RESUMEN
Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the "real life" risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature. In a series of 75 patients we only observed three cases of fungal pneumonia. Unfortunately, the early signs and symptoms were not specific for fungal infection. Diagnostic imaging, microbiology and patient history, especially previous therapies, are critical in the decision to start antifungal treatment. Recognising the subgroup of MM patients with high risk of IFI can increase the rate of diagnosis, adequate treatment and MM-treatment recovery.
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Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.
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Enfermedad Injerto contra Huésped/terapia , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/patología , Humanos , Italia , MasculinoRESUMEN
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.
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Enfermedades Cardiovasculares , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Síndrome Metabólico , Aloinjertos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Humanos , Síndrome Metabólico/etiología , Síndrome Metabólico/prevención & control , Guías de Práctica Clínica como AsuntoAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Monitoreo Fisiológico/métodos , Proteínas Nucleares/genética , Adulto , Anciano , Aloinjertos , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Proteínas Nucleares/metabolismo , Nucleofosmina , Valor Predictivo de las Pruebas , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Hematopoietic SCT (HSCT) from HLA haploidentical family donors is a promising therapy for high-risk hematological malignancies. In the past 15 years at San Raffaele Scientific Institute, we investigated several transplant platforms and post transplant cellular-based interventions. We showed that T cell-depleted haploidentical transplantation followed by the infusion of genetically modified donor T cells (TK007 study, Eudract-2005-003587-34) promotes fast and wide immune reconstitution and GvHD control. This approach is currently tested in a phase III multicenter randomized trial (TK008 study, NCT00914628). We targeted patients with advanced leukemia with a sirolimus-based, calcineurin inhibitor-free prophylaxis of GvHD to allow the safe infusion of unmanipulated PBSCs from haploidentical family donors (TrRaMM study, Eudract 2007-5477-54). Results of these approaches are summarized and discussed.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Transfusión de Linfocitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfocitos T/trasplante , Aloinjertos , Femenino , Ingeniería Genética , Humanos , MasculinoAsunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Recuperación de la Función/inmunología , Adolescente , Adulto , Anciano , Aloinjertos , Biomarcadores/sangre , Citomegalovirus/inmunología , Citomegalovirus/metabolismo , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/inmunología , Femenino , Antígenos HLA , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Tamizaje Masivo , Neoplasias Primarias Secundarias/diagnóstico , Femenino , Humanos , Masculino , Neoplasias Primarias Secundarias/epidemiología , Especificidad de Órganos , Factores de RiesgoRESUMEN
Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.
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Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Trasplante de Células Madre de Sangre Periférica , Sirolimus/uso terapéutico , Linfocitos T Reguladores/inmunología , Administración Oral , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Plaquetas/citología , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Niño , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Neutrófilos/citología , Estudios Prospectivos , Rituximab , Linfocitos T/inmunología , Donantes de Tejidos , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their 'classical' counterparts (median: 307 vs 88 days, P<0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65-38.92; P=0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05-0.46; P=0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after 'classical' and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.
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Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/inmunología , Prueba de Histocompatibilidad , Humanos , Incidencia , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Mutación , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Diagnosis of invasive fungal infection remains challenging. Here we report a case of early diagnosis of invasive aspergillosis in a neutropenic patient affected by acute myeloid leukaemia, achieved through the detection of Aspergillus fumigatus species-specific ribonucleic acid sequences by a sensitive multiplex real-time polymerase chain reaction-based molecular assay. Thanks to the early diagnosis, targeted therapy was promptly established and the severe fungal infection controlled, allowing the patient to subsequently receive allogeneic hematopoietic stem cell transplantation from a haploidentical donor, her only curative option. Also in this instance, targeted secondary antifungal prophylaxis with voriconazole avoided any other fungal infection afterwards. This report suggests how the implementation of molecular assays in combination with routine diagnostic procedures, can improve microbiological diagnosis in sepsis, particularly in case of fungal infection, difficult to detect with standard microbiological culture methods.
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Anestésicos Locales/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Lidocaína/uso terapéutico , Esclerodermia Localizada/tratamiento farmacológico , Administración Intravenosa , Adulto , Anciano , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esclerodermia Localizada/inmunologíaRESUMEN
In late May 2013, collapse of mature watermelon plants (Citrullus lanatus L.) at first harvest occurred in several drip-irrigated commercial fields in the Coachella Valley, California. Above-ground symptoms consisted of chlorosis, wilting, and death of leaves starting at the crown and progressing rapidly towards the tip of vines. Structural roots of collapsed plants appeared healthy but feeder roots exhibited a brownish discoloration. Microscopic examination revealed that almost all epidermal cells of feeder roots contained either sporangia or resting spores of a fungus tentatively identified, based upon morphological characteristics, as Olpidium bornovanus (Sahtiy.) Karling. No other fungi or fungal-like organisms were microscopically observed in or isolated from structural roots, feeder roots, or vascular tissue of collapsed plants. Leaf, root, and peduncle samples from collapsed plants were tested for Melon necrotic spot virus (MNSV), a virus known to be transmitted by O. bornovanus, and Squash vein yellowing virus (SqVYV), a whitefly-transmitted ipomovirus known to cause watermelon vine decline (1). No MNSV was detected using previously described methods (3). No SqVYV was detected by testing total RNA from symptomatic plants (RNeasy Plant Mini Kit, Qiagen, Valencia, CA) with reverse transcription-PCR using previously described primers and methods (1,2). Genomic DNA was extracted from zoospores of the fungus which were obtained from a single-sporangial isolate maintained on watermelon seedlings. Analysis of ITS 1 and 2 gene sequences and a subsequent search in NCBI GenBank revealed a 99% identity to nucleotide sequences for O. bornovanus (Accession Nos. AB205215 and AB665758). To confirm Koch's postulates, roots of three 5-day-old watermelon seedlings were inoculated by exposure to zoospores (~1 × 105) in a beaker for 2 min and then transplanted into pots containing vermiculite. Pots were irrigated daily and incubated in a growth chamber (25°C, 12-h photoperiod). Controls consisted of non-inoculated watermelon seedlings. The experiment was repeated twice. Within 15 days of inoculation, all inoculated plants were stunted, and roots of stunted plants were brown and most root epidermal cells were filled with either sporangia or resting spores of O. bornovanus. Within 30 days of inoculation, 40 to 60% of the inoculated plants died in all three experiments. No other microorganisms were microscopically observed in or isolated from necrotic roots. Control plants remained symptomless over the duration of the study. Although O. bornovanus has been reported as a root pathogen of melons in greenhouse conditions (3), this is the first worldwide report of the fungus as a root pathogen of watermelons and its association with a late season vine decline in the field. Near-saturated soil conditions resulting from a daily irrigation regime during the latter part of the growing season apparently favored extensive root colonization by this indigenous and opportunistic zoosporic fungus, suggesting that growers should exercise care regarding the duration and frequency of irrigation events. References: (1) S. Adkins et al. Phytopathology 97:145, 2007. (2) S. Adkins et al. Plant Dis. 1119, 2008. (3) M. E. Stanghellini et al. Plant Dis. 94:163, 2010.
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Citrus thrips, Scirtothrips citri (Moulton), is a plant-feeding pest most widely recognized for causing damage to citrus and mango fruits. This insect has broadened its host range to become a significant pest of commercial blueberries grown in the San Joaquin Valley of California. We evaluated Beauveria bassiana (Balsamo) for control of citrus thrips in blueberries grown under two watering regimes (drip irrigation with and without overhead sprinklers) and using two fungal formulations (commercially available spores in suspension vs. colonized seed) over two sampling periods, that is, for two 3-d periods after treatment. We found significant differences in thrips densities as a function of water regime treatment and fungal formulation. Thrips levels were reduced significantly with both fungal treatments at 3 d after treatment, but at 6 d, only results with colonized seed differed from the control treatment. These data suggest entomopathogenic fungi might be useful for control of citrus thrips on blueberries in particular situations (in organic production or as a resistance management tool) but that traditional pesticides will likely remain the preferred management option.
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Beauveria/fisiología , Arándanos Azules (Planta)/crecimiento & desarrollo , Control Biológico de Vectores , Thysanoptera/microbiología , Animales , Beauveria/genética , California , Pupa/crecimiento & desarrollo , Pupa/microbiología , Thysanoptera/crecimiento & desarrolloRESUMEN
Haploidentical SCT (haplo-SCT) has been considered a therapeutic option in patients with acquired severe aplastic anemia (SAA) failing at least one course of immune suppressive therapy with antithymocyte globulin and lacking an HLA-matched related or unrelated donor. The platforms of both ex vivo T-cell-depleted and unmanipulated grafts have been explored in children and adults. Overall, the primary objective of a stable haploidentical hematopoietic engraftment with a low rate of GVHD is unmet in a significant proportion of patients undergoing haplo-SCT for SAA. Haploidentical transplants for refractory SAA should be performed in a specialist center with major experience in hematopoietic SCT procedures and preferably performed within the framework of a local clinical protocol designed specifically to address the prevention of graft rejection and GVHD.
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Anemia Aplásica/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , HumanosRESUMEN
Graft-versus-host disease (GvHD) is one of the major complications of allogeneic hematopoietic stem cell transplantation, an otherwise highly effective therapeutic modality for patients affected by hematological diseases. The main inducers of GvHD are alloreactive donor T cells, which recognize host antigens presented by recipient cells. The critical role of lymphocytes in GvHD is well documented by the observation that T-cell depletion from the graft prevents GvHD. Unfortunately, the removal of donor lymphocytes from the graft increases the incidence of disease relapse and life-threatening infectious complications. Gene transfer technologies are promising tools to manipulate donor T-cell immunity to enforce graft-versus-tumor/graft-versus-infection while preventing or controlling GvHD. For this purpose, several cell and gene transfer approaches have been investigated at the preclinical level and implemented in clinical trials.
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Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/terapia , Animales , Terapia Genética , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfocitos T/inmunología , Trasplante Homólogo/inmunologíaRESUMEN
Greenhouse studies document, for the first time, that Olpidium bornovanus, an obligate, holocarpic, root-inhabiting zoosporic fungus heretofore regarded as a nonpathogenic parasite, is a root pathogen. Significant browning of the roots and reductions in shoot and root growth were recorded within 28 days following inoculation of melons with the fungus. Amending the recirculating nutrient solution with either a nonionic surfactant (Agral 90) or a strobilurin fungicide (azoxystrobin) resulted in efficacious management of the disease caused by the fungus.
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Antígenos HLA/genética , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Recurrencia Local de Neoplasia/diagnóstico , Trasplante de Células Madre , Donantes de Tejidos , Adolescente , Adulto , Femenino , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/terapia , Neoplasias Hematológicas/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Adulto JovenRESUMEN
Fluorescent pseudomonads have been associated, via diverse mechanisms, with suppression of root disease caused by numerous fungal and fungal-like pathogens. However, inconsistent performance in disease abatement, after their employment, has been a problem. This has been attributed, in part, to the inability of the biocontrol bacterium to maintain a critical threshold population necessary for sustained biocontrol activity. Our results indicate that a nitrogen stabilizer (N-Serve, Dow Agrosciences) selectively and significantly enhanced, by two to three orders of magnitude, the resident population of fluorescent pseudomonads in the amended (i.e., 25 microg ml(-1) nitrapyrin, the active ingredient) and recycled nutrient solution used in the cultivation of hydroponically grown gerbera and pepper plants. Pseudomonas putida was confirmed as the predominant bacterium selectively enhanced. Terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rDNA suggested that N-Serve selectively increased P. putida and reduced bacterial diversity 72 h after application. In vitro tests revealed that the observed population increases of fluorescent pseudomonads were preceded by an early growth suppression of indigenous aerobic heterotrophic bacteria (AHB) population. Interestingly, the fluorescent pseudomonad population did not undergo this decrease, as shown in competition assays. Xylene and 1,2,4-trimethylbenzene (i.e., the inert ingredients in N-Serve) were responsible for a significant percentage of the fluorescent pseudomonad population increase. Furthermore, those increases were significantly higher when the active ingredient (i.e., nitrapyrin) and the inert ingredients were combined, which suggests a synergistic response. P. putida strains were screened for the ability to produce antifungal compounds and for the antifungal activity against Pythium aphanidermatum and Phytophthora capsici. The results of this study suggest the presence of diverse mechanisms with disease-suppressing potential. This study demonstrates the possibility of using a specific substrate to selectively enhance and maintain desired populations of a natural-occurring bacterium such as P. putida, a trait considered to have great potential in biocontrol applications for plant protection.
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Asteraceae/microbiología , Capsicum/microbiología , Quelantes/farmacología , Hidroponía/métodos , Picolinas/farmacología , Pseudomonas putida/crecimiento & desarrollo , Asteraceae/crecimiento & desarrollo , Secuencia de Bases , Capsicum/crecimiento & desarrollo , ADN Bacteriano/química , ADN Bacteriano/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pseudomonas putida/efectos de los fármacos , Pseudomonas putida/genética , Distribución Aleatoria , Sideróforos/análisis , Sideróforos/metabolismoRESUMEN
Fusarium crown and stem rot of lisianthus (Eustoma grandiflorum), caused by Fusarium avenaceum, is a destructive disease in California. The pathogen produces large masses of orangecolored macroconidia on stem lesions that extend up to 35 cm in length from the soil surface. Populations of macroconidia (97% viability) range from 1.1 × 108 to 1.9 × 108 per cm of infected stem tissue. An aboveground life stage for a soilborne pathogen could serve as a source for acquisition and aerial dissemination by adult shore flies, fungus gnats, and moth flies. Our results provide evidence that these three insects are attracted to and readily acquire (either externally and/or internally) macroconidia of F. avenaceum produced on naturally infected lisianthus stems and then disseminate acquired macroconidia to healthy plants, which subsequently died, or to an abiotic substrate (Komada's medium, KM). The high percentage of transmission, as evidenced by both the number of KM plates colonized by the pathogen (up to 68.5% within 18 h) and the number of plants infected (75% within 4 days), reflects the efficiency of these insects as vectors.
RESUMEN
Vine decline of melons caused by Monosporascus cannonballus is a destructive disease worldwide. Ascospores, the only spore stage produced by this soilborne fungus, serve as the primary inoculum. Ascospore production on roots occurs primarily at the end of the cropping season, and high soil temperatures (25 to 30°C) govern, in part, the rate of reproduction of the pathogen. In vitro studies confirm that the optimal temperature for reproduction ranged from 25 to 30°C. Additionally, the root system of a single mature cantaloupe plant is capable of supporting the production of approximately 400,000 ascospores. The latter population, if incorporated uniformly into 0.03 m3 (1 ft3) of soil, would be equivalent to 10 ascospores per gram of soil. Known problem fields contain as few as 2 ascospores per gram of soil. These results offer a possible explanation for field observations that economically significant disease problems can occur after only two consecutive melon crops if environmental conditions are conducive to pathogen reproduction, and they suggest that strategies to inhibit reproduction would be instrumental in disease management.