Clinical outcomes of antimicrobial resistance in cancer patients: a systematic review of multivariable models.

BACKGROUND: Infections are major causes of disease in cancer patients and pose a major obstacle to the success of cancer care. The global rise of antimicrobial resistance threatens to make these obstacles even greater and hinder continuing progress in cancer care. To prevent and handle such infections, better models of clinical outcomes building on current knowledge are needed. This internally funded systematic review (PROSPERO registration: CRD42021282769) aimed to review multivariable models of resistant infections/colonisations and corresponding mortality, what risk factors have been investigated, and with what methodological approaches. METHODS: We employed two broad searches of antimicrobial resistance in cancer patients, using terms associated with antimicrobial resistance, in MEDLINE and Embase through Ovid, in addition to Cinahl through EBSCOhost and Web of Science Core Collection. Primary, observational studies in English from January 2015 to November 2021 on human cancer patients that explicitly modelled infection/colonisation or mortality associated with antimicrobial resistance in a multivariable model were included. We extracted data on the study populations and their malignancies, risk factors, microbial aetiology, and methods for variable selection, and assessed the risk of bias using the NHLBI Study Quality Assessment Tools. RESULTS: Two searches yielded a total of 27,151 unique records, of which 144 studies were included after screening and reading. Of the outcomes studied, mortality was the most common (68/144, 47%). Forty-five per cent (65/144) of the studies focused on haemato-oncological patients, and 27% (39/144) studied several bacteria or fungi. Studies included a median of 200 patients and 46 events. One-hundred-and-three (72%) studies used a p-value-based variable selection. Studies included a median of seven variables in the final (and largest) model, which yielded a median of 7 events per variable. An in-depth example of vancomycin-resistant enterococci was reported. CONCLUSIONS: We found the current research to be heterogeneous in the approaches to studying this topic. Methodological choices resulting in very diverse models made it difficult or even impossible to draw statistical inferences and summarise what risk factors were of clinical relevance. The development and adherence to more standardised protocols that build on existing literature are urgent.

The effectiveness of peer-support for people living with HIV: A systematic review and meta-analysis.

BACKGROUND: The practice of involving people living with HIV in the development and provision of healthcare has gained increasing traction. Peer-support for people living with HIV is assistance and encouragement by an individual considered equal, in taking an active role in self-management of their chronic health condition. The objective of this systematic review was to assess the effects of peer-support for people living with HIV. METHODS: We conducted a systematic review in accordance with international guidelines. Following systematic searches of eight databases until May 2020, two reviewers performed independent screening of studies according to preset inclusion criteria. We conducted risk of bias assessments and meta-analyses of the available evidence in randomised controlled trials (RCTs). The certainty of the evidence for each primary outcome was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: After screening 219 full texts we included 20 RCTs comprising 7605 participants at baseline from nine different countries. The studies generally had low risk of bias. Main outcomes with high certainty of evidence showed modest, but superior retention in care (Risk Ratio [RR] 1.07; Confidence Interval [CI] 95% 1.02-1.12 at 12 months follow-up), antiretroviral therapy (ART) adherence (RR 1.06; CI 95% 1.01-1.10 at 3 months follow-up), and viral suppression (Odds Ratio up to 6.24; CI 95% 1.28-30.5 at 6 months follow-up) for peer-support participants. The results showed that the current state of evidence for most other main outcomes (ART initiation, CD4 cell count, quality of life, mental health) was promising, but too uncertain for firm conclusions. CONCLUSIONS: Overall, peer-support with routine medical care is superior to routine clinic follow-up in improving outcomes for people living with HIV. It is a feasible and effective approach for linking and retaining people living with HIV to HIV care, which can help shoulder existing services. TRIAL REGISTRATION: CRD42020173433.

Tailoring mass drug administration to context: implementation research is critical in achieving equitable progress in the control and elimination of helminth neglected tropical diseases in sub-Saharan Africa.

The concept of a technological quick fix or 'magic-bullet' for control and elimination of Neglected Tropical Diseases (NTDs) is flawed. NTDs are embedded within complex biological and social systems that are shaped by ecological and political contexts. This commentary emphasises the need for implementation research to address implementation gaps in the control of NTDs. With a specific focus on sub-Saharan Africa and helminth diseases amenable to preventive chemotherapy through mass drug administration, we explore the important role of context, programme partnerships and community in achieving equitable and effective NTD control.

Evaluation of PolyMPC-Dox Prodrugs in a Human Ovarian Tumor Model.

A polymer prodrug, composed of doxorubicin (Dox) conjugated covalently to poly(methacryloyloxyethyl phosphorylcholine) (polyMPC), was evaluated for the treatment of human ovarian tumors in animals. PolyMPC-Dox prodrugs were prepared using facile conjugation chemistry to yield conjugates soluble in water and injectable saline, with a Dox loading of ∼19 weight percent. Toxicity evaluation showed that polyMPC was well-tolerated in mice at doses up to 800 mg/kg, confirming the biocompatibility of the polymer carrier at a high concentration. Additionally, the polyMPC-Dox prodrug was well-tolerated in animals at a Dox equivalent dose of 10 mg/kg, greater than twice the maximum tolerated dose of free Dox (∼4 mg/kg) in the same mouse strain. In a human ovarian tumor model (SKOV-3), polyMPC-Dox accumulated in tumors at twice the level of free Dox, with no additional off-target organ uptake, a result of improved pharmacokinetics afforded by the prodrug and passive targeting attributed to an enhanced permeability and retention effect. When administered to human ovarian tumor-bearing mice using a recurring dosing regimen comparable to that used clinically, polyMPC-Dox significantly retarded tumor growth relative to treatment with free Dox. Moreover, animals treated with multiple doses of polyMPC-Dox (eight total doses) exhibited enhanced survival, with a notably reduced incidence of toxicity or adverse events relative to mice treated with free Dox. These in vivo results demonstrate advantages of treating human ovarian tumors with polyMPC-Dox, including reduced systemic toxicity, improved drug accumulation in tumors, and enhanced therapeutic efficacy.

Assessing the potential threat landscape of a proposed reintroduction site for carnivores.

This study provides a framework to assess the feasibility of reintroducing carnivores into an area, using African wild dogs (Lycaon pictus) as an example. The Great Fish River Nature Reserve in the Eastern Cape Province, South Africa, has been identified as a potential reserve to reintroduce wild dogs, and we applied this framework to provide a threat assessment of the surrounding area to determine potential levels of human-wildlife conflict. Although 56% of neighbouring landowners and local communities were positive about a wild dog reintroduction, data collected from questionnaire surveys revealed that human-wild dog conflict is a potential threat to wild dog survival in the area. Additional potential threats include diseases, snaring, poaching and hunting wild dogs for the use of traditional medicine. A threat index was developed to establish which properties harboured the greatest threats to wild dogs. This index was significantly influenced by the respondent's first language (isiXhosa had more positive indices), education level (poorer education was synonymous with more positive threat indices), land use (wildlife ranching being the most negative) and land tenure (community respondents had more positive indices than private landowners). Although threats are present, they can be effectively mitigated through strategies such as carnivore education programs, vaccination campaigns and anti-snare patrols to promote a successful reintroduction of this endangered canid.

Post-sterilization autonomy among young mothers in South India.

This study examined the post-sterilization autonomy of women in south India in the context of early sterilization and low fertility. Quantitative data were taken from the third round of the National Family Health Survey (NFHS-3) carried out in 2005-06, and qualitative data from one village each in Kerala and Tamil Nadu during 2010-11. The incident rate ratios and thematic analysis showed that among currently married women under the age of 30 years, those who had been sterilized had significantly higher autonomy in household decision-making and freedom of mobility compared with women who had never used any modern family planning method. Early age at sterilization and low fertility enables women to achieve the social status that is generally attained at later stages in the life-cycle. Policies to capitalize on women's autonomy and free time resulting from early sterilization and low fertility should be adopted in south India.

Efficacy of polyMPC-DOX prodrugs in 4T1 tumor-bearing mice.

We report the in vivo efficacy, in tumor-bearing mice, of cancer prodrugs consisting of poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) conjugated to doxorubicin (DOX). Our synthesis of polyMPC-DOX conjugates established prodrugs with tunable drug loading, pH sensitive release kinetics, and a maximum tolerated dose in the range of 30-50 mg/kg (DOX equivalent) in healthy mice. Here we show prolonged circulation of polyMPC-DOX, with a measured in vivo half-life (t1/2) 8 times greater than that of the free drug. We observed reduced drug uptake in healthy tissue, and 2-3 times enhanced drug accumulation in tumors for polyMPC-DOX prodrugs compared to free DOX, using BALB/c mice bearing 4T1 tumors. Prolonged survival and reduced tumor growth were observed in mice receiving the polyMPC-DOX prodrug treatment. Moreover, we evaluated immunogenicity of polyMPC-DOX prodrugs by examining complete blood count (CBC) and characteristic cytokine responses, demonstrating no apparent innate or adaptive immune system response.

Promoting cell adhesion on slippery phosphorylcholine hydrogel surfaces.

The growing interest in regenerative medicine has created a need for superior polymer matrices that suit multiple physical, mechanical, and biological requirements. While the phospholipid bilayer of a cell membrane is considered optimal for interacting with biologics, polymeric materials composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) offer a cell membrane-like synthetic alternative. In this work, thiol-containing phosphorylcholine polymers were synthesized by radical copolymerization of a lipoic acid-functionalized methacrylate with MPC. The canonical cell adhesion oligopeptide (GRGDS) was incorporated into the polymers by copolymerization of a GRGDS-containing methacrylamide prepared by solid phase peptide synthesis. The relative amounts of phosphorylcholine, lipoic acid and oligopeptide were controlled by the monomer feed ratios, and the polymers were characterized by NMR spectroscopy and aqueous gel permeation chromatography (GPC). These multifunctional polymers formed hydrogels rapidly (<10 minutes) by Michael addition when poly(ethylene glycol)diacrylate (PEGDA) was added at pH 9 - an initiator-free gelation performed in a completely aqueous environment. Two cell lines, live mouse skeletal muscle myoblasts (C2C12) and human ovarian cancer (SKOV3) cells, were observed to specifically attach, spread and proliferate only on hydrogels containing the GRGDS peptide sequence, with a notable dependence on peptide concentration. The remarkable hydrophilicity and biocompatibility attributed to polyMPC combined with the facile gelation conditions of these polymers affords a platform of new bio-cooperative materials suitable for cell studies.

Disulfide cross-linked phosphorylcholine micelles for triggered release of camptothecin.

A series of block copolymers based on 2-methacryloyloxyethyl phosphorylcholine (MPC) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Incorporation of dihydrolipoic acid (DHLA) into the hydrophobic block led to formation of block copolymer micelles in water. The micelles were between 15 and 30 nm in diameter, as characterized by dynamic light scattering (DLS), with some size control achieved by adjusting the hydrophobic/hydrophilic balance. Cross-linked micelles were prepared by disulfide formation, and observed to be stable in solution for weeks. The micelles proved amenable to disassembly when treated with a reducing agent, such as dithiothreitol (DTT), and represent a potential delivery platform for chemotherapeutic agents. As a proof-of-concept, camptothecin (CPT) was conjugated to the polymer scaffold through a disulfide linkage, and release of the drug from the micelle was monitored by fluorescence spectroscopy. These CPT-loaded prodrug micelles showed a reduction in release rate compared to physically encapsulated CPT. The use of disulfide conjugation facilitated drug release under reducing conditions, with a half-life (t1/2) of 5.5 h in the presence of 3 mM DTT, compared to 28 h in PBS. The toxicity of the micellar prodrugs was evaluated in cell culture against human breast (MCF7) and colorectal (COLO205) cancer cell lines.