New Generation Pulse Modulation in Holmium:YAG Lasers: A Systematic Review of the Literature and Meta-Analysis

(1) Background: New pulse modulation (PM) technologies in Holmium:YAG lasers are available for urinary stone treatment, but little is known about them. We aim to systematically evaluate the published evidence in terms of their lithotripsy performance. (2) Methods: A systematic electronic search was performed (MEDLINE, Scopus, and Cochrane databases). We included all relevant publications, including randomized controlled trials, non-randomized comparative and non-comparative studies, and in-vitro studies investigating Holmium:YAG lithotripsy performance employing any new PM. (3) Results: Initial search yielded 203 studies; 24 studies were included after selection: 15 in-vitro, 9 in-vivo. 10 In-vitro compared Moses with regular PM, 1 compared Quanta’s, 1 Dornier MedTech’s, 2 Moses with super Thulium Fiber Laser, and 1 compared Moses with Quanta PMs. Six out of seven comparative studies found a statistically significant difference in favor of new-generation PM technologies in terms of operative time and five out of six in fragmentation time; two studies evaluated retropulsion, both in favor of new-generation PM. There were no statistically significant differences regarding stone-free rate, lasing and operative time, and complications between Moses and regular PM when data were meta-analyzed. (4) Conclusions: Moses PM seems to have better lithotripsy performance than regular modes in in-vitro studies, but there are still some doubts about its in-vivo results. Little is known about the other PMs. Although some results favor Quanta PMs, further studies are needed.


Introduction
Urinary stone disease is a frequent condition associated with several comorbidities, such as diabetes and obesity, as well as environmental risk factors that are increasing in Western countries, with an estimated prevalence of 1-20% [1,2].
Technological advances led to the development of multiple therapeutic options for the treatment of urinary stones. The use of Holmium:Yatrrium-Aluminuim-Garnet (Ho:YAG) laser has gained a dominant role in endoscopic lithotripsy since its introduction in 1980 [3,4], becoming the most popular tool in this scenario [5][6][7]. Its popularity is justified by its ability

Search Strategy
A literature search of studies published in English with no time restriction was conducted in March 2022 using PubMed/Medline, Scopus, and Cochrane databases. The literature search used both free text and MeSH terms. A manual search of bibliographies of included studies and previous systematic reviews was also performed. The search strategy used the combination of the following terms grouped according to the Boolean operators (AND, OR, NOT): "Holmium-YAG Laser", "Laser", "Holmium", "Holmium-YAG", "Pulse", "Modulation", "Moses", "Moses 2.0", "Optimized Moses", "virtual basket", "bubble blast", "vapor tunnel", "advance mode", "stabilization mode".

Eligibility Criteria
A specific population (P), intervention (I), comparator (C), outcome (O), and study design (S) framework defined the study eligibility. Studies were considered eligible if they fulfilled the following criteria:

Study Selection
Mendeley reference software removed duplicate records identified. Initial screening was performed independently by two investigators (A.S. and A.B.) based on the titles and abstracts of the article to identify ineligible reports. In case of duplicate publications, either the higher-quality or the most recent publication was selected. Reviews, meta-analyses, commentaries, abstracts of non-published studies, authors' replies, theses, and case reports were excluded. Potentially relevant studies were subjected to a full-text review, and the relevance of the reports was confirmed after the data extraction process. Disagreements were resolved by consultation with a third co-author (P.D.). Figure 1 shows the flowchart depicting the overall review process according to the PRISMA statement recommendations.

Data Extraction
Data from the studies included in the review were extracted by two authors (A.S. and A.B.) in an a-priori developed data extraction form. The reliability and completeness of data extraction was crosschecked by another member of the review team (P.D.). We independently extracted the following variables from the included studies: -For in-vitro studies: first author's name, publication year, type of laser and fiber size, pulse modulation, energy and frequency settings, fiber-stone distance, stone composition and hardness, experimental conditions, compared variables, and summarized results; -For in-vivo studies: first author's name, publication year, study design, intervention, type of laser and fiber size, pulse modulation, energy and frequency settings, population, median stone size, stone Hounsfield units, operative time, fragmentation time, retropulsion, SFR, and complications.
When more than one article was based on the same study population, we included the most recent report. All discrepancies regarding data extraction between the three authors were resolved by consensus with a senior author (E.E.).

Data Extraction
Data from the studies included in the review were extracted by two authors (A.S. and A.B.) in an a-priori developed data extraction form. The reliability and completeness of data extraction was crosschecked by another member of the review team (P.D.). We independently extracted the following variables from the included studies: -For in-vitro studies: first author's name, publication year, type of laser and fiber size, pulse modulation, energy and frequency settings, fiber-stone distance, stone composition and hardness, experimental conditions, compared variables, and summarized results; -For in-vivo studies: first author's name, publication year, study design, intervention, type of laser and fiber size, pulse modulation, energy and frequency settings, population, median stone size, stone Hounsfield units, operative time, fragmentation time, retropulsion, SFR, and complications.
When more than one article was based on the same study population, we included the most recent report. All discrepancies regarding data extraction between the three authors were resolved by consensus with a senior author (E.E.).

Assessment of Risk of Bias of Included Studies
The quality of the included studies and their design were considered according to the Jadad scale [20] for Reporting Randomized Controlled; we also used the Methodological Index for Non-randomized Studies (MINORS) [21] to assess the methodological quality of comparative and non-comparative studies. The former is a 5point scale containing two questions for randomization, two for blinding, and one for the evaluation of dropouts. The latter is a 24-point and 16-point scale for comparative and non-comparative studies respectively, containing eight items for all non-randomized studies and four additional items for comparative studies, with a maximum score for each item of 2 and a minimal score of 0.
There are no validated instruments to assess the methodological quality of in-vitro studies, so we did not assess the quality of these studies.

Assessment of Risk of Bias of Included Studies
The quality of the included studies and their design were considered according to the Jadad scale [20] for Reporting Randomized Controlled; we also used the Methodological Index for Non-randomized Studies (MINORS) [21] to assess the methodological quality of comparative and non-comparative studies. The former is a 5-point scale containing two questions for randomization, two for blinding, and one for the evaluation of dropouts. The latter is a 24-point and 16-point scale for comparative and non-comparative studies respectively, containing eight items for all non-randomized studies and four additional items for comparative studies, with a maximum score for each item of 2 and a minimal score of 0.
There are no validated instruments to assess the methodological quality of in-vitro studies, so we did not assess the quality of these studies.

Meta-Analyses for In-Vivo Studies
A meta-analysis was performed when two or more studies reported the same outcome under the same definition. For the computational part of the meta-analysis, various approaches were used to pool effect measures between studies. For continuous results, the mean and standard deviation (SD) were used. For post-operative complication and stone-free rate, we reported data as dichotomous events and calculated pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). We used either a fixed-or a random-effect model for calculations of ORs according to the heterogeneity of the pooled studies. We assessed heterogeneity using the Cochrane Q-test and quantified it using I 2 values. In case of heterogeneity (Cochrane Q-test p < 0.05 and I 2 > 50%), we used a random-effect model, otherwise the fixed-effect model was used. All statistical analyses were performed using Cochrane Collaboration Review Manager software (RevMan v.5.4; Cochrane Collaboration, Oxford, UK). Statistical significance was set at p < 0.05.

Literature Search and Inclusion Studies
A systematic review was conducted using the aforementioned databases; three authors participated in the literature search and data acquisition process (A.S., A.B., and P.D.).
The initial search yielded 203 records ( Figure 1). After the identification of these studies through database searching, 167 records were excluded. A total of 37 studies were screened and fully reviewed, excluding 13 studies that did not comply with the selected outcomes or had insufficient data, with a final selection of 24 studies: 15 in-vitro and 9 invivo. Tables 1 and 2 summarize the in-vitro and in-vivo studies characteristics, respectively, including outcome measures.  Table 1 shows a detailed description of the results of the in-vitro studies, listing the laser type, the pulse modulation, the energy and frequency settings, the fibers and stones used, the experimental conditions, the compared variables, and the main results. A total of 15 articles were included.
Three main types of experiments were performed: (1) static laser activation, (2) automatized movement of the laser fiber tip across the stone surface to generate a cut or ablation surface, and (3) lithotripsy experiments performed by urologists.
King [22] and Ballesta et al. [32] used static laser activation for crater formation. Black et al. [26] also used a static laser activation, but the fiber and the stone were placed inside a spherical test tube in order to mimic the popcorn dusting during retrograde intrarenal surgery (RIRS). For automatized movement of the laser fiber tip, Aldoukhi et al. [23] performed 2-cm linear cuts on the stone surface. To mimic a "painting" dusting lithotripsy technique, Winship et al. [24] displayed an automatized moving laser-holding arm that, with a spiral motion, generated a square lithotripsy area in the stone surface. Finally, lithotripsy experiments performed by urologists were set in different scenarios. Ibrahim, Keller, and Khajeh et al. [9,27,28] used artificial recipients to model the urinary tract, whereas Jiang et al. [31] performed retrograde intra-renal surgery (RIRS) in extracted porcine kidneys after stone placement in the renal pelvis with pyelothomy. Elhilali et al. [16] performed RIRS in living pigs under general anesthesia.
The vast majority of the articles analyzed differences between Moses PMs (MC and/or MD) and regular Lumenis short and long pulse modulation. Only three articles compared Moses PM with other lasers [17,31,32].
Jiang et al. [31] compared Moses PM in a Lumenis Pulse™ 30 H Ho:YAG laser with Lumenis Ho and Nd:YAG VersaPulse PowerSuite™ laser regular modes and super-thulium fiber laser (sTFL) (IPG Photonics). They observed that sTFL generated smaller fragment remnants than after conventional and Moses Ho:YAG RIRS in a porcine kidney model. Terry et al. [17] compared Lumenis regular and Moses PM and Quanta's Vappor Tunnel (VT), SP short and long pulses. In their experiments, Lumenis MD had better lithotripsy performance in terms of crater and cut volume, whereas MC was clearly inferior. Ballesta et al. [32] tested Quanta's VB, VT, and Bubble Blast (BB) PMs observing that, at high power settings (2 J × 30 Hz), VB had the greatest lithotripsy ablation rate, whereas VT had the lowest rate in hard stones.
When comparing different PMs, a wide range of variables were analyzed, which varied especially according to the type of experiment that was performed. The most frequently reported variables were those regarding ablated volume or mass. For Moses technology, results favored MC and MD against SP (King et al. [22]) and against both regular modes (SP and LP) (Elhilali et al. [18]). Aldouki et al. [23] found that MD had the highest ablation and fragmentation rates both at 0 and 1 mm distance when compared to the rest of the Lumenis' PMs. In another article, the same authors found better stone ablation with MD than with SP, especially at a fiber moving speed of 3 mm/s rather than 1 mm/s [25].
Terry et al. [17] found a better lithotripsy performance of MD compared to the rest of Lumenis' and Quanta's PMs. They also found MC to be the worst in this category. Winship et al. [24] also found MD to have the greatest ablation performance in soft stone at 1 mm distance but was as good as the regular modes (SP and LP) when in contact. In contrast, MC had the greatest ablation of soft stones. No difference in ablation was found between PMs on hard stones at any distance, nor for soft stones for distances > 1 mm.    In the study by Ventimiglia et al. [30], stone ablation was equal between Moses and long pulse, and both were inferior compared to sTFL. When analyzing Quanta's PMs, Ballesta et al. [32] found Virtual Basket at 2 J and 30 Hz was the combination with the greatest ablation rate compared to the three available PMs, whereas VT had the lowest ablation rate in hard stones. Finally, when Dornier's PMs were studied, Ho et al. [33] found higher crater volumes with shorter PMs.
When assessing RIRS in-vitro, Elhilali et al. [16] found no procedural nor lasing time difference when using Moses PMs when compared to regular mode, whereas Ibrahim et al. [27] reported less procedural time, a reduced number of pedal laser activation, and a higher percentage of lasing time vs. pausing time with MC.
Regarding residual fragments, Black et al. [26] reported smaller fragment size distribution with MD for both 20 W and 40 W settings, except for high frequency (80 Hz) in a popcorn RIRS model. When comparing Lumenis regular modes to Moses, Khajeh et al. [28] found no difference between the percentage of smallest fragments (<0.25 mm), but MC and MD produced a greater mass of fragments <2 mm compared to LP.

In-Vivo Studies
Nine studies met inclusion criteria, out of which seven were comparative, including one RCT, one prospective study, and the rest were retrospective studies. The remaining two studies were noncomparative observational series. A total of 1482 patients participated in the included studies.
Regarding the new generation pulse modulation used, eight studies used Moses technology (Lumenis), and one study used Virtual Basket (Quanta). In most of the studies, the surgery performed was ureteroscopy (n = 5); two studies included both ureteroscopy and RIRS. The intervention performed in the two observational noncomparative studies were mini-and ultra-mini-percutaneous nephrolithotomy (PCNL). Stone dimensions and Hounsfield units among the included studies varied widely.

Comparative Studies
Seven out of eight comparative studies included operative time as one of the main outcomes; there was a statistically significant difference in favor of new generation pulse modulation technologies in six of these studies. The study by Knoedler et al. [35] published in 2022 found no statistically significant differences; the authors state that bias could have been introduced due to the possibility of changing of laser settings across cases, relying on the accuracy of electronic medical records. In addition, the clinicians were not blinded, suggesting that the advantages of Moses mode turned out to be less noticeable.

Fragmentation time
This outcome was assessed in six studies; in five of them, a statistically significant difference was found in favor of the new generation PM technologies (i.e., Moses and Quanta system). The study by Knoedler et al. [35] did not find a statistical difference in terms of fragmentation time.

Retropulsion
Only two studies reported retropulsion as a secondary outcome. Ibrahim et al. [18] in 2020 published a prospective double-blinded RCT comparing regular and Moses modes of Ho:YAG lithotripsy; the authors measured retropulsion using a Likert scale from 0 (no retropulsion) to 3 (maximum retropulsion) and found that the Moses technology had a mean grade of 0.5 vs. 1 (p = 0.01) with the regular Holmium laser. Bozzini et al. [34] published in 2021 a prospective comparative study using the Virtual Basket technology with the regular mode and reported less retropulsion using Virtual Basket.

Stone-free rate (SFR)
All included studies measured SFR, although the definitions were different among these studies. Seven studies assessed SFR at 1 month's follow-up; in the rest it was evaluated at 2-4 months. There was a trend towards no statistically significant differences between the new PM technologies and the regular laser modes.

Complications
In terms of complications classified using the Clavien-Dindo scale, there was no statistically significant difference between the new PM technologies and the regular laser modes.

Non-Comparative Studies
Two observational non-comparative studies were included. Reddy et al. [39] in 2021 published a prospective case series of 110 patients who underwent mini PCNL using Moses p120 W; they found that the use of Moses technology in conjunction with a proper suction system may potentially achieve maximum dusting, improving SFR. In a similar way, Leotsakos et al. [40] published their series of 12 patients who underwent ultra-mini PCNL using the same technology.

Risk of Bias of Included Studies
The results of the methodological quality assessment are included in Table 2. There was only a double-blind RCT by Ibrahim et al. [18] in 2020; using the Jadad scale, a score of 5 out of 5 points was given. The mean score for non-randomized comparative studies (n = 6) was 15.5 (range 12-22 out of 24); the highest score was given to the study by Bozzini et al. [34] in 2021. For non-comparative studies (n = 2), the mean score was 10.5 (range 9-12 out of 16).

Meta-Analyses
Four studies provided data on the association between SFR and PM. The forest plot ( Figure 2) revealed no significant difference between the Moses and the regular pulse (OR 1.15, 95% CI, 0.80-1.65, p = 0.46). The Cochrane's Q and I 2 tests revealed no significant heterogeneity.

Non-Comparative Studies
Two observational non-comparative studies were included. Reddy et al. [39] in 2021 published a prospective case series of 110 patients who underwent mini PCNL using Moses p120 W; they found that the use of Moses technology in conjunction with a proper suction system may potentially achieve maximum dusting, improving SFR. In a similar way, Leotsakos et al. [40] published their series of 12 patients who underwent ultra-mini PCNL using the same technology.

Risk of Bias of Included Studies
The results of the methodological quality assessment are included in Table 2. There was only a double-blind RCT by Ibrahim et al. [18] in 2020; using the Jadad scale, a score of 5 out of 5 points was given. The mean score for non-randomized comparative studies (n = 6) was 15.5 (range 12-22 out of 24); the highest score was given to the study by Bozzini et al. [34] in 2021. For non-comparative studies (n = 2), the mean score was 10.5 (range 9-12 out of 16).

Meta-Analyses
Four studies provided data on the association between SFR and PM. The forest plot ( Figure 2) revealed no significant difference between the Moses and the regular pulse (OR 1.15, 95% CI, 0.80-1.65, p = 0.46). The Cochrane's Q and I 2 tests revealed no significant heterogeneity.
Three studies provided data on the association between operative time and pulse modulation. The forest plot ( Figure 3) revealed no significant difference between the Moses and the regular pulse (mean difference −15.76 min, 95% CI, −45.97 to 14.44; p = 0.31). The Cochrane's Q (p < 0.001) and I 2 (98%) tests revealed significant heterogeneity.
Two studies provided data on the association between fragmentation time and pulse modulation. The forest plot ( Figure 4) revealed no significant difference between the Moses and the regular pulse (mean difference −1.71 min, 95% CI, −11.81 to 8.38; p = 0.74). The Cochrane's Q (p = 0.02) and I 2 (81%) tests revealed significant heterogeneity.
Four studies provided data on the association between post-operative complication and pulse modulation. The forest plot ( Figure 5) revealed no significant difference between the Moses and the regular pulse (OR 0.63, 95% CI, 0.34-1.15, p = 0.13). The Cochrane's Q and I 2 tests revealed no significant heterogeneity.   Two studies provided data on the association between fragmentation time and pulse modulation. The forest plot (Figure 4) revealed no significant difference between the Moses and the regular pulse (mean difference −1.71 min, 95% CI, −11.81 to 8.38; p = 0.74). The Cochrane's Q (p = 0.02) and I 2 (81%) tests revealed significant heterogeneity.

Discussion
In 2017, Lumenis Moses Technology inaugurated the new pulse modulation era, followed by the other pulse modes developed by Quanta System, Dornier MedTech, and Olympus. As our systematic review shows, most of the studies, both in-vitro and in-vivo, have analyzed Moses PM. This is explained by the fact that it was the first new-generation PM, and many authors wanted to test how this possible game-changing tool could and should be applied.
Surprisingly, no articles studying the Olympus' Stabilization Mode were found to support the commercial claim that this PM produces a vapor tunnel bubble that clears a path through the water to reduce retropulsion [41].
Regarding Advance Mode (Dornier MedTech), only one in-vitro article was found [33]. Marketing material distributed by the company on the website claims that AM reduces stone movement during lithotripsy and patient treatment time [42]. However, Ho et al. [33] showed that Fragmentation Mode (with a total width at half of the maximum pulse duration of 75 μs) generated larger craters than the Advance Mode (with a longer total width at half of the maximum pulse duration of 200 μs). It seems that the only difference between these pulse settings is pulse length, and no information is available regarding their pulse shapes or associated retropulsion.
As noted above, Lumenis Moses PM is the most represented in the reviewed studies, especially when comparing Moses to regular short and long pulses. Before Moses technology, studies had shown that regular short pulse length was more ablative than long pulse [43,44,45]. Despite this apparent lower efficiency, long pulse has shown to produce less fiber tip degradation and stone retropulsion in-vivo and in-vitro [46,47], as well as generation of smaller fragments [48], being a more suitable option for dusting

Discussion
In 2017, Lumenis Moses Technology inaugurated the new pulse modulation era, followed by the other pulse modes developed by Quanta System, Dornier MedTech, and Olympus. As our systematic review shows, most of the studies, both in-vitro and in-vivo, have analyzed Moses PM. This is explained by the fact that it was the first new-generation PM, and many authors wanted to test how this possible game-changing tool could and should be applied.
Surprisingly, no articles studying the Olympus' Stabilization Mode were found to support the commercial claim that this PM produces a vapor tunnel bubble that clears a path through the water to reduce retropulsion [41].
Regarding Advance Mode (Dornier MedTech), only one in-vitro article was found [33]. Marketing material distributed by the company on the website claims that AM reduces stone movement during lithotripsy and patient treatment time [42]. However, Ho et al. [33] showed that Fragmentation Mode (with a total width at half of the maximum pulse duration of 75 μs) generated larger craters than the Advance Mode (with a longer total width at half of the maximum pulse duration of 200 μs). It seems that the only difference between these pulse settings is pulse length, and no information is available regarding their pulse shapes or associated retropulsion.
As noted above, Lumenis Moses PM is the most represented in the reviewed studies, especially when comparing Moses to regular short and long pulses. Before Moses technology, studies had shown that regular short pulse length was more ablative than long pulse [43,44,45]. Despite this apparent lower efficiency, long pulse has shown to produce less fiber tip degradation and stone retropulsion in-vivo and in-vitro [46,47], as well as generation of smaller fragments [48], being a more suitable option for dusting

Discussion
In 2017, Lumenis Moses Technology inaugurated the new pulse modulation era, followed by the other pulse modes developed by Quanta System, Dornier MedTech, and Olympus. As our systematic review shows, most of the studies, both in-vitro and in-vivo, have analyzed Moses PM. This is explained by the fact that it was the first new-generation PM, and many authors wanted to test how this possible game-changing tool could and should be applied.
Surprisingly, no articles studying the Olympus' Stabilization Mode were found to support the commercial claim that this PM produces a vapor tunnel bubble that clears a path through the water to reduce retropulsion [41].
Regarding Advance Mode (Dornier MedTech), only one in-vitro article was found [33]. Marketing material distributed by the company on the website claims that AM reduces stone movement during lithotripsy and patient treatment time [42]. However, Ho et al. [33] showed that Fragmentation Mode (with a total width at half of the maximum pulse duration of 75 µs) generated larger craters than the Advance Mode (with a longer total width at half of the maximum pulse duration of 200 µs). It seems that the only difference between these pulse settings is pulse length, and no information is available regarding their pulse shapes or associated retropulsion.
As noted above, Lumenis Moses PM is the most represented in the reviewed studies, especially when comparing Moses to regular short and long pulses. Before Moses technology, studies had shown that regular short pulse length was more ablative than long pulse [43][44][45]. Despite this apparent lower efficiency, long pulse has shown to produce less fiber tip degradation and stone retropulsion in-vivo and in-vitro [46,47], as well as generation of smaller fragments [48], being a more suitable option for dusting stone strategies.
However other studies did not show significant differences in fragmentation efficiency or fragment sizes [49].
Regarding in-vitro studies, several articles favored Moses PM over regular pulse modes in terms of ablated volume or mass (Elhilali [16], Ibrahim [27], Khajeh et al. [28]). Less retropulsion was also associated with Moses PMs when compared to regular PM in the two studies that compared them [16,27]. Regarding residual fragments, Black et al. [26] reported smaller fragment size distribution with MD (for 20 W and 40 W settings, except for high frequency at 80 Hz) in a popcorn RIRS model. In addition, Khajeh et al. [28] found no difference between the percentage of smallest fragments (<0.25 mm), but MC and MD produced a greater mass of fragments < 2 mm compared to LP. Fiber tip degradation was lower with Moses PM in Khajeh's study [28] compared to regular PM, whereas no differences were observed in Winship's [24] study.
As for in-vivo studies, the majority compared Lumenis Pulse™ 120 H to regular modes. The comparison of Moses technology versus regular modes was also assessed by Corsini et al. [50] in a narrative review published in 2022. This study affirms that the Moses effect, although widely characterized, lacks strong clinical evidence of its superiority in surgical outcomes, in particular compared to Long Pulse, as they have similar peak power, total power width, and comparable ablation efficiency and retropulsion as stated by Winship et al. [24]. Similarly, in our meta-analysis performed using included in-vivo studies that compared the use of regular PM vs. Moses PM, no statistically significant differences were found in terms SFR, operative and lasing times, or complication rates. Thus, we agree with these authors that there is no clinical certainty that Moses PM substantially improves lithotripsy performance, and that the studies available to date have several limitations and biases. However, the highest methodological quality study published by Ibrahim et al. [18], a double-blind RCT, found that operative time, fragmentation time, and retropulsion were superior in the Moses mode, although SFR and complications did not show statistical differences.
Quanta PMs were the second most studied after Lumenis Moses PM, but with a low number of published studies. Ballesta et al. [32] compared VB, VT, and BB in-vitro. They found Virtual Basket to be more ablative than Bubble Blast in both 1 J × 60 Hz and 2 J × 30 Hz, with the latter combination achieving the highest ablation. They concluded that, in high-power settings, Virtual Basket accounted for highest ablation rates, exceeding Bubble Blast. On low-power settings, Virtual Basket was superior to Vapor Tunnel. These findings happened with both soft and hard stone phantoms. From our initial selection of articles, Vizziello et al. [51] presented at the 36th World Congress of Endourology an abstract of an in-vitro study of an endoscopic laser cystolithotripsy in a synthetic bladder model, comparing VB with Standard Mode, reporting less subjective retropulsion.
Terry et al. [17] compared Quanta's VT, SP, and LP with Lumenis MC, MD, SP, and LP in-vitro. The MD mode was superior in ablative measures than the rest of the parameters. Laser-stone distance had a negative impact on ablation in all PMs except for VT, which maintained a much greater proportion of its 0.5 mm ablation efficacy once SD increases to 2 mm.
A prospective comparative study of VB versus the regular mode using Quanta System Ho:YAG also found a trend towards better performance of this new generation PM in similar outcomes. These findings lead us to believe that there may be some advantages to using the Moses and VB technologies, which may have an impact on our daily practice.
In this direction, in a published video (excluded from the systematic review), Bozzini et al. [52] presented a randomized controlled trial comparing endoscopic retrograde endoscopic surgery using Quanta VT versus regular dusting mode (105 patients per group). They reported less procedural time, less retropulsion, no needs of basket stone retrieval, and no ureteral lesions with the Vapor Tunnel mode.
High-power and high-frequency Ho:YAG laser from Lumenis is now able to use frequencies higher than 80 Hz and up to 120 Hz. This new technology is called Moses 2.0 and has a predefined pulse modulation setting called Optimized Moses when extended frequencies are being used. When utilizing >80 Hz, the option to select MD or MC modes is replaced with a system-provided optimized Moses mode using rapid pulse sequence [53].
Only Majdalany et al. [36] have investigated Moses 2.0 compared to regular Moses PM (or Moses 1.0). They retrospectively compared the use of Moses 2.0 versus 1.0 in patients that underwent f-URS for solitary stones performed by a single surgeon, showing a SFR of 71% and 90% for Moses 1.0 and 2.0, respectively. No additional information was found regarding Moses 2.0 shape and or bubble formation and interaction. Therefore, it is difficult to state if any changes in lithotripsy performance would be due to Optimized Moses PM rather than the use of higher frequency settings. The use of frequencies, up to 80 Hz for stone dusting, have shown to break stones into fine fragments [54], but little is known about the performance when extended frequencies (80-120 Hz) are used.
Thulium Fiber Laser (TFL) has recently been introduced as a endoscopic lithotripsy tool that directly competes with Ho:YAG laser. TFL has a greater water absorption peak, which corresponds to a low threshold for tissue ablation and stone lithotripsy compared to Ho:YAG laser, and it has the ability to function at very low energies and extremely high frequencies [55]. Multiple studies have reported a more efficient lithotripsy [56]. TFL has also show its advantages with respect to Ho:YAG laser in high evidence clinical studies both for shorter operative time [57] and higher stone free rate and less complications after flexible ureteroscopy [58]. In our review, two in-vitro studies pointed into the same direction [30,31].
An important issue that raises concerns are thermal lesions of the urinary system during laser lithotripsy that can lead to ureteral stricture [59]. Temperature rise because of laser activation can generate tissue damage, especially when surpassing a 43 • C threshold temperature that leads to protein coagulation and tissue injury [60]. Temperature rise depends on laser power, exposure time, and fluid irrigation. Some recommendations are to keep low power settings (<10-15 W), to use "high-frequency" settings with caution, to perform intermittent laser activity, and to ensure fluid irrigation during the procedure [61]. In this review, an in-vitro study performed by Winship et al. [29] was included, which studied temperature changes while the laser was activated inside a ureteral access sheath (UAS) with different Lumenis PMs. They found that LP laser settings produced the greatest heat at most tested energy/frequency combinations, whereas Moses PMs produced the least heat at settings of 10 W of power. Nonetheless, at ≤10 W, temperature did not surpass the threshold for injury. Thermal dose reached potentially dangerous levels at 1 J × 20 Hz, but without significant differences between pulse types. MC was the only PM that exceed the risk temperature threshold by a small margin at 0.2 J × 70 Hz, although this was not statistically significant.

Strengths and Limitations
To date, this is the first systematic review and meta-analysis analyzing new generation PMs, including pulse modulation other than Lumenis Moses Technology.
Generally, in-vitro studies aim to recreate some aspects of the in-vivo laser performance. More mass or ablated volume or less retropulsion could translate into faster or more efficient lithotripsy. Unfortunately, in-vitro results should be taken with caution because there are many factors influencing in-vivo lithotripsy that are not being considered in in-vitro experiments. Nevertheless, the most reproducible in-vitro studies would be those that recreate lithotripsies performed by clinicians in animal or artificial models.
Moreover, high heterogenicity was found when assessing in-vitro studies. Different experimental conditions, used stones, laser-stone distance, fiber sizes, and ways to calculate the reported parameters make it difficult to compare different studies. Some experimental models, such as static laser positioning or automatized laser movement, are far from the laser-stone interaction that happens during endoscopic surgery, and should be interpreted as trends and/or preclinical studies. Additionally, the use of stone phantoms with different materials adds more heterogenicity when comparing different materials and different plaster-water ratios. BegoStone (the most commonly used material) has been validated for its acoustical properties for shock wave lithotripsy research [62] but not with laser lithotripsy.
In this review none or very few articles assessing new Ho:YAG pulse modes such as Quanta's, Dornier MedTech's, and Olympus' PMs were found. Therefore, further studies are needed to issue statements about their performances.

Conclusions
Moses PM is the most studied new PM for being the first to inaugurate this new era. Most in-vitro studies grant better lithotripsy performance to Moses PM in terms of shorter operative and fragmentation time and retropulsion when compared to regular PM. However, when we meta-analyzed in-vivo studies, no statistically significant differences were found in terms of SFR, operative and lasing times, or complication rates. Thus, it is still unclear if Moses is really superior to regular Long Pulse, and more high quality in-vivo studies are required.
Very little is known about other PMs, especially with Dornier's Advance Mode, Olympus's Optimized Mode, and Lumenis' Moses 2.0. Some research has been done on Quanta PM, but its promising clinical results still have to be validated with further studies, especially comparing lasers and PM from different companies. Longer follow-up would help recognize potential long-term complications associated with endoscopic surgery such as ureteral strictures.