Seroepidemiologic Correlations in Malaria

Serologic measurements of humoral immunity have been used to estimate malaria transmission in en­demic areas. The usual methods employ enzyme linked immunosorbent assays (ELISA) and immunofluores-cent antibody tests of a wide variety of malaria antigens. In theory, higher levels of antibody reflect higher levels of exposure to malaria antigen i.e., disease. However, one must carefully consider variables such as endemicity, species of malaria present, age of the group examined, and the antigent/test array selected. Without doing so, it is easy to draw erroneous conclusions. This presentation provides guidelines to select­ing a test and antigen appropriate for deriving given epidemiologic conclusions from serologic surveys. Also, recent work on DNA probes of malaria and serum markers of cell-mediated immunity is described in con­text of epidemiologic measures of malaria transmission

INCIDENCE OF SYMPTOMATIC AND ASYMPTOMATIC \u3ci\u3ePLASMODIUM FALCIPARUM\u3c/i\u3e INFECTION FOLLOWING CURATIVE THERAPY IN ADULT RESIDENTS OF NORTHERN GHANA

Adult residents of holoendemic malaria regions in Africa have a naturally acquired immunity (NAI) to malaria that renders them more resistant to new infections, limits parasitemia, and reduces the frequency and severity of illness. Given such attributes, it is not clear how one might evaluate drug or vaccine efficacy in adults without serious confounding. To determine symptomatic and asymptomatic malaria attack rates in adults of northern Ghana, 197 men and women underwent curative therapy for any pre-existing malaria infections at the start of the high transmission (wet) season. They were monitored for first parasitemia and first clinical episode of infection by Plasmodium falciparum over a 20-week period (May–October 1996). The cumulative incidence of primary infection by P. falciparum was 0.98 and incidence density of infection was calculated to be 7.0 cases/person-year. Symptoms were reported by 19.5% of the individuals at the time of first recurrent parasitemia. Incidence of infection, parasite density, and the frequency of symptoms were comparable in males and females. The results suggest that NAI did not provide these adults with significant defense against rapid re-infection and suggest that this population-infection design could serve to demonstrate the efficacy of a drug or vaccine in preventing parasitemia

How and why might interprofessional patient- and family-centered rounds improve outcomes among healthcare teams and hospitalized patients? A conceptual framework informed by scoping and narrative literature review methods

Poor communication within healthcare contributes to inefficiencies, medical errors, conflict, and other adverse outcomes. A promising model to improve outcomes resulting from poor communication in the inpatient hospital setting is Interprofessional Patient- and Family-Centered rounds (IPFCR). IPFCR brings two or more health professions together with hospitalized patients and families as part of a consistent, team-based routine to share information and collaboratively arrive at a daily plan of care. A growing body of literature focuses on implementation and outcomes of IPFCR to improve healthcare quality and team and patient outcomes. Most studies report positive changes following IPFCR implementation. However, conceptual frameworks and theoretical models are lacking in the IPFCR literature and represent a major gap that needs to be addressed to move this field forward. The purpose of this two-part review is to propose a conceptual framework of how IPFCR works. The goal is to articulate a framework that can be tested in subsequent research studies. Published IPFCR literature and relevant theories and frameworks were examined and synthesized to explore how IPFCR works, to situate IPFCR in relation to existing models and frameworks, and to postulate core components and underlying causal mechanisms. A preliminary, context-specific, conceptual framework is proposed illustrating interrelationships between four core components of IPFCR (interprofessional approach, intentional patient and family engagement, rounding structure, shared development of a daily care plan), improvements in communication, and better outcomes

Elimination Therapy for the Endemic Malarias

Most malaria diagnosed outside endemic zones occurs in patients experiencing the consequences of what was likely a single infectious bite by an anopheline mosquito. A single species of parasite is nearly always involved and expert opinion on malaria chemotherapy uniformly prescribes species- and stage-specific treatments. However the vast majority of people experiencing malaria, those resident in endemic zones, do so repeatedly and very often with the involvement of two or more species and stages of parasite. Silent forms of these infections—asymptomatic and beyond the reach of diagnostics—may accumulate to form substantial and unchallenged reservoirs of infection. In such settings treating only the species and stage of malaria revealed by diagnosis and not others may not be sensible or appropriate. Developing therapeutic strategies that address all species and stages independently of diagnostic evidence may substantially improve the effectiveness of the control and elimination of endemic malaria

World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs

The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed

The Up-Scale Manufacture of Chondrocytes for Allogeneic Cartilage Therapies

Background: Allogeneic chondrocyte therapies need to be developed to allow more individuals to be treated with a cell therapy for cartilage repair and to reduce the burden and cost of current two-stage autologous procedures. Up-scale manufacture of chondrocytes using a bioreactor could help provide an off-the-shelf allogeneic chondrocyte therapy with many doses being produced in a single manufacturing run. Here we assess a Good Manufacturing Practice compliant hollow-fibre bioreactor (Quantum®) for adult chondrocyte manufacture. Methods: Chondrocytes were isolated from knee arthroplasty derived cartilage (n=5) and expanded in media supplemented with 10% fetal bovine serum (FBS) or 5% human platelet lysate (hPL) on tissue culture plastic (TCP) for a single passage. hPL supplemented cultures were then expanded in the Quantum® bioreactor for a further passage. Matched, parallel cultures in hPL or FBS were maintained on TCP. Chondrocytes from all culture conditions were characterised in terms of growth kinetics, morphology, immunoprofile, chondrogenic potential (chondrocyte pellet assays) and single telomere length analysis. Results: Quantum® expansion of chondrocytes resulted in 86.4±38.5x106 cells in 8.4±1.5 days, following seeding of 10.2±3.6 x106 cells. This related to 3.0±1.0 population doublings in the Quantum® bioreactor, compared with 2.1±0.6 and 1.3±1.0 on TCP in hPL and FBS supplemented media, respectively. Quantum® and TCP expanded cultures retained equivalent chondropotency and mesenchymal stromal cell markers immunoprofiles, with only integrin marker, CD49a, decreasing following Quantum® expansion. Quantum® expanded chondrocytes demonstrated equivalent chondrogenic potential (as assessed by ability to form and maintain chondrogenic pellets) with matched hPL TCP populations. hPL manufacture however, led to reduced chondrogenic potential and increased cell surface positivity of integrins CD49b, CD49c and CD51/61 compared with FBS cultures. Quantum® expansion of chondrocytes did not result in shortened 17p telomere length when compared with matched TCP cultures. Discussion: This study demonstrates that large numbers of adult chondrocytes can be manufactured in the Quantum® hollow-fibre bioreactor. This rapid, up-scale expansion, does not alter chondrocyte phenotype when compared with matched TCP expansion. Therefore, the Quantum® provides an attractive method of manufacturing chondrocytes for clinical use. Media supplementation with hPL for chondrocyte expansion may, however, be unfavourable in terms of retaining chondrogenic capacity

Perustilaselvitys direktiivilaitosten ympäristölupaharkinnassa ja pilaantuneen ympäristön puhdistamista koskevassa sääntelyssä

Tutkielman aiheena on teollisuuspäästödirektiiviin perustuva perustilaselvitys, joka on Suomessa pantu täytäntöön ympäristönsuojelulain kokonaisuudistuksen yhteydessä. Perustilaselvityksellä tarkoitetaan ympäristön tilainventaariota, jolla selvitetään direktiivilaitosten toimintaan liittyvien merkityksellisten vaarallisten aineiden maaperälle ja pohjavedelle aiheuttama muutos. Euroopan komission mukaan perustilaselvitys on työkalu, jonka avulla pilaantuneen ympäristön ennallistamisen tavoitetaso voidaan teollisen toiminnan päätyttyä määrittää. Tutkielman tavoitteena on selvittää perustilaselvityssääntelyn aiheuttama oikeustilan muutos sekä arvioida selvityksen soveltuvuutta suomalaiseen ympäristölupaharkintaan ja pilaantuneita alueita koskevaan sääntelyyn. Tutkielmassa on lyhyesti esitelty muissa jäsenvaltioissa valittuja toimeenpanoratkaisuja ja arvioitu Suomessa valitun implementointiratkaisun onnistumista suhteessa sääntelyn tavoitteisiin. Aineistona on teollisuuspäästödirektiivin ja ympäristönsuojelulakia koskevan hallituksen esityksen lisäksi käytetty perustilaselvitystä koskevia komission ja ympäristöministeriön ohjeita ja soveltuvissa määrin oikeuskirjallisuutta, joka pääsääntöisesti on peräisin ajalta ennen ympäristönsuojelulain voimaantuloa 1.9.2014. Kirjallisuuden on katsottu olevan käyttökelpoista, koska pilaantuneen ympäristön puhdistamista koskeva sääntely on ympäristönsuojelulain kokonaisuudistuksessa säilytetty pääosin ennallaan. Tutkielma on luonteeltaan lainopillinen, ongelmakeskeinen esitys, joka sijoittuu tutkimuskysymystensä, metodologiansa ja tavoitteidensa johdosta ympäristöoikeuden alalle. Tutkielman perusteella voidaan todeta, että perustilaselvityssääntely ei täysin sovellu suomalaisen ympäristön pilaantumista koskevaan sääntely-ympäristöön. Perustilaselvityksen laatimista koskeva sääntely ja ohjeistus on toteutettu teollisuuspäästödirektiivin tavoitteiden mukaisesti, mutta sääntely on tulkinnanvaraista. Perustilan palauttamista koskeva sääntely on perustilasääntelyn ongelmakohta eikä toiminnan lopettamisvaiheeseen liittyvästä menettelystä sen perusteella synny selkeää kuvaa. Perustilaselvityksen laatiminen voi olla vaikea tehtävä, koska toiminnanharjoittajilta edellytetään vaarallisten aineiden maaperälle ja pohjavedelle mahdollisesti aiheuttaman pilaantumisriskin syvällistä arviointia. Selvityksen mahdolliset hyödyt liittyvät sen ympäristönsuojelullisiin vaikutuksiin. Toiminnanharjoittajien selvilläolovelvollisuus korostuu ja perustilaselvitysten avulla saadaan ajantasaista tietoa maaperän ja pohjaveden tilasta. Tietojen avulla ennaltaehkäisymenetelmiä ja parempia tekniikoita voidaan edelleen kehittää. Maaperän ja pohjaveden laatuinventaariona perustilaselvityksen laatiminen tukee alueiden ennallistamista niiden yksilölliset tarpeet huomioivalla tavalla. Selvitys tarjoaa lupaharkinnassa käytettäväksi aikaisempaa kattavamman ympäristön tilaa koskevan aineiston

Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis

Background: The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. Methods and findings: We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. Conclusions: For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity

Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection.

Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions