 0 to 1; higher is better; MCID 0.074) was 0.81 with splinting and 0.04 points better with surgery (95% CI 0.0 to 0.08 better; 1 study, 167 participants). We are uncertain about the risk of adverse effects (very low-certainty evidence). Adverse effects were reported amongst 60 of 98 participants (61%) in the surgery group and 46 of 112 participants (41%) in the splinting group (RR 2.11, 95% CI 0.37 to 12.12; 2 studies, 210 participants). Surgery probably reduces the risk of further surgery; 41 of 93 participants (44%) were referred to surgery in the splinting group and 0 of 83 participants (0%) repeated surgery in the surgery group (RR 0.03, 95% CI 0.00 to 0.21; 2 studies, 176 participants). This corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 2 (95% CI 1 to 9). 2) Surgery compared to corticosteroid injection in the long term (> 3 months) We are uncertain if clinical improvement or symptom relief differs between surgery and corticosteroid injection (very low-certainty evidence). The RR for clinical improvement was 1.23 (95% CI 0.73 to 2.06; 3 studies, 187 participants). For symptoms, the standardised mean difference (SMD) was -0.60 (95% CI -1.88 to 0.69; 2 studies, 118 participants). This translates to 0.4 points better (95% CI from 1.3 better to 0.5 worse) on the BCTQ Symptom Severity Scale. Hand function or pain probably do not differ between surgery and corticosteroid injection (moderate-certainty evidence). For function, the SMD was -0.12 (95% CI -0.80 to 0.56; 2 studies, 191 participants) translating to 0.10 points better (95% CI 0.66 better to 0.46 worse) on the BCTQ Functional Status Scale with surgery. Pain (0 to 100 scale) was 8 points with corticosteroid injection and 6 points better (95% CI 10.45 better to 1.55 better; 1 study, 123 participants) with surgery. We found no data to estimate the difference in health-related quality of life (very low-certainty evidence). We are uncertain about the risk of adverse effects and further surgery (very low-certainty evidence). Adverse effects were reported amongst 3 of 45 participants (7%) in the surgery group and 2 of 45 participants (4%) in the corticosteroid injection group (RR 1.49, 95% CI 0.25 to 8.70; 2 studies, 90 participants). In one study, 12 of 83 participants (15%) needed surgery in the corticosteroid group, and 7 of 80 participants (9%) needed repeated surgery in the surgery group (RR 0.61, 95% CI 0.25 to 1.46; 1 study, 163 participants).

AUTHORS' CONCLUSIONS: Currently, the efficacy of surgery in people with CTS is unclear. It is also unclear if the results can be applied to people who are not satisfied after trying various non-surgical options. Future studies should preferably blind participants from treatment allocation and randomise people who are dissatisfied after being treated non-surgically. The decision for a patient to opt for surgery should balance the small benefits and potential risks of surgery. Patients with severe symptoms, a high preference for clinical improvement and reluctance to adhere to non-surgical options, and who do not consider potential surgical risks and morbidity a burden, may choose surgery. On the other hand, those who have tolerable symptoms, who have not tried non-surgical options and who want to avoid surgery-related morbidity can start with non-surgical options and have surgery only if necessary. We are uncertain if the risk of adverse effects differs between surgery and non-surgical treatments. The severity of adverse effects may also be different.

PMID:38189479 | DOI:10.1002/14651858.CD001552.pub3

PeerJ. 2024 Jan 4;12:e16732. doi: 10.7717/peerj.16732. eCollection 2024.

ABSTRACT

OBJECTIVE: This study aims to assess and compare the potential of advanced nano/micro delivery systems, including quantum dots, carbon nanotubes, magnetic nanoparticles, dendrimers, and microneedles, as theranostic platforms for oral cancer. Furthermore, we seek to evaluate their respective advantages and disadvantages over the past decade.

MATERIALS AND METHODS: A comprehensive literature search was performed using Google Scholar and PubMed, with a focus on articles published between 2013 and 2023. Search queries included the specific advanced delivery system as the primary term, followed by oral cancer as the secondary term (e.g., "quantum dots AND oral cancer," etc.).

RESULTS: The advanced delivery platforms exhibited notable diagnostic and therapeutic advantages when compared to conventional techniques or control groups. These benefits encompassed improved tumor detection and visualization, enhanced precision in targeting tumors with reduced harm to neighboring tissues, and improved drug solubility and distribution, leading to enhanced drug absorption and tumor uptake.

CONCLUSION: The findings suggest that advanced nano/micro delivery platforms hold promise for addressing numerous challenges associated with chemotherapy. By enabling precise targeting of cancerous cells, these platforms have the potential to mitigate adverse effects on surrounding healthy tissues, thus encouraging the development of innovative diagnostic and therapeutic strategies for oral cancer.

PMID:38188167 | PMC:PMC10771769 | DOI:10.7717/peerj.16732

Zhonghua Yu Fang Yi Xue Za Zhi. 2023 Dec 6;57(12):2002-2009. doi: 10.3760/cma.j.cn112150-20230105-00011.

ABSTRACT

To review and investigate the diagnosis results of local anesthetics (LA) allergy and improve the understanding of LA allergy in clinician. From March 2017 to February 2022, a total of 24 patients were investigated in Allergy Center of West China Hospital,Sichuan University on suspicion of LA allergy. Clinical data and results of skin tests and drug provocation tests (DPT) with the suspected drugs were retrospectively evaluated. The value of standardized diagnostic protocol in the LA allergy were analyzed. The results showed that 24 patients (3 men/21 women) were included with age range from 20 to 74 years. Three cases (12.5%) were positive in previous LA skin tests and proved to be tolerated through standardized tests. Twenty-one patients were initially diagnosed as "LA allergy" because of adverse reactions after previous use of LA, including 20 cases of immediate-type reaction and 1 case of delayed-type reaction. Three cases were considered LA allergy through standardized diagnosis approaches, including skin tests and DPT. One patient was diagnosed with anaphylaxis caused by chlorhexidine. Of the remaining 17 patients, 7 were considered as psychosomatic reactions (29.1%), 3 of sympathetic nervous system conditions (12.5%), 1 of spontaneous urticaria (4.2%), 2 of vasovagal syncope (8.3%), drug side effects (8.3%), skin irritation (8.3%), respectively. In conclusion, true allergic reactions to LA are rare. Through standardized skin tests and DPT, allergy can be ruled out in the vast majority of patients who complain of "LA allergy". For patients who are highly suspected of LA inducing anaphylaxis, other local anesthetics that can be used as safe alternatives should be determined by diagnostic tests according to future needs.

PMID:38186148 | DOI:10.3760/cma.j.cn112150-20230105-00011

Pediatr Infect Dis J. 2024 Jan 4. doi: 10.1097/INF.0000000000004243. Online ahead of print.

ABSTRACT

BACKGROUND: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates.

METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months.

RESULTS: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months.

CONCLUSIONS: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.

PMID:38190642 | DOI:10.1097/INF.0000000000004243

Front Med (Lausanne). 2023 Dec 21;10:1304369. doi: 10.3389/fmed.2023.1304369. eCollection 2023.

ABSTRACT

BACKGROUND: Gram-negative bacteria is a global public health problem. Treatment options include novel beta-lactamase inhibitors.

OBJECTIVES: The objective of this study was to collect information on the efficacy and safety of novel β-lactamase inhibitor combinations such as imipenem-cilastatin/relebactam (IMI/REL).

METHODS: In order to comprehensively evaluate the clinical, microbiological, and adverse events outcomes, a meta-analysis was conducted on clinical trials comparing novel β-lactamase inhibitor combinations with existing comparator therapies.

RESULTS: Four studies comprising 948 patients were included in the analysis. IMI/REL therapy demonstrated similar clinical responses to comparators across various treatment visits, including discontinuation of intravenously administered therapy visits [DCIV, RR = 1.00 (0.88, 1.12)], early follow-up visits [EFU, RR = 1.00 (0.89, 1.14)], late follow-up visits [LFU, RR = 1.00 (0.88, 1.13)]. Moreover, no significant difference in the microbiologic response of MITT patients was observed between IMI/REL and comparators across DCIV [RR = 0.99 (0.89, 1.11)], EFU [RR = 1.01 (0.95, 1.07)], and LFU visits [RR = 1.00 (90.94, 1.07)]. In terms of safety, therapy with IMI/REL and comparators exhibited similar risks of at least one adverse event (AE), drug-related AEs, and discontinuation due to AEs. The incidence of serious AEs (SAEs) was significantly lower in the IMI/REL group compared to the comparison groups. The predominant AEs were gastrointestinal disorders, with no significant difference observed between the IMI/REL group and comparators.

CONCLUSION: The clinical and microbiologic response to IMI/REL in the treatment of bacterial infection was comparable to that of the comparator. Furthermore, the incidence of AEs and the tolerability of IMI/REL were similar among the comparators. Based on these findings, IMI/REL can be considered as a viable alternative treatment option.

PMID:38188339 | PMC:PMC10767998 | DOI:10.3389/fmed.2023.1304369

Hosp Pediatr. 2024 Jan 8:e2023007265. doi: 10.1542/hpeds.2023-007265. Online ahead of print.

ABSTRACT

OBJECTIVES: Hospital at home (HAH) replaces acute inpatient hospital care for selected patients by providing care in their homes. We sought to describe the characteristics, management, and complications of patients with osteoarticular infections (OAIs) treated in an HAH program and its economic impact.

METHODS: We conducted a retrospective observational study evaluating an HAH program in a pediatric hospital in Spain, describing the characteristics of patients with confirmed OAIs requiring intravenous antibiotic therapy admitted to this program between January 2019 and December 2022. The program operates as a virtual ward with possible daily visits by physicians and nurses and 24/7 telephone contact.

RESULTS: A total of 88 patients (median age, 4.1 years; interquartile range [IQR], 1.7-10.6) with OIAs were admitted to the HAH program. Osteomyelitis (57%) and septic arthritis (29%) were the most frequent infections. Cefuroxime (42%) and cefazolin (39%) were the most frequently prescribed antibiotics. Caregiver self-administration was performed in 99%, allowing multiple daily doses of antimicrobial therapy, 80% by peripheral line. Thirteen patients (15%) had drug-related adverse events, only 3 requiring drug modification. Two patients (2%) were readmitted during HAH, and 1 was readmitted within 30 days of HAH discharge. The median HAH stay was 7 days (IQR, 4-8.75). For osteomyelitis, hospital days lowered from 8.5 days (IQR, 4.5-12) to 4 days (IQR, 3-7) after HAH implementation (P = .005) with 68% per-patient estimated cost savings.

CONCLUSIONS: HAH treatment of OAIs is effective and cost-efficient. Patient support by medical and nursing staff, adequate family training, and regular communication are essential to ensure safe home admission.

PMID:38186289 | DOI:10.1542/hpeds.2023-007265

Sci Rep. 2024 Jan 5;14(1):620. doi: 10.1038/s41598-024-51302-5.

ABSTRACT

Salinity stress has detrimental effects on various aspects of plant development. However, our understanding of strategies to mitigate these effects in crop plants remains limited. Recent research has shed light on the potential of sodium acetate as a mitigating component against salinity stress in several plant species. Here, we show the role of acetate sodium in counteracting the adverse effects on oat (Avena sativa) plants subjected to NaCl-induced salinity stress, including its impact on plant morphology, photosynthetic parameters, and gene expression related to photosynthesis and antioxidant capacity, ultimately leading to osmoprotection. The five-week experiment involved subjecting oat plants to four different conditions: water, salt (NaCl), sodium acetate, and a combination of salt and sodium acetate. The presence of NaCl significantly inhibited plant growth and root elongation, disrupted chlorophylls and carotenoids content, impaired chlorophyll fluorescence, and down-regulated genes associated with the plant antioxidant defense system. Furthermore, our findings reveal that when stressed plants were treated with sodium acetate, it partially reversed these adverse effects across all analyzed parameters. This reversal was particularly evident in the increased content of proline, thereby ensuring osmoprotection for oat plants, even under stressful conditions. These results provide compelling evidence regarding the positive impact of sodium acetate on various plant development parameters, with a particular focus on the enhancement of photosynthetic activity.

PMID:38182773 | PMC:PMC10770181 | DOI:10.1038/s41598-024-51302-5

Sci Rep. 2024 Jan 5;14(1):591. doi: 10.1038/s41598-023-48640-1.

ABSTRACT

Proton pump inhibitors (PPIs) are commonly used in cancer patients, but their impact on treatment outcomes in multiple myeloma (MM) patients remains unclear. This study investigated the association of PPI use with survival and adverse effects in MM patients across three randomized-control trials initiating daratumumab, lenalidomide, or bortezomib combination treatments. Cox proportional hazard analysis and logistic regression were employed to assess the associations with treatment outcomes, while adjusting for age, sex, weight, MM international staging system stage, ECOG-performance status, comorbidity count, and presence of gastrointestinal disorders. Pooled data involving 1804 patients revealed that 557 (32%) used PPIs at baseline. PPI use was independently associated with worse overall survival (adjusted HR [95% CI] 1.32 [1.08-1.62], P = 0.007) and grade ≥ 3 adverse events (adjusted OR [95% CI] 1.39 [1.03-1.88], P = 0.030). However, the association with progression-free survival did not reach statistical significance (adjusted HR [95% CI] 1.14 [0.97-1.33], P = 0.112). Findings were consistent across trials and treatment arms. PPI use was identified as a negative prognostic factor in MM patients, potentially enhancing clinical decisions regarding its use. Further research is needed to fully comprehend the impacts and safety of PPI use in MM patients.

PMID:38182614 | PMC:PMC10770405 | DOI:10.1038/s41598-023-48640-1

PLoS One. 2024 Jan 5;19(1):e0296384. doi: 10.1371/journal.pone.0296384. eCollection 2024.

ABSTRACT

PURPOSE: Metastatic breast cancer [MBC] is the leading cause of cancer death in women globally with no cure. Women diagnosed with MBC endure a catastrophic upheaval to multiple aspects of their life and a radically transformed future landscape. Evidence suggests that the provision of care for women living with metastatic breast cancer is inadequate, socially isolating and stigmatising. To date, this topic has received little research attention. To increase understanding of the experiences of women living with MBC, a synthesis of current evidence is required. This paper presents a review of qualitative evidence on women's experiences of MBC.

METHODS: A qualitative evidence synthesis [QES] was conducted to synthesise primary qualitative research on the experiences of women living with MBC. Searches were performed of electronic databases Medline, Medline Ovid, PsycINFO, Psych articles, PubMED, CINAHL Complete, Scopus and grey literature databases. The methodological quality of the included studies was appraised using a modified version of the Critical Appraisal Skills Programme [CASP]. Title, abstract, and full-text screening were undertaken. A 'best fit' framework approach using the ARC [Adversity, Restoration, Compatibility] framework was used to guide data extraction and synthesis. Confidence in the findings was assessed using the Grading of Recommendations Assessment, Development and Evaluation, Confidence in the Evidence from Reviews of Qualitative research [GRADE-CERQual].

RESULTS: 28 papers from 21 research studies containing 478 women's experiences of living with MBC were deemed suitable for inclusion in this qualitative evidence synthesis. Findings are presented in a new conceptual framework RAAW [adapted from ARC] for women living with MBC under themes: Reality, Adversity, Adjustment and Wellbeing. Findings revealed that a diagnosis of MBC impacted every aspect of women's lives; this is different to a diagnosis of early breast cancer. An overarching theme of lack of support extended across various facets of their lives. A lack of psychological, emotional, and psychosocial support was evident, with a critical finding that models of care were not fit for purpose. Deficits included a lack of information, knowledge, inclusion in shared decision-making and MDT support, specifically the need for palliative care/oncology support access. Some women living with MBC wanted to be identified as having a chronic illness not a life-limiting illness. Culture and socioeconomic standing influenced the availability of various types of support. The impact of treatment and symptoms had an adverse effect on women's quality of life and affected their ability to adjust.

CONCLUSION: This review synthesised the qualitative literature on the experiences of women living with MBC. The ARC framework used in the synthesis was adapted to develop a revised conceptual framework titled RAAW to represent the evidence from this review on experiences for women living with MBC; Reality & Adversity: A diagnosis of MBC; Adjustment: Living with MBC; Wellbeing: Awareness, meaning, engagement [RAAW; MBC].

PMID:38181009 | PMC:PMC10769043 | DOI:10.1371/journal.pone.0296384

Elife. 2024 Jan 5;12:RP87271. doi: 10.7554/eLife.87271.

ABSTRACT

Acute stress can change our cognition and emotions, but what specific consequences this has for human prosocial behaviour is unclear. Previous studies have mainly investigated prosociality with financial transfers in economic games and produced conflicting results. Yet a core feature of many types of prosocial behaviour is that they are effortful. We therefore examined how acute stress changes our willingness to exert effort that benefits others. Healthy male participants - half of whom were put under acute stress - made decisions whether to exert physical effort to gain money for themselves or another person. With this design, we could independently assess the effects of acute stress on prosocial, compared to self-benefitting, effortful behaviour. Compared to controls (n = 45), participants in the stress group (n = 46) chose to exert effort more often for self- than for other-benefitting rewards at a low level of effort. Additionally, the adverse effects of stress on prosocial effort were particularly pronounced in more selfish participants. Neuroimaging combined with computational modelling revealed a putative neural mechanism underlying these effects: more stressed participants showed increased activation to subjective value in the dorsal anterior cingulate cortex and anterior insula when they themselves could benefit from their exerted effort relative to when someone else could. By using an effort-based task that better approximates real-life prosocial behaviour and incorporating trait differences in prosocial tendencies, our study provides important insights into how acute stress affects prosociality and its associated neural mechanisms.

PMID:38180785 | DOI:10.7554/eLife.87271

Eur J Hosp Pharm. 2024 Jan 5:ejhpharm-2023-003779. doi: 10.1136/ejhpharm-2023-003779. Online ahead of print.

ABSTRACT

OBJECTIVES: The anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAb) are effective in migraine; however, few studies have examined the benefit of switching from one anti-CGRP-mAb to another. In order to better inform clinical practice in this situation, we present our real-world findings of switching anti-CGRP-mAb in chronic migraine.

METHODS: Individuals with chronic migraine that switched anti-CGRP-mAb treatment (erenumab, fremanezumab or galcanezumab) due to ineffectiveness or adverse effects were retrospectively identified. Headache diary data before and up to 6 months after anti-CGRP-mAb switch were analysed. Main outcome measures were monthly red days (days with headaches limiting activity or requiring triptans), headache days (days with any kind of headache), triptan use, other analgesic use and headache disability (Headache Impact Test-6 (HIT-6) score) at 3 months.

RESULTS: The analysis included 66 instances of switching among 54 individuals. There were non-significant reductions of -1.2 (-2.7, 0.3) red days from baseline at 3 months, with 10 individuals (15%) showing ≥50% improvement and 22 (33%) experiencing a ≥30% improvement. Improvements in headache days, triptan days, other painkiller use and HIT-6 score were non-significant. When individuals that switched due to side effects were excluded from the analysis, significant reductions in headache (Friedman p=0.044) and a trend for improvement in red days (Friedman p=0.083) were observed. With regard to side effects, on 12 occasions these improved or resolved on switching to a different anti-CGRP-mAb, while new symptoms were reported on eight occasions following a switch.

CONCLUSION: We recorded modest improvements in headache outcomes, although significant results were only observed in those that switched anti-CGRP-mAb due to ineffectiveness. Switching may therefore be a viable option for these individuals.

PMID:38182276 | DOI:10.1136/ejhpharm-2023-003779

Transpl Infect Dis. 2024 Jan 5:e14233. doi: 10.1111/tid.14233. Online ahead of print.

ABSTRACT

BACKGROUND: Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug-induced side effects and dose reduction due to decline in kidney function.

METHOD: In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections.

RESULTS: In the studied cohort, 18.7% of patients showed a high-risk (HR) constellation (D+/R-) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients.

CONCLUSION: The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post-KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir.

PMID:38180168 | DOI:10.1111/tid.14233

Int J Tuberc Lung Dis. 2024 Jan 1;28(1):6-12. doi: 10.5588/ijtld.23.0038.

ABSTRACT

BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â-"149.0 (IQR â-"299.3 to â-"98.3 (), â-"225.5 (IQR â-"309.3 to â-"181.8 ) and â-"242.5 (IQR â-"364.8 to â-"153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

PMID:38178298 | DOI:10.5588/ijtld.23.0038

Nat Med. 2024 Jan 4. doi: 10.1038/s41591-023-02719-4. Online ahead of print.

ABSTRACT

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate-mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6-14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg-1 single dose; n = 364) or to artesunate-mefloquine (antimalarial dosage: artesunate 4 mg kg-1 and mefloquine 8 mg kg-1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate-mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate-mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of -2.5% (95% confidence interval (CI) -9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate-mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate-mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

PMID:38177851 | DOI:10.1038/s41591-023-02719-4

Cochrane Database Syst Rev. 2024 Jan 4;1:CD013474. doi: 10.1002/14651858.CD013474.pub2.

ABSTRACT

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain.

OBJECTIVES: To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL.

SEARCH METHODS: We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies.

SELECTION CRITERIA: We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs).

MAIN RESULTS: We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found. The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low. Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone. Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group. One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference -1.70, 95% CI -8.59 to 5.19; 480 participants; 1 study; low-certainty evidence). Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. No studies assessed HRQoL. Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs.

AUTHORS' CONCLUSIONS: There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.

PMID:38174814 | DOI:10.1002/14651858.CD013474.pub2

World J Gastrointest Pharmacol Ther. 2023 Dec 12;14(5):39-49. doi: 10.4292/wjgpt.v14.i5.39.

ABSTRACT

BACKGROUND: Amino-acid based medical foods have shown promise in alleviating symptoms of drug induced gastrointestinal side effects; particularly, diarrhea-predominant symptoms. Irritable bowel syndrome (IBS) is a gastrointestinal disorder that affects up to 9% of people globally, with diarrhea predominant IBS (IBS-D) being the most prevalent subtype. Further trials are needed to explore potential added benefits when integrated into standard care for IBS-D.

AIM: To assess the effectiveness of an amino acid-based medical food as an adjunct to standard of care for adults with IBS-D.

METHODS: This is a pragmatic, real world, open label, single arm study comparing a 2-week baseline assessment to a 2-week intervention period. One hundred adults, aged 18 to 65 years, with IBS-D, according to Rome IV criteria, were enrolled after completing a 2-week baseline assessment period and received a 2-week supply of an amino acid based medical food which was consumed at home twice daily on top of their standard of care. The primary outcome was an assessment of tolerability after 2-weeks of consumption, while secondary outcomes included changes in stool consistency (Bristol Stool Form Scale), severity of abdominal pain & discomfort, symptoms of urgency, Global Improvement Survey (GIS), and the IBS severity scoring system (IBS-SSS).

RESULTS: The test product was well-tolerated as each participant successfully completed the full 14-day trial, and there were no instances of dropouts or discontinuation of the study product reported. Forty percent of participants achieved a 50% or more reduction in the number of days with type 6-7 bowel movements (IBS-D stool consistency responders). Fifty-three percent of participants achieved a clinically meaningful reduction of 30% in mean weekly pain scores, and 55% experienced the same for mean weekly discomfort scores (IBS-D pain and discomfort responders). Participants experienced a mean -109.4 (95% confidence interval: -130.1, -88.8) point reduction on the IBS-SSS and 52% experienced a minimally clinically important difference of > 95 points. An IBS-SSS category shift from severe to moderate or mild occurred in 69% of participants. For functional symptoms, 76% of participants reported symptom relief on the GIS.

CONCLUSION: The amino acid-based medical food was well-tolerated, when added to the standard of care, and demonstrated improvements in both overall IBS symptom severity and IBS-D symptoms within just 2 wk.

PMID:38174291 | PMC:PMC10758599 | DOI:10.4292/wjgpt.v14.i5.39

J Cheminform. 2024 Jan 3;16(1):1. doi: 10.1186/s13321-023-00796-8.

ABSTRACT

Safety is one of the important factors constraining the distribution of clinical drugs on the market. Drug-induced liver injury (DILI) is the leading cause of safety problems produced by drug side effects. Therefore, the DILI risk of approved drugs and potential drug candidates should be assessed. Currently, in vivo and in vitro methods are used to test DILI risk, but both methods are labor-intensive, time-consuming, and expensive. To overcome these problems, many in silico methods for DILI prediction have been suggested. Previous studies have shown that DILI prediction models can be utilized as prescreening tools, and they achieved a good performance. However, there are still limitations in interpreting the prediction results. Therefore, this study focused on interpreting the model prediction to analyze which features could potentially cause DILI. For this, five publicly available datasets were collected to train and test the model. Then, various machine learning methods were applied using substructure and physicochemical descriptors as inputs and the DILI label as the output. The interpretation of feature importance was analyzed by recognizing the following general-to-specific patterns: (i) identifying general important features of the overall DILI predictions, and (ii) highlighting specific molecular substructures which were highly related to the DILI prediction for each compound. The results indicated that the model not only captured the previously known properties to be related to DILI but also proposed a new DILI potential substructural of physicochemical properties. The models for the DILI prediction achieved an area under the receiver operating characteristic (AUROC) of 0.88-0.97 and an area under the Precision-Recall curve (AUPRC) of 0.81-0.95. From this, we hope the proposed models can help identify the potential DILI risk of drug candidates at an early stage and offer valuable insights for drug development.

PMID:38173043 | DOI:10.1186/s13321-023-00796-8

Exp Biol Med (Maywood). 2023 Nov;248(21):1937-1943. doi: 10.1177/15353702231220669. Epub 2024 Jan 2.

ABSTRACT

The US drug labeling document contains essential information on drug efficacy and safety, making it a crucial regulatory resource for Food and Drug Administration (FDA) drug reviewers. Due to its extensive volume and the presence of free-text, conventional text mining analysis have encountered challenges in processing these data. Recent advances in artificial intelligence (AI) for natural language processing (NLP) have provided an unprecedented opportunity to identify key information from drug labeling, thereby enhancing safety reviews and support for regulatory decisions. We developed RxBERT, a Bidirectional Encoder Representations from Transformers (BERT) model pretrained on FDA human prescription drug labeling documents for an enhanced application of drug labeling documents in both research and drug review. RxBERT was derived from BioBERT with further training on human prescription drug labeling documents. RxBERT was demonstrated in several tasks using regulatory datasets, including those involved in the National Institutes of Technology Text Analysis Challenge Dataset (NIST TAC dataset), the FDA Adverse Drug Event Evaluation Dataset (ADE Eval dataset), and the classification of texts from submission packages into labeling sections (US Drug Labeling dataset). For all these tasks, RxBERT reached 86.5 F1-scores in both TAC and ADE Eval classification, respectively, and prediction accuracy of 87% for the US Drug Labeling dataset. Overall, RxBERT was shown to be as competitive or have better performance compared to other NLP approaches such as BERT, BioBERT, etc. In summary, we developed RxBERT, a transformer-based model specific for drug labeling that outperformed the original BERT model. RxBERT has the potential to be used to assist research scientists and FDA reviewers to better process and utilize drug labeling information toward the advancement of drug effectiveness and safety for public health. This proof-of-concept study also demonstrated a potential pathway to customized large language models (LLMs) tailored to the sensitive regulatory documents for internal application.

PMID:38166420 | DOI:10.1177/15353702231220669