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Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity. Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS). Patients with CHNM and CMOS diagnosed between 2000 and 2018 were included. Locoregional control, distant metastasis-free survival, melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. Of 3007 CHNM and 10,637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs 58.5, P <.001; median Breslow thickness 1.7 mm vs 1.2 mm, P <.001; and ulceration 21.2% vs 18.2%, P <.001). CHNM had worse locoregional control (hazard ratio (HR) 1.17, P <.001) and distant metastasis-free survival (HR 1.25, P <.001) but there were no significant differences in MSS or OS. Among stage IV patients who received immune checkpoint inhibitor, CHNM had better MSS (HR 0.56, P =.001) and OS (HR 0.57, P <.001) on multivariable analyses. Retrospective study, offset by prospective data collection. CHNM is associated with a distinct clinicopathological and prognostic profile. [ABSTRACT FROM AUTHOR]

Targeted muscle reinnervation (TMR) has been shown to reduce phantom limb pain (PLP) and residual limb pain (RLP) after major limb amputation. However, the effect of the timing of surgery on pain control and quality of life outcomes is controversial. We conducted a retrospective study to compare the outcomes of acute TMR for pain prevention with non-acute TMR for the treatment of established pain. All patients treated with TMR in our institution between January 2018 and December 2021 were evaluated at 6, 12, 18 and 24 months post-operatively. Pain intensity and quality of life outcomes were assessed using the Brief Pain Inventory (Pain Severity and Pain Interference scales) and Pain Catastrophizing Scale. Outcomes were compared between acute and non-acute TMR using the Wilcoxon ranked-sum test or Fisher's exact test as appropriate. Multilevel mixed-effects linear regression was used to account for repeat measures and potential pain confounders. Thirty-two patients with 38 major limb amputations were included. Acute TMR patients reported significantly lower RLP and PLP scores, pain interference and pain catastrophisation at all time points (p < 0.05). Acute TMR was significantly associated with lower pain severity and pain interference in a linear mixed-effects model accounting for patient age, gender, amputation indication, amputation site, time post-TMR and repeated surveys (p < 0.05). There was no significant difference in the complication rate (p = 0.51). Acute TMR was associated with clinically and statistically significant pain outcomes that were better than that in non-acute TMR. This suggests that TMR should be performed with preventative intent, when possible, as part of a multidisciplinary approach to pain management, rather than deferred until the development of chronic pain. [ABSTRACT FROM AUTHOR]

Opioid-induced esophageal dysfunction (OIED) often presents as spastic esophageal disorders (SEDs) and esophagogastric junction outflow obstruction (EGJOO). The aim of this study was to evaluate and compare clinical outcomes of peroral endoscopic myotomy (POEM) for SEDs and EGJOO among opioid users and nonusers. This propensity score (PS) matching study included consecutive opioid users and nonusers who underwent POEM for SEDs and EGJOO between January 2018 and September 2022. The following covariates were used for the PS calculation: age, sex, duration of symptoms, Eckardt score, type of motility disorder, and length of myotomy during POEM. Clinical response was defined as a post-POEM Eckardt score ≤3. A total of 277 consecutive patients underwent POEM during the study period. PS matching resulted in the selection of 64 pairs of patients strictly matched 1:1 (n = 128) with no statistically significant differences in demographic, baseline, or procedural characteristics or in the parameters considered for the PS between the 2 groups. Clinical response to POEM was significantly lower among opioid users (51 of 64 [79.7%]) versus nonusers (60 of 64 [93.8%]) (P =.03) at a median follow-up of 18 months. Among opioid users, higher opioid dose (>60 morphine milligram equivalents per day) was associated with a higher likelihood of failure to respond to POEM (odds ratio, 4.59; 95% confidence interval, 1.31-3.98; P =.02). Clinical response to POEM for SEDs and EGJOO is significantly lower among opioid users versus nonusers. There was a dose-relationship between opioids and response to POEM, with higher daily opioid usage associated with a higher likelihood of treatment failure. [ABSTRACT FROM AUTHOR]

In some cases of right-sided lung cancer, tumor extension, bronchial involvement, or pulmonary artery infiltration may necessitate bilobectomy. Although the middle lobe is believed to represent a fraction of total lung function, the morbidity and mortality associated with bilobectomy is not well described. We retrospectively identified patients in The Society of Thoracic Surgeons Database who underwent lobectomy, bilobectomy, or pneumonectomy for lung cancer from 2009 to 2017. The primary outcome was 30-day perioperative mortality. We performed propensity matching by patient demographics, comorbidities, and perioperative variables for each surgical type against bilobectomy and ran Cox proportional hazard models. Secondary outcomes of 30-day morbidity and mortality of upper vs lower bilobectomy were also compared. Within the study period 2911 bilobectomy, 65,506 lobectomy, and 3370 pneumonectomy patients met the inclusion criteria. Patients undergoing pneumonectomy and bilobectomy had fewer comorbidities than lobectomy patients. After propensity matching 30-day mortality of bilobectomy was comparable with left pneumonectomy (hazard ratio [HR], 1.35; 95% CI, 0.95-1.91; P =.09) and significantly worse than left (HR, 0.40; 95% CI, 0.29-0.56; P <.0001) or right (HR, 0.43; 95% CI, 0.31-0.59; P <.0001) lobectomy. Bilobectomy was associated with a survival advantage compared with right pneumonectomy (HR, 2.54; 95% CI, 1.72-3.74; P <.0001). Thirty-day morbidity was higher for bilobectomy compared with lobectomy, and upper bilobectomy had a significant unadjusted 30-day mortality advantage compared with lower bilobectomy (98.3% vs 97%, P =.04). The morbidity and mortality of bilobectomy is significantly worse than lobectomy and is comparable with left pneumonectomy. The addition of middle lobectomy to a pulmonary resection is not without risk and should be carefully considered during preoperative risk stratification. [ABSTRACT FROM AUTHOR]

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Adjuvant chemotherapy is indicated for patients with resectable stage II and IIIa non-small cell lung cancer. With the revised definition of T4 tumors with nodules in a different ipsilateral lobe, the survival advantage imparted by adjuvant chemotherapy has yet to be defined. We evaluated the role of adjuvant chemotherapy in patients with T4 disease characterized by additional tumor nodules in a different ipsilateral lobe treated with surgical resection. We identified patients with T4 disease and additional tumor nodules in a different ipsilateral lobe treated with surgical resection alone or with adjuvant chemotherapy in the National Cancer Database between 2010 and 2016. The primary outcome was 3-year overall survival (OS). A total of 920 patients with T4 tumors and additional tumor nodules in a different ipsilateral lobe were identified. We excluded patients with lymph node metastases, tumors 4 cm or greater, and local invasion. Of the remaining 373 patients, 152 received surgery and adjuvant multiagent chemotherapy whereas 221 received surgery alone. When adjusted for patient, tumor, and treatment factors, the use of adjuvant chemotherapy was associated with improved 3-year OS compared with surgery alone (hazard ratio = 0.572; 95% confidence interval, 0.348-0.940; P =.03). Adjuvant chemotherapy in patients with T4 non-small cell lung cancer with additional tumor nodules in a different ipsilateral lobe is associated with improved 3-year OS. Accurate identification of T4 disease is important to define patients in whom adjuvant chemotherapy should be considered. Further prospective study is needed to delineate further the use of adjuvant chemotherapy for this patient population. [ABSTRACT FROM AUTHOR]

Calculating an accurate prognosis for melanoma patients who have a positive sentinel node (SN) biopsy is important both for them and for their treating doctors to guide decision-making, particularly when adjuvant systemic therapy is being considered. The recently published EORTC-DeCOG nomograms aim to provide this via an online portal that predicts 5-year rates for recurrence, distant metastasis and overall mortality. The present study provides external validation of these nomograms. De-identified data from patients with a positive SN biopsy between 2003 and 2015 were extracted from the prospectively maintained Melanoma Institute Australia (MIA) research database. ROC-curves with C-statistics, regression co-efficients and Decision Curve Net Benefit analyses were performed using the integrated private validation portal on the nomograms' hosting platform (Evidencio). Complete data were available for 352 patients. The respective C-statistics for recurrence, distant metastasis and overall mortality nomogram validations were 0.68, 0.69 and 0.66. The performance of the nomograms in predicting recurrence and distant metastasis was similar in the MIA and the development populations, suggesting that they are robust. However, the overall mortality nomogram performance was significantly poorer in the MIA population (C-statistic 0.66) than in the original EORTC-DeCOG derivation cohort (C-statistic 0.70) and may therefore be less reliable for clinical use. • Predicting outcomes for sentinel node-positive melanoma patients is important. • A recently published EORTC-DeCOG online nomogram estimates their prognosis. • This nomogram was externally validated in an Australian population. • The recurrence and distant metastasis prediction models were found to be robust. • The overall survival prediction model was less reliable for Australian patients. [ABSTRACT FROM AUTHOR]

The pathogenetic pathways leading to increasing prevalence of advanced fibrosis in the setting of nonalcoholic fatty liver disease (NAFLD) and resulting in higher rates of liver-related and cardiovascular morbidity and mortality in the United States are multifactorial.1 The negative health impact of "low–normal" thyroid function, which is defined as a higher level of thyroid-stimulating hormone (TSH) within the euthyroid reference range, may be comparable with overt and subclinical hypothyroidism.2–4 We reported a strong association between biopsy-proven advanced fibrosis in NAFLD with increasing TSH levels in a dose-dependent manner even within the euthyroid reference range.5 To generalize our findings across all ethnicities, we examined the association of both low–normal thyroid function and subclinical hypothyroidism with advanced fibrosis in the US general population. [ABSTRACT FROM AUTHOR]

The introduction of direct-acting antiviral (DAA) agents and the opioid epidemic have resulted in an increased interest in liver transplantation (LT) of organs from donors with hepatitis C virus (HCV)-related viremia.1 In March of 2015, the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) implemented a policy to perform HCV nucleic acid testing (NAT) in all HCV-seropositive donors. An open-label, single-center experience with 10 patients using a multistep informed consent reported successful transplantation of HCV-seropositive viremic (HCV-V) kidneys into HCV-seronegative recipients.2 Subsequently, a case was reported in which an HCV-V liver was transplanted into a HCV-seronegative recipient.3 In collaboration with OPTN/UNOS, we identified cases in which HCV-V deceased donor livers were transplanted into HCV-seronegative recipients. [ABSTRACT FROM AUTHOR]

The biology of Korarchaeia remains elusive due to the lack of genome representatives. Here, we reconstruct 10 closely related metagenome-assembled genomes from hot spring habitats and place them into a single species, proposed herein as Panguiarchaeum symbiosum. Functional investigation suggests that Panguiarchaeum symbiosum is strictly anaerobic and grows exclusively in thermal habitats by fermenting peptides coupled with sulfide and hydrogen production to dispose of electrons. Due to its inability to biosynthesize archaeal membranes, amino acids, and purines, this species likely exists in a symbiotic lifestyle similar to DPANN archaea. Population metagenomics and metatranscriptomic analyses demonstrated that genes associated with amino acid/peptide uptake and cell attachment exhibited positive selection and were highly expressed, supporting the proposed proteolytic catabolism and symbiotic lifestyle. Our study sheds light on the metabolism, evolution, and potential symbiotic lifestyle of Panguiarchaeum symbiosum , which may be a unique host-dependent archaeon within the TACK superphylum. [Display omitted] • Panguiarchaeum symbiosum belongs to a previously unknown order within the Korarchaeia • P. symbiosum has a symbiotic lifestyle by fermenting peptides and reducing sulfur • Genes related to proteolytic catabolism and cell attachment exhibit positive selection • Genes related to proteolytic catabolism and cell attachment are highly expressed Qu et al. report 10 closely related genomes from hot springs with the name Panguiarchaeum symbiosum proposed. By focusing on ecological niches and evolution, they reveal a symbiotic lifestyle of these microbes, where genes associated with nutrient acquisition and cell attachment are prone to be positively selected and highly transcribed. [ABSTRACT FROM AUTHOR]

Biological and physiological aspects of blood feeding in nymph and adult Ornithodoros turicata were investigated using an in vitro technique combined with electrophysiological recordings and respirometry. The duration of blood feeding through a Parafilm® membrane was similar (19.2–22.6 min) in both developmental stages. The mean (±SD) size of blood meal ingested by nymphs, females, and males was 44.2 ± 17.9, 150.6 ± 48.7, and 74.2 ± 36.9 mg, respectively, representing a 2.5-, 2.8- and 3.0-fold increase from their respective unfed weights. Electrophysiological recordings of the pharyngeal pump during blood feeding revealed that ticks ingested blood at a rate of 6.1–6.4 suctions per second. Mean blood volume ingested per suction was 0.013 μl in females and 0.007 μl in both males and nymphs. Blood meal size (mg) correlated with unfed body weight (mg) ( r 2 = 0.50, p < 0.05) and with blood volume ingested per suction ( r 2 = 0.71, p < 0.05). Unfed ticks exhibited a circadian ventilation rhythm with discontinuous gas exchange pattern during the daytime and continuous pattern during nighttime. Mean standard metabolic rates (SMR, V ̇ CO 2 ) in unfed nymphs, females and males of 1.4, 3.0 and 0.9 μl h −1 increased to 2.0, 5.7 and 2.4 μl h −1 , respectively, after a blood meal. SMR correlated positively with blood meal size ( r 2 = 0.89, p < 0.05). Mean coxal fluid weight excreted after a blood meal in nymphs, females, and males was 8.7, 20.0, and 7.7 mg, respectively, which represents 27.0%, 23.4% and 26.7% of their blood meal size. This study revealed biological and physiological characteristics of soft tick blood feeding and metabolism important to tick survival. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries can result in lifelong disability. Primary coaptation is the treatment of choice when the gap between transected nerve ends is short. Long nerve gaps seen in more complex injuries often require autologous nerve grafts or nerve conduits implemented into the repair. Nerve grafts, however, cause morbidity and functional loss at donor sites, which are limited in number. Nerve conduits, in turn, lack an internal scaffold to support and guide axonal regeneration, resulting in decreased efficacy over longer nerve gap lengths. By comparison, peptide amphiphiles (PAs) are molecules that can self-assemble into nanofibers, which can be aligned to mimic the native architecture of peripheral nerve. As such, they represent a potential substrate for use in a bioengineered nerve graft substitute. To examine this, we cultured Schwann cells with bioactive PAs (RGDS-PA, IKVAV-PA) to determine their ability to attach to and proliferate within the biomaterial. Next, we devised a PA construct for use in a peripheral nerve critical sized defect model. Rat sciatic nerve defects were created and reconstructed with autologous nerve, PLGA conduits filled with various forms of aligned PAs, or left unrepaired. Motor and sensory recovery were determined and compared among groups. Our results demonstrate that Schwann cells are able to adhere to and proliferate in aligned PA gels, with greater efficacy in bioactive PAs compared to the backbone-PA alone. In vivo testing revealed recovery of motor and sensory function in animals treated with conduit/PA constructs comparable to animals treated with autologous nerve grafts. Functional recovery in conduit/PA and autologous graft groups was significantly faster than in animals treated with empty PLGA conduits. Histological examinations also demonstrated increased axonal and Schwann cell regeneration within the reconstructed nerve gap in animals treated with conduit/PA constructs. These results indicate that PA nanofibers may represent a promising biomaterial for use in bioengineered peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Summary: Background: Complex, lower-extremity, soft-tissue defects pose a significant challenge to the reconstructive surgeon and often require the use of free flaps, which puts significant demands on the patient, the surgeon and the health-care system. Bipedicled flaps are random but receive a blood supply from two pedicles, allowing the surgeon to use local tissue with an augmented nutrient blood flow. They are simple to elevate and economical in operating time. This study describes our experience with lower-extremity wound reconstruction using the bipedicled flap as an alternative to pedicled flaps and free flaps. Methods: Ten patients with lower-extremity defects underwent bipedicled flap reconstruction. Operative times, length of stay following flap procedure and postoperative complications were documented. Data were collected in a prospective fashion. Results: Two patients had minimal areas of flap necrosis, both of which resolved with conservative local wound care and one patient developed a postoperative wound infection remedied with a course of oral antibiotics. We experienced one major complication involving wound dehiscence requiring an additional flap. Conclusions: Bipedicled flaps provide a safe, fast and relatively easy alternative for coverage of certain complex open wounds in the lower extremities. Their use does not preclude the use of more traditional options of pedicled muscle or free flap coverage at a later time should they be required. Clinical questions addressed/Level of evidence: What are alternative strategies for lower-extremity wound reconstruction. Level of Evidence V. [Copyright &y& Elsevier]

Abstract: Biogenic amines are known to play critical roles in key insect behaviors such as feeding and reproduction. This study documents the effects of reserpine on mating and egg-laying behaviors of the stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae), which is one of the most significant biting fly pests affecting cattle. Two sperm staining techniques were adapted successfully to reveal the morphology of stable fly sperm, for the first time, and determine successful mating in females through the assessment of sperm transfer. This approach was also applied to assess sperm transfer by males treated with different doses of reserpine. Mating or sperm transfer did not occur in flies during the first 3days after emergence. Thereafter, the percentage of females that mated increased with age. Reserpine treatment of males reduced sperm transfer in a dose-dependent manner. Older males were more sensitive to reserpine treatment than younger flies. Reserpine treatment of 5days old females reduced the number of eggs laid, but had no effect on egg-hatching rates. Results of immunoreactivity (IR) experiments indicated that serotonin in the neuronal processes innervating male testes was completely depleted by reserpine within 5h after treatment. This effect was transient as the serotonin immunoreactive signal was recovered in 33.3% of the males at 1day post-treatment and in 94.4% of the flies at 3days post-treatment. The results of this study concur with previous findings in other insect species and extend our knowledge of the critical roles biogenic amines play in mating and oviposition behaviors of the stable fly. The work could provide a foundation to further characterize the specific roles of individual biogenic amines and their receptors in stable fly reproduction. [Copyright &y& Elsevier]

Abstract: A survey of ectoparasites on feral pigs identified two commonly occurring ixodid tick species; Amblyomma triguttatum triguttatum and Ixodes australiensis. Molecular screening of A. t. triguttatum and I. australiensis for the presence of Rickettsia species detected the presence of rickettsiae belonging to the Spotted Fever Group (SFG) in 78.4% of screened A. t. triguttatum. None of the screened I. australiensis were positive for rickettsiae. Sequence analysis of the gltA and ompA loci of positive Rickettsia isolates were 100% homologous to the newly described species Rickettsia gravesii sp. nov. BWI-1. Serological screening of feral pigs detected antibodies to SFG Rickettsia in 50% of serum samples tested. These findings suggest that A. t. triguttatum is a vector/reservoir for R. gravesii sp. nov. [Copyright &y& Elsevier]

Abstract: Integrating a number of theoretical perspectives, this paper examined predictors of Asian international students’ sociocultural adjustment. A total of 117 students (aged 18–46years) from 17 Asian countries and regions completed questionnaires about their sociocultural adjustment, contact with the hosts, ethnic identity, and cross-cultural self-efficacy. As hypothesized, contact with the hosts partially mediated the effect of cross-cultural self-efficacy on sociocultural adjustment. The hypothesis that contact with the hosts would mediate the effect of ethnic identity on sociocultural adjustment was not supported. [Copyright &y& Elsevier]

As a transcription factor, p53 recognizes a specific consensus DNA sequence and activates the expression of the target genes involved in either growth arrest or apoptosis. Despite our wealth of knowledge on the genes that are targeted by p53 in growth arrest and apoptosis, relatively little is known about the promoter specificity triggered by p53 in these processes. Here we show that interaction with c-Abl stabilized p53 tetrameric conformation, and as a consequence c-Abl stimulated p53 DNA binding only when all quarter binding sites (a perfect binding sequence) on p53-responsive promoters were present. This result suggests that in response to DNA damage, c-Abl binding may specifically stimulate p53 DNA binding on the promoters with perfect binding sequences. A sequence comparison of several known p53-responsive elements illustrates the presence of the perfect binding sequences on the p21 but not the Bax promoter. Significantly, we show that c-Abl indeed enhanced p53 DNA binding and transcription from p21 but not Bax. These results suggest that the promoter specificity plays an important role in selective activation of p53 DNA binding by c-Abl. The implications of this with relation to selective activation of p53 target genes involved in either growth arrest or apoptosis are discussed. [ABSTRACT FROM AUTHOR]

Objective: Epidemiologic data suggest that the malignant transformation of ovarian epithelium may be linked to altered steroid hormone homeostasis.Study Design: Estrogen receptor-alpha, estrogen receptor-beta, progesterone receptor A, and progesterone receptor B messenger RNA and protein expression were evaluated by reverse transcriptase-polymerase chain reaction and Western blot analysis in primary cell cultures of human ovarian surface epithelium (n = 23 cultures) and Cedars-Sinai ovarian cancer (n = 23 cultures).Results: The ratio of estrogen receptor-alpha/estrogen receptor-beta messenger RNA expression was 10 times higher in primary ovarian cancer cultures (9.94 +/- 3.90) than in normal ovarian surface epithelium cultures (1.00 +/- 0.16, P =.04). Estrogen receptor-alpha/estrogen receptor-beta protein ratio in primary ovarian cancer cultures (2.13 +/- 0.43) was twice that of normal human ovarian surface epithelium cultures (1.00 +/- 0.13, P =.05). Individual estrogen receptor-alpha and estrogen receptor-beta messenger RNA and protein expression were not significantly different. Progesterone receptor B protein levels in primary ovarian cancer cultures (2.08 +/- 0.42) were twice that of normal surface ovarian epithelium cultures (1.00 +/- 0.10, P =.04), although differences in progesterone receptor B messenger RNA and progesterone receptor A protein expression were not observed.Conclusion: Malignant ovarian epithelial cells demonstrated multiple alterations in the expression of sex steroid hormone receptors. [ABSTRACT FROM AUTHOR]

We show in this study that PTEN regulates p53 protein levels and transcriptional activity through both phosphatase-dependent and -independent mechanisms. The onset of tumor development in p53+/−;Pten+/− mice is similar to p53−/− animals, and p53 protein levels are dramatically reduced in Pten−/− cells and tissues. Reintroducing wild-type or phosphatase-dead PTEN mutants leads to a significant increase in p53 stability. PTEN also physically associates with endogenous p53. Finally, PTEN regulates the transcriptional activity of p53 by modulating its DNA binding activity. This study provides a novel mechanism by which the loss of PTEN can functionally control “two” hits in the course of tumor development by concurrently modulating p53 activity. [Copyright &y& Elsevier]

• Past authoritarian experience affects current online political psychology. • The cultural legacy of history should be considered to explain OPE. • The influence of new media is contingent on both current and historical variables. This paper represents an effort to investigate the impact of perceived new media credibility on citizens' online political efficacy (OPE) in new democracies. Unlike their counterparts in mature democracies and outright authoritarian states, citizens of new democracies face the challenge to reconcile their democratic present with the authoritarian past. Their online political behaviors therefore are likely to be shaped by the interaction between democratic realities and authoritarian legacies or memories. The current study argues that in new democracies, the relationship between credibility of new media and OPE is contingent upon citizens' authoritarian experience. Since authoritarian experience delivers a sense of relative acquisition through a comparison mechanism, it is expected to play a positive role in moderating the association between credibility of new media and OPE. We test the proposition by studying a sample of Taiwanese residents interviewed during the 2015 Taiwan Communication Survey (TCS). Our empirical analyses produce strong supportive evidence for the positive conditioning effect of authoritarian experience and the result is robust to different model specifications and alternative measures of authoritarian experience. [ABSTRACT FROM AUTHOR]

Nanoparticle-mediated photoporation is a novel delivery platform for intracellular molecule delivery. We studied the dependence of macromolecular delivery on molecular weight and sought to enhance delivery efficiency. DU145 prostate cancer cells were exposed to pulsed laser beam in the presence of carbon-black nanoparticles. Intracellular uptake of molecules decreased with increasing molecular weight. Attributing this dependence to molecular diffusivity, we hypothesized that macromolecular delivery efficiency could be enhanced by increasing either laser fluence or laser exposure duration at low fluence. We observed increased percentages of macromolecule uptake by cells in both cases. However, trade-off between cell uptake and viability loss was most favorable at low laser fluence (25-29 mJ/cm2) and longer exposure durations (4-5 min). We conclude that long exposure at low laser fluence optimizes intracellular macromolecule delivery by nanoparticle-mediated photoporation, which may be explained by longer time for macromolecules to diffuse into cells, during and between laser pulses. Intracellular delivery of macromolecules to access the cytosol requires crossing the phospholipid bilayer of cell membranes. Nanoparticle-mediated photoporation enables transient poration of cell membranes, providing a diffusive pathway for transport. We optimized conditions for intracellular delivery of a widely sized range of macromolecules using nanoparticle-mediated photoporation using long-duration exposures at low laser fluence. [Display omitted] [ABSTRACT FROM AUTHOR]